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Human recombinant erythropoietin is the main treatment for anemia in renal patients. Recently, there have been case reports of pure red blood cell aplasia (PRCA) developing in renal patients administered erythropoietin, probably because of neutralizing antibodies detected in all these patients. All reports were from the West, and most patients were treated with erythropoietin-alpha. Cyclosporine is an immunosuppressive agent used to treat a spectrum of autoimmune conditions. We report a series of Chinese renal patients who developed PRCA after treatment with erythropoietin-alpha, suggesting that this is a problem worldwide. They were treated successfully with cyclosporine and became transfusion independent. Am J Kidney Dis41:692-695. © 2003 by the National Kidney Foundation, Inc.

The cure index and apparent activation energy of vulcanization of one grade of natural rubber (SMR L) and two grades of epoxidized natural rubbers (ENR 25 and ENR 50) were studied in the presence of three types of antioxidants [viz., 2,2'methylene-bis(4-methyl-6-tertbutylphenol) (AO 2246), poly-2,2,4-trimethyl-1,2-dihydroquinoline (TMQ), and N-isopropyl-N'-phenyl-p-phenylenediamine (IPPD)] in the temperature range of 120–180°C by using a Monsanto automatic Mooney viscometer. Accelerated sulfur vulcanization system and up to 5 phr of antioxidant concentration was used throughout the investigation. Results indicate that both cure index and apparent activation energy of vulcanization are dependent on the type and concentration of the antioxidant used. AO 2246 (a phenol-based antioxidant) would retard vulcanization as reflected by the higher cure index and activation energy, an observation which is attributed to the solvation and steric hindrance effects of the antioxidant. On the contrary, both TMQ and IPPD (amine-based antioxidants) exhibit reverse behavior due to the catalytic effect of the antioxidants in generating more active sulfurating agents for vulcanization. In all cases, SMR L gives higher cure index and apparent activation energy than the corresponding ENR, a phenomenon which is associated with the activation of the adjacent double bond by epoxide group in the latter. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 3234–3238, 2000

The effect of concentration of antioxidants on the Mooney scorch time of two grades of epoxidized natural rubbers (ENR 25 and ENR 50) and one grade of natural rubber (SMR L) was studied using a Monsanto automatic Mooney viscometer (MV 2000). Three types of antioxidants, viz., 2,2′‐methylene‐bis(4‐methyl, 6‐tertbutylphenol) (AO 2246), N‐isopropyl‐N′‐phenyl‐p‐phenylenediamine (IPPD) and poly‐2,2,4‐trimethyl‐1,2‐dihydroquinoline (TMQ) were used, and the concentration range was varied from 0 to 5 phr. The conventional vulcanization system with 2‐mercaptobenzothiazole (MBT) as the accelerator was used throughout the study. Results show that increasing the phenol‐based antioxidant (AO 2246) concentration will increase the scorch time of ENR at a lower temperature of vulcanization while its effect on SMR L is not significant. This retardation effect is attributed to the “solvation” of epoxide group by the phenolic group in AO 2246, thus reducing the activation of adjacent double bond in ENR. The scorch time, however, is shortened by the amine‐based antioxidants (IPPD and TMQ) for the three rubbers studied, a phenomenon associated with the ability of the amine group to enhance the formation of more active sulfurating agent and subsequently increases the cure rate as the concentration of the amine‐based antioxidants is increased. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 2940–2946, 1999

Large-scale genotyping is required to generate dense identity-by-descent maps to map genes for human complex disease. In some studies the number of genotypes needed can approach or even exceed 1 million. Generally, linkage and linkage disequilibrium analyses depend on clear allele identification and subsequent allele frequency estimation. Accurate grouping or categorization of each allele in the sample (allele calling or binning) is therefore an absolute requirement. Hence, a genotyping system that can reliably achieve this is necessary. In the case of affected sib-pair analysis without parents, the need for accurate allele calling is even more critical. We describe methods that permit precise sizing of alleles across multiple gels using the fluorescence-based, Applied Biosystems (ABI) genotyping technology and discuss ways to reduce genotyping error rates. Using database utilities, we show how to minimize intergel allele size variation, to combine data effectively from different models of ABI sequencing machines, and automatically bin alleles. The final data can then be converted into a format ready for analysis by statistical genetic packages such as MENDEL.

Large-scale genotyping is required to generate dense identity-by-descent maps to map genes for human complex disease. In some studies the number of genotypes needed can approach or even exceed 1 million. Generally, linkage and linkage disequilibrium analyses depend on clear allele identification and subsequent allele frequency estimation. Accurate grouping or categorization of each allele in the sample (allele calling or binning) is therefore an absolute requirement. Hence, a genotyping system that can reliably achieve this is necessary. In the case of affected sib-pair analysis without parents, the need for accurate allele calling is even more critical. We describe methods that permit precise sizing of alleles across multiple gels using the fluorescence-based, Applied Biosystems (ABI) genotyping technology and discuss ways to reduce genotyping error rates. Using database utilities, we show how to minimize intergel allele size variation, to combine data effectively from different models of ABI sequencing machines, and automatically bin alleles. The final data can then be converted into a format ready for analysis by statistical genetic packages such as MENDEL.

Strong toroidal asymmetries in power deposition during lower hybrid current drive experiments have been observed on TdeV and Tore Supra. These asymmetries are characterized by high heat loads on components magnetically connected to the LHCD antenna. The experimental results indicate that fast electrons generated by the rf fields in the scrape-off layer in front of the antenna are responsible for the localized heat loads. The rf power lost in the edge though this channel increases with both the edge density and the rf power level. In TdeV, the fraction of the injected power lost can exceed 10% at high power and high density, while it stays under 2% in Tore Supra. A simple model describing the trajectories of electrons in front of the antenna suggests that the high N &z.sfnc; components of the near field spectrum are responsible for the acceleration of the scrape-off layer electrons.

The main aspects of radiative plasma experiments carried out in the LH-heated TdeV tokamak are summarized. D 2 , N 2 and Ne puffing, and divertor biasing, are assessed in terms of their ability to increase edge and divertor radiative losses and reduce neutralizer plate heat loads. Detailed patterns of radiation and plate power deposition are compared. Combined N 2 and D 2 puffing gives the best results. Biasing enhances divertor radiation but also causes an increase in power conducted and convected to one of the divertor legs. The improvements obtained are still insufficient due to disruptive instabilities that appear at high impurity puffing rates. The instability is triggered at the edge with N 2 and in the core with Ne.

The disappearance rate of insulin antibodies was studied after cessation of insulin treatment which had been given for 3 months to 6 years in 42 Type 2 (non-insulin-dependent) diabetic patients. Insulin antibodies were measured before and 15 days after interruption of insulin treatment, and every 30 days until the disappearance of insulin antibodies. The mean ± SD value of insulin binding in the entire group before the interruption of insulin treatment was 32±14%. There was no relationship between the antibody level at that time and the duration of insulin treatment. However, the insulin antibody level was significantly higher in 17 diabetic patients on an insulin dose of >20 U/day (p<0.02) than in 25 on an insulin dose of <20 U/day (39±13% versus 28±12%). A positive correlation was found between intial insulin binding and the time required for it to fall below 10% (r= 0.74). Antibodies were absent 60 days after discontinuing insulin treatment in eight of ten subjects presenting with initial binding of <20%. In contrast, in only two of 12 patients with an initial binding of >40% were insulin antibodies detectable 150 days after discontinuation of insulin therapy. Disappearance of insulin antibodies sometimes took up to 1 year and occasionally even more than 2 years.

Summary The phenoxy herbicides MCP and 2,4,5-T undergo extensive conjugation with plant constituents. ThereFore, in order to measure total herbicide residues, a method must be used which will extract and hydrolyze such conjugates. The studies reported here showed that heating plant tissue under dilute alkaline conditions is adequate to measure total herbicide residues. Using the alkaline extraction method, it was shown that there were no detectable residues of MCP or 2,4,5-T in the grain of wheat plants treated with these herbicides.

JAK2 is the most common mutated gene in bcr-abl-negative chronic myeloproliferative disorders (MPDs) making it an attractive target for drug discovery. Pre-clinical studies have shown that inhibition of JAK2 signaling pathways confer therapeutic benefits in animal models of MPD. We describe here SB1518, a potent, selective and orally active inhibitor of JAK2 with therapeutic potential for the treatment of MPDs. SB1518 is a potent ATP-competitive inhibitor of both JAK2 kinase (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) without significant activity against 40 other representative kinases across the human kinome. SB1518 selectively inhibits the proliferation of cell lines driven by JAK2 or its mutants (e.g. IC50 = 81 nM for a murine BaF3 cell line stably transfected to express erythropoietin receptor and GFP-labeled JAK2V617F). It reduces basal phosphorylation of JAK2 and STAT5 in BaF3-JAK2V617F cells in a concentration-dependent manner. The excellent physicochemical, metabolic and pharmacokinetic properties of SB1518 render it amenable to oral dosing. SB1518 was investigated in a model of advanced MPD established by intravenous injection of BaF3-JAK2V617F cells in nude mice. In several studies using different initial tumor burden and/or drug regimen, we observed dose-dependent and statistically significant therapeutic effects including normalization of elevated white blood cell count and reduction of GFP-labeled BaF3 cells in the peripheral blood, resolution of hepatosplenomegaly, reduction of phospho-STAT5 in diseased organs, prolonged survival and alleviation of terminal-stage anemia and thrombocytopenia. These therapeutic effects were observed at doses well tolerated by the animals. In conclusion, our data demonstrate the therapeutic potential of SB1518 for the treatment of myeloproliferative disorders caused by aberrant JAK2 signaling.

JAK2 is the most common mutated gene in bcr-abl-negative chronic myeloproliferative disorders (MPDs) making it an attractive target for drug discovery. Pre-clinical studies have shown that inhibition of JAK2 signaling pathways confer therapeutic benefits in animal models of MPD. We describe here SB1518, a potent, selective and orally active inhibitor of JAK2 with therapeutic potential for the treatment of MPDs. SB1518 is a potent ATP-competitive inhibitor of both JAK2 kinase (IC50= 22 nM) and its JAK2V617Fmutant (IC50= 19 nM) without significant activity against 40 other representative kinases across the human kinome. SB1518 selectively inhibits the proliferation of cell lines driven by JAK2 or its mutants (e.g.IC50= 81 nM for a murine BaF3 cell line stably transfected to express erythropoietin receptor and GFP-labeled JAK2V617F). It reduces basal phosphorylation of JAK2 and STAT5 in BaF3-JAK2V617Fcells in a concentration-dependent manner. The excellent physicochemical, metabolic and pharmacokinetic properties of SB1518 render it amenable to oral dosing. SB1518 was investigated in a model of advanced MPD established by intravenous injection of BaF3-JAK2V617Fcells in nude mice. In several studies using different initial tumor burden and/or drug regimen, we observed dose-dependent and statistically significant therapeutic effects including normalization of elevated white blood cell count and reduction of GFP-labeled BaF3 cells in the peripheral blood, resolution of hepatosplenomegaly, reduction of phospho-STAT5 in diseased organs, prolonged survival and alleviation of terminal-stage anemia and thrombocytopenia. These therapeutic effects were observed at doses well tolerated by the animals. In conclusion, our data demonstrate the therapeutic potential of SB1518 for the treatment of myeloproliferative disorders caused by aberrant JAK2 signaling.

T cell subsets analyzed with Ortho monoclonal antibodies (mo ab) on microsamples of blood obtained by heel puncture on 38 infants in a high-risk nursery revealed that after birth, the OKT8subset gradually increases while the OKT4subset and T4/T8ratio decrease. Mean ± SEM values of lymphocyte subsets at different ages are shown below:In each group, lower T4/T8 ratios were noted in infants who had been given blood transfusions, and linear regression analysis in a restricted age group(2-12wk) revealed a significant reduction in T4/T8 ratio with increasing numbers of transfusions(p=<0.05).A high frequency of genetic polymorphism of the OKT4 antigen was noted in blacks. Lymphocytes of 3/7 black infants failed to react with OKT4 mo ab but had normal reactivity with mo ab OKT4A. Incubation with thymic epithelial monolayers and thymosin fr. V failed to induce the T4 antigen on these lymphocytes which were otherwise functionally normal. Family studies suggest that transmission of this feature may either be autosomal dominant or recessive. Cautious interpretation of T cell subsets is advised in blacks and in infants given multiple transfusions.