THE PHARMACOLOGICAL ROLE OF P-GLYCOPROTEIN IN THE INTESTINAL EPITHELIUM

P-glycoprotein, a membrane-associated transport protein, has recently been recognised as an important element of the intestinal epithelium. This paper summarises thein vivodata on the pharmacological role of intestinal P-glycoprotein. These data show that P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen. In addition, there is also evidence that this protein can limit oral drug absorption. Hence, inhibition of intestinal P-glycoprotein, e.g. by a reversal agent like cyclosporin A, may be a promising strategy for improving the oral bioavailability of P-glycoprotein substrate drugs. Indeed, several preclinical and clinical studies have shown that coadministration of drugs with a reversal agent can substantially increase oral drug absorption.     

Ultrastructural, Protein, and Lipid Changes in Liver Associated with Chlordecone Treatment of Mice

Pretreatment of mice with chlordecone (CD) reduced hepatic accumulationof a subsequent dose of [¹⁴C]CD without significantly changing[¹⁴C]CD biotransformation. To determine if CD-induced changesin hepatic [¹⁴C]CD accumulation were coincident with alteredcell composition, we examined the effects of CD on hepatic proteinand lipid content, on fatty acid profiles of liver and kidney,and on the ultrastructure of hepatocytes. SDS-polyacrylamidegel electrophoresis detected an apparent CD dose-related increasein a microsomal protein with a molecular weight of about 23kDa. Total liver or kidney lipid contents were not altered byCD but relative amounts of several hepatic fatty acids werechanged. CD caused marked hepatic mitochondrial swelling, increasedamounts of endoplasmic reticulum, apparently increased numbersof peroxisome-like structures, and decreased numbers of lipiddroplets in cytoplasm of hepatocytes. Numbers of lipid dropletswere not decreased in perisinusoidal fat storage cells. In addition,the numbers of cytoplasmic lipoprotein vesicles were apparentlyincreased in some hepatocytes. Overall these changes indicatedan increased hepatocyte secretory activity and suggested thatCD changed hepatocellular lipid transport, storage, and metabolismpathways.     

Controlled Clinical Trial of Treatment with Cimetidine for Non-ulcer Dyspepsia

ABSTRACT The effect of cimetidine (1 g daily) and placebo was studied in a controlled clinical trial comprising 50 patients with non-ulcer dyspepsia in whom an organic abnormality responsible for the dyspeptic symptoms was not disclosed by a standardized and extensive examination programme. Reduction of symptoms occurred in 13 (54%) out of 24 patients treated with cimetidine and in 16 (62%) out of 26 treated with placebo. The difference was insignificant, as were the alterations in the individual dyspeptic symptoms between the groups. Only 6 patients (25%) on cimetidine and 8 (31%) on placebo treatment had a total relief of symptoms. Of these, all cimetidine-treated patients remained free from symptoms during the successive 3-month observation period, while the dyspeptic symptoms relapsed in 3 (38%) placebo-treated patients. Subsequent resumption of placebo treatment reduced the symptoms in all 3 patients, but only one became free from symptoms. Cimetidine does not seem to be superior to placebo in the treatment of non-ulcer dyspepsia in patients without any previous history of ulcer or without any sign on endoscopy of an active or previous ulcer disease.     

The permeability of the blood—brain barrier during electrically induced seizures in man

The blood-brain barrier (BBB) in man was studied during various conditions using the indicator dilution method of Crone [8]. Using 113m In-DTPA as reference substance the extraction, E, of the small test substances 24Na+, 36Cl-, 14C-urea and 14C-thiourea was estimated from the areas under the venous outflow curves following intracarotid slug injection of tracers. Interlaminar diffusion and red cell carriage were taken into consideration when calculating E. Cerebral blood flow (CBF) was measured using the intra-arterial 133Xe-injection method. Twenty-two patients receiving electroconvulsive therapy (ECT) were studied before and during seizures and during hypercapnia. Before seizures the extraction values in % were as follows: ENa+ 1.6, ECl- 1.9, Eurea 3.9 and Ethiourea 7.8; the corresponding values for the permeability-surface area products (PS) in ml/100 g x min were 0.5, 0.3, 0.7, 4.1, respectively. During seizure a decrease of Ethiourea and an increase of PSurea were significant. During hypercapnia PSNa and PSthiourea rose significantly. Due to the similarity of the findings in those two high flow situations it is suggested that the changes of CBF and not the epileptic activity are responsible for the changes in permeability. The mechanism of action may be a stretching of endothelial cells in the cerebral vessels or an opening up of new capillaries, or a combination of both.     

α-Amylases from Thermoactinomyces vulgaris: characteristics,primary structure and structure prediction

Two amylolytic active protein fractions (named α-amylase 1 and α-amylase 2) were isolated from the bacterium Thermoactinomyces vulgaris strain 94-2A. α-Amylase 1 had a molecular mass of 51.6 kDa, whereas α-amylase 2 consists of two fragments which have molecular masses of 17.0 and 34.6 kDa, respectively. These two fragments are products from a proteolytic cleavage of a-amylase 1 at amino acid position 303 (tryptophan) by a serine protease (thermitase) which is also produced by T. vulgaris. The purified α-amylase 1 and 2 follow the Michaelis-Menten kinetics in the presence of starch as substrate with K_m values of 1.37 ± 0.07 and 1.29 ± 0.18 mg/mL, respectively. In effect they differ in their stability characteristics. The amino acid sequence of α-amylase from T. vulgaris derived from DNA sequence (1) was compared with those of other α-amylases. It reveals high homologies to α-amylases from other microorganisms (e.g. B. polymyxa, A. oryzae, S. occidentalis and S.fibuligera). A three-dimensional structure model for α-amylase 1 on the basis of the 3 Å X-ray structure of Taka-amylase was constructed.     

An alternative treatment in cases with advanced localized attrition

A combined orthodontic/prosthetic treatment of patients with advanced localized attrition has been described. In one patient the effect of the orthodontic treatment upon the morphological face height has been studied using an X-ray cephalographic technique and the results have been discussed.     

THE EFFECTS OF INTERMITTENT POSITIVE PRESSURE VENTILATION ON LUNG FUNCTION IN HYALINE MEMBRANE DISEASE

Fifty-eight infants with hyaline membrane disease were admittedto an intensive care unit. Twenty of these developed respiratoryfailure despite bicarbonate and oxygen therapy. They were thentreated by intermittent positive pressure ventilation and 13of the 20 survived. The mechanism of IPPV was determined in12 of these by the measurement of lung function and blood-gastensions. Results indicated that a normal alveolar ventilationcould be produced in these infants by a 50 per cent increasein their original minute volume. An adequate tidal volume (20ml) could only be obtained by a high peak transpulmonary pressure(35 cm H²O) and this volume had to be delivered at a mean rateof 56 cycles per minute. A reduction in either transpulmonarypressure or the rate of cycling resulted in an inadequate alveolarventilation and a precipitious fall in Pa_o2. Assisted breathingappeared to be more effective than passive ventilation overa short period of time. Measurements were made within 4 minutesof paralyzing the respiratory muscles, and must therefore beaccepted with reserve.     

Heavy drinking in the restaurant business: the role of social modelling and structural factors of the work-place

The role of social modelling and structural factors of the work-place in predicting the probability of heavy drinking was investigated in a sample of 3267 Norwegian male and female waiters and cooks. In the logistic regression analysis, the probability of heavy drinking was increased by two social modelling factors and one structural factor. Having co-workers who, at least weekly, took an end-of-work drink at the work-place gave an odds ratio for heavy drinking of 2.8 (95% CI1.9–4.1), and having co-workers who went out after work at least every week gave an odds ratio of 1.8 (95% CI 1.2–2.8). Working at a place with a liberal alcohol policy gave an odds ratio 1.5 (95% CI 1.1–2.2). Among the background factors, only household type significantly predicted heavy drinking. As compared with living with children, the odds for heavy drinking when living alone was 4.3 (95% CI 2.9–6.4). The results indicate that preventive measures in the restaurant business should not only concentrate on the individual, but also deal with factors related to the occupational activity that promote and sustain heavy drinking.     

Measuring mobility limitations in children with cerebral palsy: content and construct validity of a mobility questionnaire (MobQues)

Aim The objective of this study was to assess the validity of a mobility questionnaire (MobQues) that was developed to measure parent‐reported mobility limitations in children with cerebral palsy (CP). Method The parents of 439 children with CP (256 males and 183 females; age range 2–18y; Gross Motor Function Classification System [GMFCS] levels I–IV) completed the mobility questionnaire (MobQues). To assess content validity, we linked all meaningful concepts of the MobQues items to the International Classification of Functioning, Disability and Health (ICF). To assess construct validity, we compared the total scores of the two versions of the MobQues (MobQues47 and MobQues28) according to GMFCS level, and determined Pearson’s correlation coefficient (r) with the Gross Motor Function Measure‐66 (GMFM‐66). Results Content validity was demonstrated by the fact that 46 of the 47 MobQues items were linked to categories in the ‘Mobility’ chapter of the ICF. Construct validity was demonstrated by the finding that MobQues scores decreased with increasing GMFCS levels (p<0.001). In a subgroup of 162 children, positive correlations were found between total scores and the GMFM‐66 (MobQues47, r=0.75; MobQues28, r=0.67, p<0.001). Interpretation The results of this study provide evidence supporting the content and construct validity of the MobQues as a measure of mobility limitation in children with CP.     

Comparison of health inequalities between East and West Germany

Background: The major objective of the study was to assess whetherthe extent of health inequalities varies between East and WestGermany and whether differences in social Inequalities betweenboth parts of Germany are associated with differences in healthinequalities. Methods: Data were available from a representativesample of 5,311 persons from West Germany and 2,414 personsfrom East Germany in the same age group (25–69 years).The study protocol was nearly identical in both studies. Socioeconomicstatus (SES) was assessed by household equivalent income andby educational level. Health status was assessed by perceivedgeneral health and by the number of chronic conditions. Absolutedifferences as well as relative differences (odds ratios) inthe morbidity rates between low and high SES groups were calculated.All analyses were performed separately for men and women. Results:Income inequalities are larger in West Germany as compared withEast Germany, but there are minor differences between East andWest Germany concerning educational inequalities and morbidityrates. Just about all measures indicated that health inequalitiesfavouring the upper socioeconomic groups exist in East Germanyas well as in West Germany and that there are no significantdifferences in the extent of health inequalities between bothparts of Germany. Conclusion: Using two data sets which wereraised with nearly identical study protocols, it can be concludedthat health inequalities are very stabile as they do not seemto differ substantially despite the fact that both parts ofGermany have experienced different social systems during thepast 45 years.