Failure of inhaled corticosteroids to modify bronchoconstrictor or bronchodilator responsiveness in middle-aged smokers with mild airflow obstruction.

We have compared the effects of three-month periods of treatment with an inhaled corticosteroid, budesonide 600 micrograms twice daily and with placebo on bronchial responses to inhaled histamine and to bronchodilators in a double-blind crossover trial in 14 middle-aged male smokers (mean age, 59.6 years) with mild airways obstruction (mean FEV1 2.42 L, 80 percent predicted [range, 48 to 110 percent]). Responsiveness to inhaled histamine was assessed monthly by the provocative concentration (mg/ml) reducing FEV1 by 20 percent (PC20). Bronchodilator response to a combination of inhaled salbutamol (5 mg) and ipratropium (0.5 mg) was assessed before and after three months' treatment. Compliance with treatment was checked by weighing aerosol canisters, and by measuring plasma budesonide and metabolites. There was no significant change in FEV1 (budesonide mean 2.38 L [SEM 0.17] vs placebo 2.40 L [0.17]), vital capacity (budesonide mean 3.69 L [0.17] vs placebo 3.81 L [0.17]) or in bronchodilator responsiveness (mean increase over baseline FEV1, budesonide 11.6 [2.7] percent vs placebo 10.5 [3.2] percent). There was a small overall reduction in bronchoconstrictor responsiveness over the period of the trial, but there was no effect of 12 weeks of budesonide treatment compared with 12 weeks of placebo treatment (mean log PC20 during budesonide 0.595 [SEM 0.063], placebo 0.591 [SEM 0.055]). Following the three-month crossover trial, six men continued for nine more months to receive budesonide in a single-blind trial and the results were compared with those in six men who took no active treatment for the subsequent nine months. No improvements in baseline spirometry, home peak flow measurements, bronchoconstrictor or bronchodilator responsiveness were observed after 12 months of budesonide treatment. Thus, a regimen of budesonide treatment that consistently attenuates bronchial responsiveness in asthmatic subjects had no effect in these men; larger and longer trials will be required to establish whether a subgroup of smokers shows a favorable response.     

Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat

The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448±48 µg/g to 82±2 µg/g (P<0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454±446 IU/liter and 2571±2944 IU/liter, respectively) compared to those without misoprostol treatment (1348±480 IU/liter and 6077±3025 IU/liter, respectively,P<0.01). TNBT staining showed a reduced area of damage from 28.6±22.3% to 7.3±8.9% (P<0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose. Late administration of misoprostol may also be beneficial and thus may be considered in treating patients with APAP toxicity.This study is supported by the Australian National Health and Medical Research Council Grant 91/0662.     

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial

Background

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.

Methods

The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.

Conclusions

The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

     

Hemoglobinopathies in the Christmas Island population

Christmas Island is a remote Australian territory 2,400 km north of Perth. Health care is administered from Perth. The population is predominantly Chinese, with some Malay, Indian and European. As hemoglobinopathies are known to be common amongst these ethnic groups, a study was performed to determine their prevalence and significance in the Christmas Island population. Three-hundred and sixty-four individuals (adults and children) were tested. All subjects were assessed by full blood count, alpha-globin multiplex polymerase chain reaction (PCR) and PCR testing for Hb Constant Spring [alpha142, Term-->Gln, TAA-->CAA (alpha2)]. Microcytic patients (MCV <80 fL) were further investigated by high performance liquid chromatography (HPLC) and serum ferritin was determined. Where present, beta-thalassemia (thal) mutations were characterised by PCR. Thirty-four subjects (9.3%) were microcytic and of these five were iron deficient. The remainder were heterozygous for a hemoglobinopathy, giving a 9.1% incidence of hemoglobinopathies in Christmas Islanders. alpha-Thalassemia was identified in 23 subjects, seven of whom were heterozygous for alpha(-3.7); the remaining 16 were heterozygous for the - -SEA deletion. One case of heterozygous deltabeta-thal and one case of heterozygous Hb E [beta26(B8)Glu-->Lys] was detected. Of the eight subjects heterozygous for beta-thal, at least five mutations are represented, indicating a diverse and heterogeneous origin for this population.     

Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases

Translocations and deletions of the short arm of chromosome 12 [t(12p) and del(12p)] are common recurring abnormalities in a broad spectrum of hematologic malignant diseases. We studied 20 patients and one cell line whose cells contained 12p13 translocations and/or 12p deletions using fluorescence in situ hybridization (FISH) with phage, plasmid, and cosmid probes that we previously mapped and ordered on 12p12-13. FISH analysis showed that the 12p13 translocation breakpoints were clustered between two cosmids, D12S133 and D12S142, in 11 of 12 patients and in one cell line. FISH analysis of 11 patients with deletions demonstrated that the deletions were interstitial rather than terminal and that the distal part of 12p12, including the GDI-D4 gene and D12S54 marker, was deleted in all 11 patients. Moreover, FISH analysis showed that cells from 3 of these patients contained both a del(12p) and a 12p13 translocation and that the affected regions of these rearrangements appeared to overlap. We identified three yeast artificial chromosome (YAC) clones that span all the 12p13 translocation breakpoints mapped between D12S133 and D12S142. They have inserts of human DNA between 1.39 and 1.67 Mb. Because the region between D12S133 and D12S142 also represents the telomeric border of the smallest commonly deleted region of 12p, we also studied patients with a del(12p) using these YACs. The smallest YAC, 964c10, was deleted in 8 of 9 patients studied. In the other patient, the YAC labeled the del(12p) chromosome more weakly than the normal chromosome 12, suggesting that a part of the YAC was deleted. Thus, most 12p13 translocation breakpoints were clustered within the sequences contained in the 1.39 Mb YAC and this YAC appears to include the telomeric border of the smallest commonly deleted region. Whether the same gene is involved in both the translocations and deletions is presently unknown.     

Variation in stated management of acute myocardial infarction in five countries

We examined the variation in stated practice in the management of acute myocardial infarction (AMI) among doctors in Australia, Brazil, Chile, India and Thailand. Hospitals were identified as primary, secondary or tertiary by investigators from around their own region. All doctors within each hospital who would be expected to treat patients with AMI were asked to indicate which investigations and treatments they would offer to a patient with an AMI who develops angina on Day 3 after admission. The numbers of hospitals ranged from 5 to 26 per country, and doctor response rates varied from 70 to 100%. Within-country variation was large, and statistically significant variations were seen between countries in the use of most interventions. The large variation both between and within a range of countries across the economic spectrum suggests a widespread need for agreement about what constitutes appropriate management after AMI.     

Determination of Secondary and Tertiary Structural Features of Transfer RNA Molecules in Solution by Nuclear Magnetic Resonance

High-resolution 300-MHz proton nuclear magnetic resonance spectra of the hydrogen-bounded protons in three different purified tRNA molecules are presented. The resonances in the region between -11 and -15 ppm from 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) are assigned to the ring NH protons of specific base pairs by two approaches. First, intrinsic positions of -14.8 ppm and -13.7 ppm are taken for the AU and GC ring NH protons, respectively, and the spectra are calculated by including ring current shifts from the nearest neighbors. The spectra calculated in this way on the basis of the cloverleaf are in good agreement with the observed. Second, fragments of yeast tRNA(Phe) were obtained, which helped in assignments of the spectrum of intact molecules. The close agreement strongly supports the cloverleaf model.Tertiary structural features were determined in a few cases where the ring currents at the terminal base pairs of helical regions depended upon stacking of the helices. In this way, we were able to show that in Escherichia coli tRNA(Glu) the CCA stem forms a continuous helix with the TPsiC stem, which is in accord with the preliminary x-ray structure of yeast tRNA(Phe), suggesting that this stacking is observed in solution and may be a general property of different tRNA molecules. Similar reasoning suggests that in E. coli tRNA(fMet) G-27 is stacked upon the dihydrouridine helix.     

Gender differences in plaque characteristics of culprit lesions in patients with ST elevation myocardial infarction

There is limited research on plaque characteristics of ST elevation myocardial infarction (STEMI) patients according to the gender and age. 280 Consecutive STEMI patients who underwent VH-IVUS imaging on culprit before percutaneous coronary intervention (PCI) were enrolled in this study. Women were significantly older than men (69.8 ± 10 vs. 55.9 ± 11.3, p < 0.001). After propensity matching, men had higher plaque burden (79.7 ± 7.8 vs. 73.7 ± 13.0 %, p = 0.010), more fibro-fatty tissue (12.8 ± 9.9 vs. 9.5 ± 6.8 %, p = 0.04) and less dense calcium than women (8.4 ± 5.8 vs. 12.3 ± 8.7 %, p = 0.007). Subgroups dividing by 50, 65, 75 years old, plaque burden was higher in elderly men aged 66–75 years compared to the young men aged less than 50 (75.5 ± 9.2 vs. 68.4 ± 10.1 %, p = 0.012). And middle aged men ranged 51–65 years showed significantly more plaque burden at minimal lumen area site than matched aged women (77.5 ± 8.0 vs. 69.0 ± 17.6 %, p = 0.012). Elderly women aged 66–75 years showed significantly more necrotic core (28.6 ± 7.3 %) and dense calcium (14.9 ± 7.5 %) compared to all the younger or matched subgroups of men. These differences in plaque composition are blunted in the very elderly of men and women aged over 75 years. The findings may explain the gender differences in clinical prognosis in STEMI patients.     

Increased p21(CIP1/WAF1) and B cell lymphoma leukemia-x(L) expression and reduced apoptosis in alveolar macrophages from smokers

Alveolar macrophages (AMs) are the predominant defense cells in the airway, and their numbers are increased in smokers and subjects with chronic obstructive pulmonary disease. This increase may result from increased recruitment, increased proliferation, or reduced cell death. Apoptosis regulates inflammatory cell survival, and p21(CIP1/WAF1) is an important inhibitory regulator of cycle progression after oxidative stress. We have investigated whether chronic smoke exposure influences the expression and localization of cell cycle and apoptotic proteins in AM and bronchial epithelial cells in vivo. The increased numbers of AMs seen in smokers were only partially due to enhanced proliferation. p21(CIP1/WAF1) protein expression was increased in AMs and biopsies isolated from smokers and was found predominantly within the cytoplasm. In addition, B cell lymphoma leukemia (Bcl)-x(L), an antiapoptotic regulator, was also highly expressed in macrophages from smokers compared with nonsmokers and subjects with asthma. Hydrogen peroxide, an oxidative stress, induced cytoplasmic expression of p21(CIP1/WAF1) and failed to induce apoptosis in an in vitro model. These results suggested that AM and bronchial epithelial cells from smokers, in contrast to those from normal subjects and subjects with asthma, have reduced cell death. Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis.