MH_dev_192

Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . DB00207 SUB was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx 3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .

Multi-parametric spinal cord Q9BWK5 as potential progression marker in amyotrophic lateral sclerosis . OBJECTIVE : To evaluate multimodal Q9BWK5 of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis ( P35858 ) patients . MATERIALS AND METHODS : After a first Q9BWK5 ( Q9BV20 ) , 29 P35858 patients were clinically followed during 12 months ; 14/29 patients underwent a second Q9BWK5 ( MRI 2 ) at 11 ± 3 months . Cross-sectional area ( Q13216 ) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from P24752 - weighted images . Fractional anisotropy ( FA ) , axial / radial / mean diffusivities ( λ ⊥ , λ / / , MD ) and magnetization transfer ratio ( Q99707 ) were measured within the lateral corticospinal tract in the cervical region . Imaging metrics were compared with clinical scales : Revised P35858 Functional Rating Scale ( ALSFRS-R ) and manual muscle testing ( MMT ) score . RESULTS : At Q9BV20 , Q13216 correlated significantly ( P < 0.05 ) with MMT and arm ALSFRS-R scores . FA correlated significantly with leg ALFSRS-R scores . One year after Q9BV20 , Q13216 predicted ( P < 0.01 ) arm ALSFSR-R subscore and FA predicted ( P < 0.01 ) leg ALSFRS-R subscore . From Q9BV20 to MRI 2 , significant changes ( P < 0.01 ) were detected for Q13216 and Q99707 . Q13216 rate of change ( i . e . atrophy ) highly correlated ( P < 0.01 ) with arm ALSFRS-R and arm MMT subscores rate of change . CONCLUSION : Atrophy and DTI metrics predicted P35858 disease progression . Cord atrophy was a better biomarker of disease progression than diffusion and Q99707 . Our study suggests that multimodal Q9BWK5 could provide surrogate markers of P35858 that may help monitoring the effect of disease-modifying drugs .

The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft-versus-host disease . The influence of Q13216 on T-cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 ( + ) CD16 ( + ) P55040 ( + ) NK cells and a reciprocal increase in CD56 ( + ) CD16 ( - ) P55040 ( - ) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK-cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 + ) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand-expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK-cell differentiation , progenitor cells gave rise to more CD56 ( + ) P55040 ( - ) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK-cell function and phenotype , which may have important implications for graft-versus-leukemia effects .

P10275 abnormalities in identical twins with oligospermia . Clinical and biochemical studies . Identical twin brothers presented with oligospermia , small testes , normal male phenotypes , elevated serum luteinizing hormone levels , and normal or elevated serum testosterone levels . Both men had low to low-normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens . Qualitative abnormalities of cellular androgen receptors were suggested by low-normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother . In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non-aromatizable androgen fluoxymesterone . DB01185 MEN suppressed serum luteinizing hormone and serum testosterone / estradiol-binding globulin , and although testosterone suppressed both serum luteinizing hormone and serum follicle-stimulating hormone , the suppression of serum luteinizing hormone by testosterone was subnormal . Both subjects showed marked exaggeration of the serum 17 - hydroxyprogesterone increase after administration of human chorionic gonadotropin , despite normal serum testosterone increases , suggesting a block in testicular 17,20- desmolase , which converts 17 - hydroxyprogesterone to testosterone . These studies suggest that oligospermia and block of the enzyme 17,20- desmolase may be the earliest manifestations of androgen resistance , and the finding of the syndrome of oligospermia , normal male phenotype , and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder .

Effects of cyclosporin and FK - 506 on glomerular mesangial cells . Evidence for direct inhibition of thromboxane synthase by low cyclosporin concentrations . The cellular sources or molecular mechanisms responsible for the derangement of vasoactive prostanoid levels during immunosuppressive cyclosporin ( Q13216 ) therapy have not been defined . Using cultured rat glomerular mesangial cells ( MC ) , the cytostatic , cytotoxic and prostanoid synthesis modulating effects of Q13216 and FK - 506 have been measured and compared with the immunosuppressive action of these drugs . Both , Q13216 and FK - 506 inhibited proliferation of MC at similar doses ( IC50 approximately 1 microgram.ml - 1 ) . Lymphoproliferation was suppressed with IC50s of 50 ng.ml - 1 and < 1 ng.ml - 1 , respectively . In contrast , and unlike FK - 506 , Q13216 caused mesangiolysis ( IC50 = 4.5 micrograms.ml - 1 ) and concentration dependently inhibited the interleukin - 1 beta ( P01584 ) stimulated mesangial cell release of TXB 2 at nanomolar doses ( IC50 = 50 ng.ml - 1 ) . In kinetic experiments ( 6-48 h ) , Q13216 1 ng.ml - 1 partially and 1 microgram.ml - 1 completely abolished the P01584 augmented mesangial secretion TXB 2 at all the time points tested . Both , low and high doses of Q13216 reduced DB00917 release by only 20-40 % and then not until at least 24 h of incubation . Measuring enzymatic capacity of membrane fractions of MC to generate TXB 2 or DB00917 from added arachidonic acid ( 10 ( - 5 ) M ) , Q13216 ( 0.1- 1000 ng.ml - 1 ) caused a dose dependent reduction in cyclooxygenase ( P36551 ) / thromboxane synthase activity up to 76 % , while DB00917 synthesis ( P36551 / prostaglandin synthase ) was decreased by 34 % . Immunoblots with a specific P23219 antiserum revealed that P23219 protein expression of MC was not affected by Q13216 . ( ABSTRACT TRUNCATED AT 250 WORDS )

Targeting of T lymphocytes to Neu / P04626 - expressing cells using chimeric single chain Fv receptors . Cell surface molecules essential for the transformed phenotype or growth of malignant cells are attractive targets for anticancer immunotherapy . Antibodies specific to Neu / P04626 , a human adenocarcinoma-associated growth factor receptor , were demonstrated to have tumor-inhibitory capacity . Yet , the inefficient accessibility of antibodies to solid tumors limits their clinical use . To redirect effector lymphocytes to adenocarcinomas , we constructed and functionally expressed in T cells chimeric single chain receptor genes incorporating both the Ag-binding domain of anti-Neu / P04626 antibodies and the zeta-signal-transducing subunit of the TCR / CD3 complex or the gamma-signal-transducing subunit of the Ig Fc receptor complex . Surface expression of the anti-Neu / P04626 chimeric genes in cytotoxic T cell hybridomas endowed them with specific Neu / P04626 recognition enabling their activation for P60568 production and lysis of transformed cells overexpressing Neu / P04626 . These chimeric genes hold promise for the immunotherapy of cancer .

N - 3 polyunsaturated fatty acids regulate lipid metabolism through several inflammation mediators : mechanisms and implications for obesity prevention . Obesity is a growing problem that threatens the health and welfare of a large proportion of the human population . The n - 3 polyunsaturated fatty acids ( PUFA ) are dietary factors that have potential to facilitate reduction in body fat deposition and improve obesity-induced metabolic syndromes . The n - 3 PUFA up-regulate several inflammation molecules including serum amyloid A ( P0DJI8 ) , tumor necrosis factor-alpha ( P01375 ) and interleukin - 6 ( P05231 ) in hepatocytes and adipocytes . Actions of these inflammation mediators resemble those of n - 3 PUFA in the modulation of many lipid metabolism-related genes . For instance , they both suppress expressions of perilipin , sterol regulatory element binding protein - 1 ( P36956 ) and lipoprotein lipase ( P06858 ) to induce lipolysis and reduce lipogenesis . This review will connect these direct or indirect regulating pathways between n - 3 PUFA , inflammation mediators , lipid metabolism-related genes and body fat reduction . A thorough knowledge of these regulatory mechanisms will lead us to better utilization of n - 3 PUFA to reduce lipid deposition in the liver and other tissues , therefore presenting an opportunity for developing new strategies to treat obesity .

Anemia in heart and kidney allograft recipients : is there a role for hepcidin ? The production by hepatocytes of hepcidin , a small defensin-like peptide , is modulated in response to anemia , hypoxia , or inflammation . We studied hepcidin as a marker of iron status ( serum iron , ferritin , and soluble receptor of transferrin [ sTfR ] , and as a marker of inflammation among 170 prevalent kidney transplantation ( KT ) patients and 168 prevalent orthotopic heart transplant ( OHT ) patients . In addition , we assessed the prevalence of anemia and its relation to measurements of hepcidin , sTfR , and high-sensitivity P02741 , using commercially available enzyme-linked immunosorbent assay ( ELISA ) kits . Prevalence of anemia was 37 % in KT patients and 34 % in OHT patients according to the World Health Organisation ( WHO ) definition . Anemic KT patients displayed significantly higher values of serum creatinine , hepcidin , hsCRP , ferritin , and proteinuria associated with greater use of P42345 and significantly lower Q13216 therapy . The hemoglobin and estimated glomerular filtration rate ( eGFR ) . Upon multiple regression analysis eGFR , ferritin , and hsCRP independently predicted hepcidin levels , explaining 78 % of the variation in hepcidin . Anemic OHT patients showed significantly lower Q92565 , red blood cell ( RBC ) , and hemoglobin values and significantly higher creatinine and NT-proBNP content . Upon multiple regression analysis the predictors of serum hepcidin were eGFR and ferritin , which explained 68 % of the variation in hepcidin . The prevalence of anemia is relatively high and not adequately treated ( mainly due to reimbursement regulations ) among heart and kidney allograft recipients . In conclusion , elevated hepcidin levels in heart and kidney transplant recipients suggest subclinical inflammation and impaired kidney function .

Oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus . DB00149 MEN activates the intracellular mammalian target of the rapamycin ( P42345 ) pathway , and hypothalamic P42345 signaling regulates food intake . Although central infusion of leucine reduces food intake , it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance . We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine . We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem . DB00149 MEN did not induce the expression of Fos in hypothalamic nuclei , but it increased the number of Fos-immunoreactive neurons in the area postrema . In addition , oral gavage of leucine acutely increased the 24 h food intake of mice . Nonetheless , chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob / ob mice and of wild-type mice consuming a low - or a high-fat diet . We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes ( P54687 , O15382 and O14874 ) that metabolize branched-chain amino acids . Despite these effects , leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus . In conclusion , our data show that the brain is able to sense oral leucine intake . However , the food intake is not modified by chronic oral leucine supplementation . These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity .

Linear and conformational B cell epitope prediction of the HER 2 O95905 - subdomain III by in silico methods . Human epidermal growth factor receptor 2 ( P04626 ) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases that play important roles in all processes of cell development . Their overexpression is related to many cancers , including examples in the breast , ovaries and stomach . Anticancer therapies targeting the P04626 receptor have shown promise , and monoclonal antibodies against subdomains II and IV of the P04626 extra-cellular domain ( O95905 ) , DB06366 MEN and Herceptin , are currently used in treatments for some types of breast cancers . Since anti P04626 antibodies targeting distinct epitopes have different biological effects on cancer cells ; in this research linear and conformational B cell epitopes of P04626 O95905 , subdomain III , were identified by bioinformatics analyses using a combination of linear B cell epitope prediction web servers such as ABCpred , BCPREDs , Bepired , Bcepred and Elliprro . Then , Discotope , CBtope and SUPERFICIAL software tools were employed for conformational B cell epitope prediction . In contrast to previously reported epitopes of P04626 O95905 we predicted conformational B cell epitopes P1C : 378-393 ( PESFDGDPASNTAPLQ ) and P2C : 500-510 ( PEDECVGEGLA ) by the integrated strategy and and P4 : PESFDGD-X-TAPLQ ; Q15084 : PESFDGDP X TAPLQ ; P6 : ESFDGDP X NTAPLQP ; Q0GE19 : PESFDGDP-X-NTAPLQ ; P8 : ESFDG-XX-TAPLQPEQL and P9 : ESFDGDP - X-NTAPLQP by SUPERFICIAL software . These epitopes could be further used as peptide antigens to actively immune mice for development of new monoclonal antibodies and peptide cancer vaccines that target different epitopes or structural domains of P04626 O95905 .

Salmonid Tollip and MyD 88 factors can functionally replace their mammalian orthologues in TLR-mediated trout P0DJI8 promoter activation . Many functional details of the piscine Toll-like receptor ( TLR ) signal-mediated activation of immune defense are still elusive . We used an established reconstitution system of mammalian TLR signaling to examine if this system would allow for pathogen-dependent promoter activation of the serum amyloid A ( P0DJI8 ) - encoding gene from rainbow trout ( Oncorhynchus mykiss ) and if the key mediators MyD 88 and Tollip from trout can functionally substitute for their mammalian orthologues . Cells of the established human embryonic kidney line P29320 - 293 were transiently co-transfected with vectors expressing bovine O60603 or O00206 factors and a reporter gene driven by the promoter of the trout P0DJI8 gene . Escherichia coli stimulation increased reporter gene expression more than 3 - fold . Deletion series and point mutations identified in the proximal P0DJI8 promoter a composite overlapping binding site for NF-κB and P49715 factors as crucial for promoter activation . Overexpression of NF-κB p65 , but not of p50 or different members of the P49715 factor family proved this factor as an essential driver for P0DJI8 expression . Overexpression of a transdominant-negative mutant of the trout MyD 88 factor reduced TLR-mediated P0DJI8 promoter activation confirming functional conservation of its TIR domain . Overexpression of the Tollip factor from trout also quenched TLR-mediated NF-κB and O00206 - mediated P0DJI8 promoter activation . The MyD 88 mutant and Tollip expression studies confirm the functional homology of both piscine factors and their mammalian counterparts . We provide for the first time evidence that also the Tollip-mediated negative loop of TLR signaling may be conserved in non-mammalian organisms .

Mechanisms of atrial-selective block of Na ⁺ channels by ranolazine : I . Experimental analysis of the use-dependent block . Atrial-selective inhibition of cardiac Na ( + ) channel current ( I ( Na ) ) and I ( Na ) - dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation . The present study examined the basis for the atrial-selective actions of ranolazine . Whole cell I ( Na ) was recorded at 15 ° C in canine atrial and ventricular myocytes and in human embryonic kidney ( P29320 ) - 293 cells expressing Q14524 . Tonic block was negligible at holding potentials from - 140 to - 100 mV , suggesting minimal drug interactions with the closed state . Trains of 40 pulses were elicited over a range of holding potentials to determine use-dependent block . Guarded receptor formalism was used to analyze the development of block during pulse trains . Use-dependent block by ranolazine increased at more depolarized holding potentials , consistent with an interaction of the drug with either preopen or inactivated states , but was unaffected by longer pulse durations between 5 and 200 ms , suggesting a weak interaction with the inactivated state . Block was significantly increased at shorter diastolic intervals between 20 and 200 ms . Responses in atrial and ventricular myocytes and in P29320 - 293 cells displayed a similar pattern . DB00243 MENMAX DB00243 MEN is an open state blocker that unbinds from closed Na ( + ) channels unusually fast but is trapped in the inactivated state . Kinetic rates of ranolazine interactions with different states of atrial and ventricular Na ( + ) channels were similar . Our data suggest that the atrial selectivity of ranolazine is due to a more negative steady-state inactivation curve , less negative resting membrane potential , and shorter diastolic intervals in atrial cells compared with ventricular cells at rapid rates .

Simvastatin , an P04035 inhibitor , exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer . OBJECTIVE : Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells . METHODS : Cell proliferation in the ECC - 1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay . Apoptosis and cell cycle were detected by P08758 assay and propidium iodide staining , respectively . Reactive oxygen species and cell adhesion were assessed using ELISA assays . Invasion was analyzed using a transwell invasion assay . Mitochondrial DNA damage was confirmed using qPCR . The effects of simvastatin on the AKT / P42345 and MAPK pathways were determined by Western blotting . RESULTS : Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells . Simvastatin treatment resulted in P55008 cell cycle arrest , a reduction in the enzymatic activity of HMG - DB01992 MEN , induction of apoptosis as well as DNA damage and cellular stress . Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT / P42345 pathway in the ECC - 1 and Ishikawa cells . Minimal change in AKT phosphorylation was seen in both cell lines . An increase in phosphorylated S6 was seen in ECC - 1 and a decrease was seen in Ishikawa . Treatment with simvastatin reduced cell adhesion and invasion ( p < 0.01 ) in both cell lines . CONCLUSION : Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells , possibly through modulation of the MAPK and AKT / P42345 pathways , suggesting that statins may be a promising treatment strategy for endometrial cancer .

Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex . BACKGROUND : Cannabinoids have deleterious effects on prefrontal cortex ( P27918 ) - mediated functions and multiple evidences link the endogenous cannabinoid ( endocannabinoid ) system , cannabis use and schizophrenia , a disease in which P27918 functions are altered . Nonetheless , the molecular composition and the physiological functions of the endocannabinoid system in the P27918 are unknown . METHODOLOGY / PRINCIPAL FINDINGS : Here , using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v / vi of the mouse prelimbic area of the P27918 : presynaptic cannabinoid P21554 receptors ( CB1R ) faced postsynaptic P41594 while diacylglycerol lipase alpha ( Q9Y4D2 ) , the enzyme generating the endocannabinoid 2 - arachidonoyl-glycerol ( 2 - AG ) was expressed in the same dendritic processes as P41594 . Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents . Prolonged synaptic stimulation at 10Hz induced a profound long-term depression ( LTD ) of layers V / VI excitatory inputs . The endocannabinoid - LTD was presynaptically expressed and depended on the activation of postsynaptic P41594 , phospholipase C and a rise in postsynaptic Ca ( 2 + ) as predicted from the localization of the different components of the endocannabinoid system . Blocking the degradation of 2 - AG ( with Q76M96 602 ) but not of anandamide ( with Q76M96 597 ) converted subthreshold tetanus to LTD-inducing ones . Moreover , inhibiting the synthesis of 2 - AG with DB01083 , blocked endocannabinoid-mediated LTD . All together , our data show that 2 - AG mediates LTD at these synapses . CONCLUSIONS / SIGNIFICANCE : Our data show that the endocannabinoid - retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the P27918 . Alterations of endocannabinoid - mediated synaptic plasticity may participate to the etiology of P27918 - related pathologies .

P42898 , Q99707 , and P11586 gene polymorphisms compared to homocysteine and asymmetric dimethylarginine concentrations and their metabolites in epileptic patients treated with antiepileptic drugs . PURPOSE : The purpose of the study was to determine the frequency of occurrence of polymorphisms of genes P42898 ( C677T ) , Q99707 ( A2756G ) , and P11586 ( G1958A ) , as well as to analyze the concentration of homocysteine ( Hcy ) , methionine ( DB00134 MEN ) , asymmetric dimethylarginine ( DB01686 ) , and arginine ( DB00125 ) in epileptics treatment with antiepileptic drugs ( AEDs ) , and controls . METHOD : The study included 65 epileptic patients treated with variable AEDs and 61 controls . The levels of Hcy and DB00134 MEN were determined by HPLC / EC , DB01686 and DB00125 by HPLC with fluorescence detection . Polymorphisms of the studied genes were determined by PCR-RFLP . RESULTS : The study demonstrates that AEDs treatment in epileptics leads to increase in Hcy ( p < 0.05 ) and DB01686 ( p < 0.01 ) concentrations . Greater increases in Hcy concentration during AEDs treatment appear to occur in individuals with the P42898 CT ( C677T ) and P11586 GG ( G1958A ) genotypes . Genetic conditions also appear to be related with changes in the ratios of Hcy , DB00134 MEN , DB00125 , and DB01686 . It seems that in cases of AEDs treatment ' s effect on hyperhomocysteinemia , epileptic individuals appear to have a disturbed control of Hcy over DB01686 . CONCLUSIONS : It is possible , that polymorphisms of genes related to Hcy-to - DB00134 MEN metabolism , in epileptics treated with AEDs may have an effect on the regulation of levels of risk factors of vascular diseases , Hcy and DB01686 .

Mechanism of oral absorbent DB05269 MEN in lipid abnormalities in experimental uremic rats . BACKGROUND : We have reported that oral sorbent DB05269 MEN ( Q9NRA2 ) is effective in delaying the induction of dialysis in patients with chronic renal failure ( CRF ) because of its effect on lipid metabolism . To clarify the precise mechanism of Q9NRA2 in lipid abnormalities in CRF , we examined the effect of Q9NRA2 on plasma lipid profile , total bile acids ( TBA ) , and lipoprotein lipase ( P06858 ) activity in experimental uremic rats . METHODS : Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery . Uremic rats were randomly divided into two groups as follows : a control group in which rats were maintained on the standard diet and an Q9NRA2 group in which rats were maintained on a diet containing 5 g of Q9NRA2 per 100 g of standard diet for 10 weeks . Plasma P06858 activity was measured as free fatty acid ( FFA ) generation after intravenous administration of heparin . RESULTS : Plasma creatinine at 1.5 + / - 0.1 mg / dl was lower in the Q9NRA2 group than the 1.9 + / - 0.5 mg / ml level in the control group . Q9NRA2 significantly decreased plasma total cholesterol from 192 + / - 29 to 142 + / - 25 mg / dl , triglycerides from 198 + / - 71 to 99 + / - 38 mg / dl , and TBA from 19.6 + / - 2.6 mumol / liter to 8.8 + / - 3.5 mumol / ml . Plasma P06858 activity at 0.22 + / - 0.01 mumol FFA / min / hr was significantly higher in the Q9NRA2 group than 0.15 + / - 0.03 mumol FFA / min / hr in the control group . CONCLUSIONS : These results suggest that Q9NRA2 may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of P06858 activity in experimental uremic rats .

Delayed haemolytic transfusion reaction caused by anti-M antibody in a patient receiving interleukin - 2 and interferon for metastatic renal cell cancer . Anti-M is usually a naturally occurring cold-reactive immunoglobulin M ( IgM ) antibody , often with an immunoglobulin G ( IgG ) component , and is seldom implicated in delayed haemolytic transfusion reactions ( P10275 ) . However , cases have been reported . In the majority , a P10275 is not suspected until further blood is requested and a new antibody is detected on pretransfusion testing . We describe the case of a young man receiving therapy with interleukin - 2 ( P60568 ) and interferon-alpha ( IFN-alpha ) for metastatic renal cell cancer who developed a clinically suspected P10275 that was confirmed serologically to be caused by anti-M , reactive at 37 degrees C . We discuss the possible role of his biochemotherapy in the development of the P10275 .

Synthesis and biological evaluation of a library of resveratrol analogues as inhibitors of P23219 , P35354 and NF-kappaB . DB02709 MEN ( 4,3 ' , 5 ' - trihydroxystilbene ) is a naturally occurring antioxidant that inhibits cyclooxygenase - 1 ( P23219 ) , cyclooxygenase - 2 ( P35354 ) and the transcription factor NF-kappaB . A 78 - membered library of resveratrol analogues in which the substituents on the two aryl rings and alkene were varied was synthesized using a solid-phase Wittig olefination reaction . The library contains inhibitors against all three proteins that were more potent than resveratrol itself . Preliminary structure-activity relationships were also obtained from these data that permitted the derivation of pharmacophore models for each of the three targets .

Glutamate transporter GLT - 1 mediates DB06151 MEN inhibition of cocaine reinstatement . Both pre-clinical and clinical studies indicate that DB06151 MEN ( Q9C000 ) may be useful in treating relapse to addictive drug use . Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT - 1 in the nucleus accumbens , and Q9C000 treatment normalizes these two glial processes critical for maintaining glutamate homeostasis . However , it is not known if one or both of these actions by Q9C000 is needed to inhibit relapse to cocaine seeking . To determine whether the restoration of GLT - 1 and / or cystine-glutamate exchange is required for Q9C000 to inhibit cue-induced reinstatement of cocaine seeking , we utilized the rat self-administration / extinction / reinstatement model of cocaine relapse . Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT - 1 or Q9UPY5 ( catalytic subunit of the cystine-glutamate exchanger ) overlapping with daily Q9C000 administration during extinction ( 100 mg / kg , i . p . for the last 5 days ) . Rats then underwent cue-induced reinstatement of active lever pressing in the absence of Q9C000 , to determine if preventing Q9C000 - induced restoration of one or the other protein was sufficient to block the capacity of chronic Q9C000 to inhibit reinstatement . The vivo-morpholino suppression of Q9UPY5 reduced cystine-glutamate exchange but did not affect Q9C000 - induced reduction of reinstated cocaine seeking . In contrast , suppressing Q9C000 - induced restoration of GLT - 1 not only prevented Q9C000 from inhibiting reinstatement , but augmented the capacity of cues to reinstate cocaine seeking . We hypothesized that the increased reinstatement after inhibiting Q9C000 induction of GLT - 1 resulted from increased extracellular glutamate , and show that augmented reinstatement is prevented by blocking P41594 . Restoring GLT - 1 , not cystine-glutamate exchange , is a key mechanism whereby daily Q9C000 reduces cue-induced cocaine reinstatement .

Cyclophosphamide and other new agents for the treatment of severe aplastic anemia . Severe aplastic anemia ( P0DJI8 ) has a poor prognosis in the absence of treatment . Current accepted therapeutic strategies include allogeneic stem-cell transplantation and immunosuppression , both resulting in long-term survival in the majority of patients . Although human leukocyte antigen ( HLA ) - matched sibling stem-cell transplantation is highly effective , the 25 % probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients . Transplantation using HLA-matched , unrelated donors carries a high risk of treatment failure along with considerable toxicity . While combined immunosuppression with both antithymocyte globulin ( ATG ) and cyclosporine A ( Q13216 ) produces hematologic improvement in most patients , relapse is common . Late evolution of aplastic anemia to other serious hematologic disorders , including paroxysmal nocturnal hemoglobinuria ( PNH ) , myelodysplasia , and acute leukemia , is also a significant problem following treatment with ATG / Q13216 . Recently , results of immunosuppression in P0DJI8 with another potent immunosuppressive agent , cyclophosphamide , were reported in a small number of patients . The overall response rate was similar to that seen with ATG / Q13216 , but relapse and late clonal disease were not observed during a long period of follow-up . A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG / Q13216 or high-dose cyclophosphamide and Q13216 is now underway ; secondary end points include response duration , event-free survival , and overall survival . Additionally , a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed .

Two-dimensional liquid crystalline growth within a phase-field-crystal model . By using a two-dimensional phase-field-crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic-A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of +1/2 and -1/2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite -1/2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings .