Rationale: Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the β2-adrenergic receptor may not benefit from short-acting β-agonists.

Objectives: We investigated whether such genotype-specific effects occur when patients are treated with long-acting β-agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use.

Methods: We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS.

Results: In both trials, B16Arg/Arg subjects did not benefit compared with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with B16Gly/Gly subjects (salmeterol, n = 13; placebo, n = 13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently (n = 8) had a lower A.M. PEF (36.8 L/min difference, p = 0.048) than B16Gly/Gly subjects (n = 22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects.

Conclusions: Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group.

/pdf/b-adrenergic-receptor-polymorphisms-and-response-to-wkdi0h7vjy.pdf

β-Adrenergic Receptor Polymorphisms and Response to Salmeterol

The main goal of post-transplantation monitoring in hematopoietic stem cell transplantation (HSCT) is to predict negative events, such as disease relapse, graft rejection and graft-versus-host disease, in order to intervene with appropriate therapy. In this context, chimerism analysis is an important method in monitoring post HSCT outcome. Mixed chimerism (MC) is mainly evaluated to define engraftment and relapse. Detection of MC is a prerequisite in both myeloablative and nonmyeloablative HSCT, in order to assess the graft status and decide later therapeutic strategies such as donor lymphocyte infusion. In this review, we discuss various techniques including erythrocyte phenotyping, cytogenetic analysis, fluorescent in situ hybridization, restriction fragment length polymorphism, STR/VNTR analysis and real-time quantitative PCR, along with the various methods used to detect minimal residual disease (MRD) in different diseases such as chronic myeloid leukemia, acute myelomonocytic leukemia or acute lymphoblastic leukemia. The review mainly highlights the optimal methodological approach, which needs to be informative, sensitive and quantitatively accurate for MC detection. Future of post HSCT graft monitoring lies in the selection of the most accurate and sensitive technique to determine both MC and MRD. Such an approach would be helpful in not only determining relapse or rejection, but also in ascertaining various responses to different treatment modalities.

Significance of chimerism in hematopoietic stem cell transplantation: new variations on an old theme

Characterization of GATA3 Mutations in the Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome

GATA3 mutations in the hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome

Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC 50 s) for PM and CCG ( P 50 s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC 50 s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC 50 s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease ( P

Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

Detection of ΔF508 deletion by amplification refractory mutation system

A plasmid "cassette" system is presented that allows the development of amplification refractory mutation system (ARMS) primers. Primer development may be accomplished even in the absence of appropriate clinical material from patients demonstrating mutated alleles. The use of such cassettes is demonstrated here in the assessment of primers prepared for ARMS analysis of the gene coding for the normal and Z variant alleles of the human serine protease inhibitor alpha-1-antitrypsin.

A plasmid cassette system that allows optimization of primers for use in the amplification refractory mutation system.

We haveimprovedthe "polymerasechainreaction"(PCR)to permit rapid analysisof any known mutation in genomic DNA. We demonstratea system, ARMS (AmplificationRefractoryMutation System),thatallowsgenotypingsolelyby inspection of reaction mixtures after agarose gel electrophoresis. The system is simple, reliable andnon-isotopic.It willclearlydistinguish heterozygotesat a locusfromhomozygotesfor eitherallele. The system requiresneitherrestriction enzyme digestion, allelespecificoligonucleotides as conventionallyapplied,nor the sequenceanalysisof PCR products.The basisof theinventionis thatunexpectedly,oligonucleotides witha mismatched3'-residue will not functionas primersin the PCR under appropriate conditions. We have analysed DNA from patientswith calantitrypsin(AAT)deficiency,fromcarriersof thedisease and from normalindividuals.Our findingsare in completeagreement with allele assignmentsderivedby direct sequencingof PCR products.

Analysis ofanypoint mutation inDNA.Theampliflcation refractory mutation system (ARMS)

Amplification Refractory Mutation System for Prenatal Diagnosis and Carrier Assessment in Cystic Fibrosis

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Detection of ΔF508 deletion by amplification refractory mutation system

A plasmid cassette system that allows optimization of primers for use in the amplification refractory mutation system.

Analysis ofanypoint mutation inDNA.Theampliflcation refractory mutation system (ARMS)

Amplification Refractory Mutation System for Prenatal Diagnosis and Carrier Assessment in Cystic Fibrosis