Salmeterol tachyphylaxis in steroid treated asthmatic subjects.

BACKGROUND: Tachyphylaxis to the protection afforded by salmeterol to broncho-constrictor stimuli after regular use has been described in patients with mild asthma not receiving inhaled corticosteroids. The present study was performed to investigate whether airway tachyphylaxis occurs in symptomatic asthmatic subjects receiving inhaled corticosteroids, the group for whom salmeterol is recommended in clinical practice. METHODS: Thirty one adult patients with symptomatic chronic asthma who were receiving inhaled corticosteroids were randomised in a double blind manner and on a 2:1 basis to receive salmeterol 50 micrograms (n = 22) or placebo (n = 9) twice daily. Baseline forced expiratory volume in one second (FEV1) was measured during the run-in period, on day 0, and after four and eight weeks of regular treatment (following a 36 hour test drug washout period). Airway responsiveness to methacholine was measured one hour after administration of the test drug on these occasions. Diary cards were kept throughout the study and for a two week follow up period. RESULTS: Baseline FEV1 was not significantly different between the treatment groups or between visits. There was significant bronchodilatation one hour after salmeterol administration at 0, four, and eight weeks. No significant tachyphylaxis of the bronchodilator action of salmeterol was seen. Protection against methacholine induced bronchoconstriction reduced from 3.3 doubling dilutions after the first dose of salmeterol to two doubling dilutions after four and eight weeks of regular treatment. Symptom scores and "rescue" salbutamol use were significantly reduced during salmeterol treatment and daytime improvements were maintained into the follow up period. CONCLUSIONS: Inhaled corticosteroids did not prevent tachyphylaxis to the protection afforded by salmeterol to methacholine induced bronchoconstriction. The clinical significance, if any, of these findings remains to be defined.     

How we improved turn around time through voice-communication technology

This hospital phlebotomy team tackled their age-old turn around time (TAT) problem by implementing a technology that is becoming commonplace in a variety of businesses. Through the use of two-way communication headsets, this hospital laboratory significantly reduced TAT, improved service perceptions by the medical and nursing staffs, and diminished stress levels of the venipuncture team.     

Permeant lipophilicity and vehicle composition influence accumulation of dyes in hair follicles of human skin

In skin and hair research drug targeting to the hair follicle is of great interest. Therefore the influence of permeant lipophilicity and vehicle composition on local accumulation has been examined using confocal laser scanning microscopy (CLSM). Formulations saturated with either Oregon Green^® 488, Bodipy^® FL C₅ or Bodipy^® 564/570 C₅ were prepared. The dyes were applied in citric acid buffer, 8% (w/v) surfactants in citric acid buffer or 8% (w/v) surfactants/20% (w/v) propylene glycol in citric acid buffer. Flow-through diffusion experiments were performed with fresh human scalp skin, after which the skin was imaged using CLSM. Diffusion studies showed for Oregon Green^® 488 (low lipophilicity) a higher flux when applied in citric acid buffer compared to surfactants. In contrast the fluxes of the more lipophilic dyes (Bodipy^® FL C₅ and Bodipy^® 564/570 C₅) are highest when applied in surfactants/propylene glycol. CLSM studies revealed that follicular accumulation increased with (i) a lipophilic dye and (ii) application of lipophilic dyes in surfactants–propylene glycol. Therefore we conclude that targeting to the hair follicle can be increased by the use of lipophilic drugs in combination with surfactant solutions and propylene glycol.     

Postprandial factor VII metabolism: the effect of the R353Q and 10 bp polymorphisms

Elevated levels of coagulation factor VII activity (FVIIc) are associated with increased risk of CHD. FVIIc is strongly determined by two polymorphisms (R353Q and 0/10 base pairs (bp)) and plasma triacylglycerol (TAG) concentrations. The Q and 10 bp polymorphisms show strong linkage disequilibrium and have been associated with lower levels of fasting FVII, but there has been little investigation of the effect of these genotypes on the postprandial FVII metabolism. The present study demonstrated that fasting activated factor VII (FVIIa) and factor VII antigen (FVIIag) levels were significantly lower in the heterozygotes carrying the Q and 10 bp alleles (n 12), than in the R/0 bp homozygotes (n 12) (43.0 (SE 4.8) v. 23.9 (SE 6.5) mU/ml and 85.7 (SE 5.4) v. 71.6 (SE 7.5)% respectively). During postprandial lipaemia there was a significant increase in FVIIa in R/0 bp homozygotes but not in the heterozygotes carrying the Q and 10 bp alleles. The proportion of FVIIa (FVIIa:FVIIag) increased in the homozygotes but not in the heterozygotes (2.04 (SE 0.35) v. 1.20 (SE 0.26) respectively). Therefore possession of the relatively common Q and 10 bp alleles is not associated with postprandial activation of FVII, which may in turn have a protective effect against CHD.     

Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers

This molecular epidemiologic case-control study of lung cancer incorporated three complementary biomarkers: the glutathione S- transferase M1 (GSTM1) null genotype, a potential marker of susceptibility, and polycyclic aromatic hydrocarbon-DNA adducts (PAH- DNA) and sister chromatid exchanges (SCE), both indicators of environmentally induced genetic damage. Associations between biomarkers and lung cancer were investigated, as were possible gene-environment interactions between the GSTM1 null genotype and tobacco smoke exposure. Subjects included 136 primary non-small cell lung cancer surgical patients and 115 controls at the Columbia Presbyterian Medical Center. Questionnaire and Tumor Registry data, pre-treatment blood samples and biomarker measurements on blood were obtained. Overall, GSTM1 null genotype was significantly associated with lung cancer [odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.13-3.68]. ORs for GSTM1 and lung cancer were significant in females (2.50, 1.09-5.72) and smokers (2.25, 1.11-4.54) and not significant in males (1.4, 0.58-3.38) and non-smokers (0.88, 0.18-4.33). However, ORs for males versus females and smokers versus non-smokers did not differ significantly. The OR for GSTM1 and lung cancer in female smokers was 3.03 (1.09- 8.40), compared with 1.42 (0.53-4.06) in male smokers. In contrast to PAH-DNA adducts in leukocytes, SCE did not differ between cases and controls. Neither biomarker differed significantly between the two GSTM1 genotypes. The combined effect of elevated PAH-DNA adducts and GSTM1 genotype on case-control status (16.19, 1.2-115) appeared multiplicative. Results suggest that the effect of the GSTM1 null genotype is greatest in female smokers, which is consistent with other evidence that indicates that women are at higher risk of lung cancer than males, given equal smoking. Persons with both the GSTM1 deletion and elevated PAH-DNA adducts may represent a sensitive subpopulation with respect to carcinogens in tobacco smoke and other environmental media.      

Naturally occurring amino acid substitutions at Arg1174 in the human insulin receptor result in differential effects on receptor biosynthesis and hybrid formation, leading to discordant clinical phenotypes

Missense mutations in the tyrosine kinase domain of the human insulin receptor frequently result in a dominantly inherited form of insulin resistance. We noted a marked disparity in the clinical phenotypes of our study subjects with different missense mutations at the same residue (Arg1174) of the insulin receptor. Subjects with a tryptophan substitution (W) were only moderately hyperinsulinemic, whereas those with a glutamine substitution (Q) had severe clinical and biochemical insulin resistance. Studies were undertaken to explore the molecular mechanisms underlying these differences. Both W and Q mutant receptors bound insulin normally but were kinase inactive. The W mutation resulted in more rapid degradation of newly synthesized mutant receptor, which contrasted with the near-normal biosynthesis of the Q receptor. The propensity of the W receptor to form hybrids with the cotransfected wild-type (WT) receptor was also markedly impaired compared with the Q receptor, to an extent greater than could be explained by lower steady-state expression. Thus, the more clinically benign consequences of the heterozygous W mutant receptor are likely to relate to its impaired biosynthesis and/or reduced capacity to form hybrids with WT receptors. In addition to providing an explanation for the milder phenotype of 1174W versus 1174Q carriers, these studies provide further support for the notion that the dominant-negative effect of insulin receptor tyrosine kinase mutations involves the competition between inactive mutant homodimers and WT/mutant hybrids with active WT homodimers for both ligands and intracellular substrates.     

Radiologically placed temporary hepatic artery catheter for treatment of liver cancer

Hepatic artery infusion (HAI) chemotherapy is associated with higher response rates compared to systemic chemotherapy in those patients with unresectable liver malignancies. Operative hepatic artery catheter (HAC) insertion has significant morbidity and mortality, especially in patients with high‐volume disease, some of whom may not respond to HAI chemotherapy. We report our experience in 45 patients with high‐volume liver disease who were initially treated with HAI chemotherapy via a radiologically placed temporary HAC to try to select the responders who then went on to have an operative HAC. In these 45 patients who had 62 radiologically placed HAC, we found very few major complications, and certainly no complications such as cholecystitis, vascular or malperfusion problems.