The brefeldin A resistance protein Bfr1p is a component of polyribosome-associated mRNP complexes in yeast.

The yeast gene BFR1 was originally isolated from a genetic screen for high-copy suppressors of brefeldin A-induced lethality in Saccharomyces cerevisiae. While this result suggested a possible role for the encoded protein, Bfr1p, in the secretory pathway, subsequent data have not fully supported this conclusion. Alternatively, Bfr1p has also been found by yeast two-hybrid analysis to interact with Bbp1p, a component of the spindle pole body. Finally, we have reported that Bfr1p associates with cytoplasmic mRNP complexes containing Scp160p, raising the possibility that Bfr1p may function in mRNA metabolism. Here, we have explored this possibility further. We report that Bfr1p associates with yeast polyribosomes and mRNP complexes even in the absence of Scp160p, and that its interaction with Scp160p-containing mRNP complexes is RNA-dependent. Furthermore, we have determined by fluorescence microscopy and subcellular fractionation that Bfr1p and Scp160p demonstrate similar cytoplasmic localization with enrichment around the nuclear envelope/endoplasmic reticulum. Finally, we report that loss of Bfr1p disrupts the interaction of Scp160p with polyribosomes, thereby demonstrating that the relationship between these two proteins is functional as well as physical. Considered together, these data raise the intriguing possibility that Bfr1p may provide a link between mRNA metabolism, the chromosomal segregation machinery and perhaps secretion in yeast.

Dose-response comparison of systemic bioactivity with inhaled budesonide and triamcinolone acetonide in asthmatic adults.

BACKGROUND: Budesonide (BUD) has recently been licensed for treatment of asthma in the United States, whereas triamcinolone acetonide (TAA) has been used for many years. OBJECTIVE: We sought to evaluate the dose-response effect of inhaled BUD and TAA in terms of adrenal, bone, and blood markers. METHODS: Twelve asthmatic subjects (mean age, 32 years; mean FEV1, 91% of predicted value) were studied in a randomized design comparing 3 days of treatment with placebo and low (200 micrograms twice daily), medium (400 micrograms twice daily), and high (800 micrograms twice daily) doses of BUD (Pulmicort Turbuhaler, 100 micrograms) and TAA (Azmacort integrated actuator/spacer, 100 micrograms) with a 7-day period at crossover, when patients received their usual inhaled corticosteroid therapy. Measurements were made at 8 am for serum cortisol, osteocalcin, and blood eosinophils. Measurements were also made for overnight urinary cortisol/creatinine excretion. RESULTS: For all measurements there were no significant differences between the 2 treatments at any dose level. Ratios between BUD and TAA (95% CI) at the highest dose levels were as follows: 8 am serum cortisol, 1.08-fold (0.63 to 1. 85); urinary cortisol, 1.09-fold (0.63 to 1.86); eosinophils, 0. 98-fold (0.69 to 1.38); and osteocalcin 1.05-fold (0.78 to 1.41). There was no evidence of a significant overall dose-response effect for any parameter of hypothalamo-pituitary-adrenocortical axis activity, with neither drug being significantly different from placebo at any dose. For the 3 dose levels of both drugs, total abnormal low values for 8 am serum cortisol (ie, <5.4 micrograms/dL [<150 nmol/L]) showed 2 of 36 for BUD and 2 of 36 for TAA. There was also no significant overall dose-response effect for eosinophils or osteocalcin, although both drugs were significantly (P <.05) different from placebo at the highest dose: eosinophils (x10(9)/L), placebo: 0.36, TAA: 0.24, and BUD: 0.23; and osteocalcin (nmol/L), placebo: 1.04, TAA: 0.73, and BUD: 0.77. CONCLUSION: There were no significant differences in the systemic bioactivity profiles, in terms of adrenal, blood, and bone markers, between BUD administered by means of Turbuhaler and TAA administered by means of an integrated actuator/spacer in a dose range of 400 micrograms to 1600 micrograms/day. Both drugs exhibited a significant degree of detectable systemic bioactivity but only at the highest dose of 1600 micrograms/day for effects on eosinophil count and osteocalcin.

Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial.

OBJECTIVES: To assess the efficacy of specific immunotherapy with standardized cat dander extract, using objective endpoints and simulated 'natural' exposure to cats. DESIGN: Double-blind, randomized, placebo-controlled study carried out at a UK Allergy research clinic. SUBJECTS: Twenty-eight patients with moderate to severe allergic rhinoconjunctivitis with asthma due to cat allergy. Subjects were stratified for cat sensitivity, cat ownership and asthma, and the groups were well matched for all relevant parameters. MAIN OUTCOME MEASURES: Symptom scores and peak flow rate during and after exposure to cats in a cat-room. Skin tests and conjunctival provocation thresholds. RESULTS: The actively treated group showed a marked reduction in symptoms during the cat exposure (mean score 61.6-17.1; P < 0.001) with no change in the placebo group (64.7 vs 62.1). The active group also showed a reduced peak flow response to cat exposure (mean fall of 85 L/min pretreatment, 29 L/min after treatment, P < 0.005) as well as reductions in conjunctival provocation sensitivity, skin sensitivity to cat extract and skin sensitivity to house dust mite (D.pteronyssinus). Skin reactivity to histamine and codeine were unaltered. No significant adverse reactions were encountered. CONCLUSIONS: Specific immunotherapy seems to be an effective treatment for cat allergy. Allergy to cats is common and often poorly controlled on conventional pharmacotherapy. Although cat allergy has not traditionally been considered as a valid indication for immunotherapy in the UK, it should now be considered as a legitimate treatment, especially for those who are unable to avoid exposure.

Safety aspects of local endobronchial allergen challenge in asthmatic patients.

Local endobronchial allergen challenge is being increasingly used to investigate the role of allergic inflammation in asthma. However, little information is available about the safety of this procedure and the changes induced in airway physiology. BAL and biopsy were performed at 10 min and at 4 to 6 h, or 24 h after segmental allergen challenge in 49 patients with atopic asthma. Two hours after challenge, FEV1 was reduced from 97.6 +/- 13.9 (mean +/- SD) to 83.4 +/- 21.7% predicted. FEV1 remained reduced at 4 to 6 h (87.7 +/- 20.4%), but it had nearly returned to baseline by 24 h (93.2 +/- 14.0%). When endobronchial challenge was combined with BAL and biopsy, the initial fall in FEV1 was slightly greater (from 101.8 +/- 14.2 to 78.5 +/- 13.6%). Bronchial responsiveness to methacholine was measured in 10 subjects, and it showed a twofold increase 24 h after local challenge and lavage. Significant changes in FEV1 and methacholine PC20 were still detectable 72 h after challenge. Widespread wheezing occurred in 29% of the subjects, but none of the them had to be admitted to hospital. We conclude that local endobronchial allergen challenge, although producing measurable changes in airway physiology, is in general well tolerated and is an acceptable method to investigate airway pathophysiologic processes in patients with mild to moderate asthma.

Aid and the growth of income in aid-favoured developing countries: policy issues.

PIP: This paper opens by expressing disappointment in the disparities between published estimations of the effectiveness of foreign aid to developing countries and effectiveness data which arise from the application of complex econometric methods. The new dilemmas for aid policy include the fact that aid increasingly devoted to human development at the expense of productive activity is unlikely to create the material development which will allow maintenance of human development targets. The second part of the paper presents comparative statistics on gross national product, official development assistance, and savings growth which paint a disturbing picture because the growth of domestic savings has been negative in the period 1967-87 in nine of the 11 less developed countries with data available. Section 3 covers the shortcomings of econometric experiments which neither confirm nor deny the findings of other studies on the effectiveness of aid. The fourth section describes constraints to the growth of income imposed by the foreign exchange, the rate of return on investment, and the growth of labor productivity and presents statistical evidence supporting aid policy which would 1) take advantage of opportunities to rehabilitate output growth in traditional industries without the addition of a great deal of capital, 2) direct attention to increasing the absolute gross national product (GNP) to raise the growth of per capital income, and 3) strategically reorient the structure of aid to increase the absolute GNP faster to accelerate reversal of the negative savings pattern and speed the reduction of fertility. Section 5 considers suggested shifts in aid policy orientation dealing with 1) population growth, income level, and food security; 2) reconstruction and structural adjustment; 3) rationalizing aid for social, institutional, and human development and technical assistance. The concluding section notes that the suggested strategic reorientation of the structure of aid should result in reduced population growth.^ieng

Determination of shunt flow in a case of multiple arteriosystemic connections.

A 64-year-old woman presented with acute congestive heart failure and atrial fibrillation, with good response to medical management. Selective coronary and left ventricular cineangiography demonstrated multiple arteriosystemic connections arising from both left and right coronary arteries, but normal (although tortuous) coronary vessels and ventricular contraction pattern. Determination of the magnitude of the shunt flow and concommitant measurement of myocardial lactate extraction suggested that this type of coronary vascular abnormality was an angiographic curiosity without discernible clinical import; however, the etiology of the patient's heart disease remains an enigma.

Mechanism of the hypolipemic effect of clofibrate in postabsorptive man.

Splanchnic metabolism of triglycerides and other major substrates was studied in the postabsorptive state in normotriglyceridemic and hypertriglyceridemic human subjects who received (1/2) g of clofibrate four times daily for 3 wk. Transport in blood plasma of triglycerides produced in the splanchnic region was quantified by three methods: (a) measurement of the transsplanchnic gradient of (14)C-labeled triglycerides during constant intravenous infusion of [1- (14)C] palmitate (b) chemical measurement of the transplanchnic gradient in concentration of triglycerides of very low density lipoproteins; and (c) determination of clearance of (14)C-labeled triglycerides in extrasplanchnic tissues. The first method measures only triglycerides derived from free fatty acids and the last two measure total splanchnic production. In hypertriglyceridemic subjects treated with clofibrate, average rates of total splanchnic production of triglycerides and production from free fatty acids were the same as those of comparable untreated subjects despite a consistent fall in plasma triglyceride levels. The hypotriglyceridemic effect of the drug was therefore accompanied by improved disposal of triglycerides in extrasplanchnic tissues. In treated normotriglyceridemic subjects, unlike their untreated counterparts, total splanchnic production was significantly higher than production from free fatty acids. Failure of clofibrate to reduce triglyceride levels in normotriglyceridemic subjects may have been related to increased total splanchnic production, coupled with improved extrasplanchnic disposal. Systemic transport and net splanchnic uptake of free fatty acids were similar in treated and control subjects but the fraction of [1-(14)C]palmitate converted to acetoacetate in splanchnic tissues was significantly higher in treated subjects. Net splanchnic extraction of plasma amino acids that enter the glucogenic pathway via pyruvate was increased in treated subjects and their arterial concentrations were reduced.