Occupational asthma.

Occupational asthma. The Council on Scientific Affairs of the California Medical Association presents the following inventory of items of progress in chest diseases. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items of progress in chest diseases that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items of progress listed below were selected by the Advisory Panel to the Section on Chest Diseases of the California Medical Association, and the summaries were prepared under its direction.


The second century of the antibody. Molecular perspectives in regulation, pathophysiology, and therapeutic applications. The modern age of immunology began in 1890 with the discovery of antibodies as a major component of protective immunity. The 2nd century of the antibody begins with a focus on the molecular physiology and pathophysiology of immunoglobulin production. Numerous human variable-region antibody genes have been identified through advances in molecular cloning and anti-variable-region monoclonal antibodies. Some of these variable-region genes are now known to be involved in specific stages of B-lymphocyte differentiation and immune development. This connection has yielded new insights into the pathogenesis of immune dyscrasias and lymphoid neoplasia; common variable immunodeficiency and cryoglobulinemia are highlighted here. The molecular regulation of immunoglobulin expression suggests new targets for pathogenesis and clinical intervention. Finally, genetically engineered antibodies offer novel opportunities for diagnostic and therapeutic applications.


Abdominal aortic aneurysm. Incidence in a hospital population at risk. The incidence of abdominal aortic aneurysms has been studied in various selected patient groups. In this study, 100 male patients on a cardiology service who were older than 60 years and over 170 cm (5 ft 7 in) tall were examined by abdominal ultrasonograms. A total of 11 aneurysms were found, 2 of which were more than 4.5 cm in diameter. Other abnormalities that were found included renal disease in 20 patients (1 carcinoma treated with a curative nephrectomy), gallbladder disease in 22 patients, and miscellaneous intra-abdominal disease in 6 patients; 47 patients had no abnormalities found. The aneurysms of these patients were classified by a patient's height in 5-cm (2-in) increments. No significant difference in the incidence of aneurysms was found within the groups, but these groups are small and a significant difference would not be expected. It is of interest that the two large aneurysms were in persons taller than 180 cm (5 ft 11 in). Previous ultrasonographic studies of aneurysmal incidence have not reported other intra-abdominal disease.


Radiation retinopathy.

Radiation retinopathy. Radiation therapy is effective against many cancerous and noncancerous disease processes. As with other therapeutics, side effects must be anticipated, recognized, and managed appropriately. Radiation retinopathy is a vision-threatening complication of ocular, orbital, periorbital, facial, nasopharyngeal, and cranial irradiation. Factors that appear important in the pathogenesis of radiation retinopathy include total radiation dosage, fraction size, concomitant chemotherapy, and preexisting vascular disorders. Clinical manifestations of the disorder include macular edema and nonproliferative and proliferative retinopathy, similar to changes seen in diabetic retinopathy. Argon laser photocoagulation has proved efficacious for managing macular edema and fibrovascular proliferation in some of these patients. Ongoing basic laboratory and clinical research efforts have led to a better understanding of the pathogenesis, natural history, and treatment response of radiation retinopathy. The ultimate goal of this knowledge is to improve the prevention, recognition, and management of this vision-threatening complication.


Effects of the multiple risk factor intervention trial smoking cessation program on pulmonary function. A randomized controlled trial. To determine whether the decline in pulmonary function in smokers is modified by stop-smoking intervention, a randomized controlled study (the Multiple Risk Factor Intervention Trial) was done comparing participants in a special intervention group that included an intensive smoking cessation program with those assigned to usual care. The subjects were 6,347 middle-aged male smokers who had serial measurements of pulmonary function--principally the forced expiratory volume in 1 second (FEV1)--during 6 to 7 years of follow-up. No overall differences were detected in the rate of loss of FEV1 in the two groups. The use of beta-blockers, which had detrimental effects on FEV1, was significantly more common in the intervention group. Among nonusers of beta-blockers, heavy smokers lost FEV1 at a rate about 11 ml per year slower in the intervention group than in the control group (2P = .09) and ended the trial with an FEV1 about 90 ml higher (2P = .05). These results support the inference from observational studies that smoking cessation has a beneficial effect on pulmonary function in heavy smokers.


Wake up and smell the coffee. Caffeine, coffee, and the medical consequences. Caffeine is a methylxanthine whose primary biologic effect is antagonism of the adenosine receptor. Its presence in coffee, tea, soda beverages, chocolate, and many prescription and over-the-counter drugs makes it the most commonly consumed stimulant drug. Initially caffeine increases blood pressure, plasma catecholamine levels, plasma renin activity, serum free fatty acid levels, urine production, and gastric acid secretion. Its long-term effects have been more difficult to substantiate. Most of the caffeine consumed in the United States is in coffee, which contains many other chemicals that may have other biologic actions. The consumption of coffee is a self-reinforcing behavior, and caffeine dependence and addiction are common. Coffee and caffeine intake have been linked to many illnesses, but definitive correlations have been difficult to substantiate. Initial trials showing coffee's association with coronary disease and myocardial infarction have been difficult to reproduce and have many confounding variables. Recent studies showing a larger effect over long follow-up periods and with heavy coffee consumption have again brought the question of the role of coffee in disease states to the fore. Caffeine in average dosages does not seem to increase the risk of arrhythmia. At present there is no convincing evidence that caffeine or coffee consumption increases the risk for any solid tumor. The intake of coffee and caffeine has clearly been decreasing in this country over the past two decades, largely brought about by the increasing health consciousness of Americans. Although there have been many studies that hint that the fears of increased disease with coffee drinking may be warranted, many questions have yet to be answered about the health effects of coffee and caffeine use.


Transesophageal echocardiography.

Transesophageal echocardiography. The Council on Scientific Affairs of the California Medical Association presents the following inventory of items of progress in anesthesiology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of these items of progress in anesthesiology, that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items of progress listed below were selected by the Advisory Panel to the Section on Anesthesiology of the California Medical Association, and the summaries were prepared under its direction.


Urinary tract infections in children. An update. Urinary tract infection is a common and frequently recurring condition in children. The susceptibility of the host, the presence of urinary tract abnormalities, and the virulence of the urinary pathogens are of primary importance in the development of the infection. Renal parenchymal scarring, hypertension, and renal insufficiency are well-established complications of the infection in children. To reduce the risk of renal damage, diagnosis and treatment must be prompt. The diagnosis demands radiologic evaluation of the urinary tract in all boys, all children younger than 5 years, all patients with voiding dysfunction, and school-aged girls with recurrent infection to identify those patients with vesicoureteral reflux, obstruction, or other urinary tract abnormalities. Both voiding cystourethrography and renal ultrasonography are the initial examinations to use to determine the next appropriate study. Children with vesicoureteral reflux or with recurrent urinary tract infections should receive prophylactic antibiotic therapy and should be observed closely to prevent renal scarring.


Costs and coverage. Pressures toward health care reform. Signs of discontent with the health care system are growing. Calls for health care reform are largely motivated by the continued increase in health care costs and the large number of people without adequate health insurance. For the past 20 years, health care spending has risen at rates higher than the gross national product. As many as 35 million people are without health insurance. As proposals for health care reform are developed, it is useful to understand the roots of the cost problem. Causes of spiraling health care costs include "market failure" in the health care market, expansion in technology, excessive administrative costs, unnecessary care and defensive medicine, increased patient complexity, excess capacity within the health care system, and low productivity. Attempts to control costs, by the federal government for the Medicare program and then by the private sector, have to date been mostly unsuccessful. New proposals for health care reform are proliferating, and important changes in the health care system are likely.


[Results of conventional treatment of severe congestive heart failure with vasodilators]. In 61 patients with NYHA IV class chronic congestive heart failure, treated in succession with digoxin (D) and furosemide (F) for two weeks, with D+F and isosorbide dinitrate (S) or nifedipine (N) for two weeks, with D+F+S or N without C for two weeks, clinical status, chest X-ray picture and two dimensional echocardiography were evaluated at the end of each stage of the treatment. There were analyzed heart rate (HR), arterial systolic (Ps) and diastolic (Pd) blood pressure, body weight (Mc), 24-hour urinary output (Dd), cardio-thoracic index (CTI), cardiac volume index (CVI) and dimensions of the left ventricle: systolic (LVIDs), and diastolic (LVIDd). The mean daily doses of the drugs were as follows: D-0.290 +/- 0.108 mg, F-13.0 +/- 4.1 mg, S-44.5 +/- 9.8 mg, N-42.0 +/- 12.2 mg, and C-75.1 +/- 24.4 mg. The treatment with vasodilators (Vd) induced decreases in Mc, CVI, LVIIDs and LVIDd in comparison with the treatment with D and F. The largest lowerings in HR, Ps, Pd and Mc were observed during the treatment with D and F. The most beneficial effects with regard to CVI, LVIDs and LVIDd were obtained during four-week treatment with captopril.


[Results of the treatment of Sjögren's syndrome with TFX (thymus factor X)]. Seven patients with Sjögren's syndrome (6 with primary and 1 with secondary form of the syndrome developing during SLE) were treated with TFX Polfa in ampoules of 10 mg during 6-12 month. Before the treatment, besides evaluation of the general clinical condition, the following immunological parameters were determined: IgG, IgA and IgM levels, absolute lymphocyte count, T-cell and B-cell counts, absolute neutrophil count, antinuclear antibodies, circulating immune complexes and skin tests with recall antigens (tuberculin and distreptase). The clinical condition of the patients was determined at monthly intervals and the immunological investigations were repeated after the treatment which lasted 6-12 months. In all patients alleviation was observed of the clinical manifestations of the disease with decreased proneness to infections. In some patients improvement was observed of the determined immunological parameters, in the first place, reversal of cutaneous tests from negative to positive.


[Value of laparoscopy in the diagnosis of liver cirrhosis and chronic hepatitis]. The purpose of the study was evaluation of laparoscopy in the diagnosis of cirrhosis and chronic hepatitis. The studied material comprised 197 cases of cholestasis in which for diagnostic-prognostic purposes laparoscopy was done. During visual observation of the abdominal cavity in 81 cases cirrhosis and in 25 chronic hepatitis was diagnosed. The reliability of the laparoscopic diagnosis was verified by the microscopic verification of the material obtained by guided biopsy of the liver or during operation. Among 81 cases of cirrhosis diagnosed during laparoscopy histological confirmation was obtained in 68 cases (83.9%). In the group of 25 cases with laparoscopic diagnosis of chronic hepatitis the diagnosis was confirmed histologically in 21 (84%) cases. The authors believe that laparoscopy extends the diagnostic possibilities in liver diseases. However reliable diagnosis can be obtained by microscopic examination of liver fragments obtained by guided biopsy or operation.


[Diagnostic and prognostic value of the assessment of selected indicators of humoral immunity in alcoholism-related pathology of the liver]. The purpose of the study was evaluation of the usefulness of selected indices of humoral immune responsiveness in the differential diagnosis of post-alcoholic hepatocellular damage. The study was carried out in 105 patients: 10 patients with a history of alcohol abuse without clinical and biochemical evidence of hepatocellular damage, 2) patients with alcoholic cirrhosis, 3) patients with post-inflammatory cirrhosis. The prognostic usefulness of the determinations of serum IgM, C3 and C4 complement components and circulating immune complexes in early diagnostic of alcoholic liver disease was demonstrated. It was noted also that increased serum IgA level may be a useful index differentiating of cirrhosis after hepatitis from alcoholic cirrhosis.


[Hepatitis A in drug addicts].

[Hepatitis A in drug addicts]. In the years 1982-1988 among patients admitted with the diagnosis of acute virus hepatitis to the Department of Infectious Hepatology, Institute of Infectious and Parasitic Diseases in Warsaw were 25 drug addicts. In 15 of them virus hepatitis B and in 10 virus hepatitis A was recognized. Virus hepatitis A had in the group of addicts a milder course than in controls not taking narcotics.


[Phenomenon of increased resistance of yeast-like fungi to nystatin]. The results are presented of in vitro investigations of the sensitivity of 225 strains of yeast-like fungi to nystatin. The strains were isolated from cutaneous and mucosal lesions. In the study nystatin concentration 10 micrograms/ml of the substrate was used and a two-grade scale of evaluation was applied: sensitive or resistant to the drug. It was found that 56.7% of the tested strains were resistant to this nystatin concentration. The obtained data were compared with those obtained in 1972 when all the tested strains were sensitive to nystatin in this concentration. The study showed that the resistance to nystatin has been rising in these organisms with years.


[Sliding hiatal hernia in endoscopic examination]. Among 1000 successive endoscopic examinations carried out in the first 6 months of 1990 in a laboratory of endoscopy 443 cases (44.3%) of sliding hiatus hernia were analysed. The examination was carried out with an Olympus GIF-Q10 fibroscope without pharmacological premedication. The diagnosis was based on the criteria described by Dagradi and Trujillo at all. In 296 cases sliding hiatus hernia was the only pathological abnormality in the endoscopic examination. In 85 cases it was associated with mucosa inflammation in the oesophagus, and in 1 case with carcinoma of the oesophagus. No correlation was found between frequency of endoscopic finding of hiatus hernia and sex and age. The analysis showed that in 110 out of 172 cases earlier routine radiological examination (63.9%) failed to demonstrate the hernia, whose direct signs were found in endoscopic examination. In no case radiological findings suggested the presence of oesophageal changes. It seems that endoscopic diagnostic of sliding hiatus hernia may contribute to explanation of the cause of "non-characteristic" gastric symptoms which in over half the cases were the cause of referral of the patients to this examination.


[Further studies of the acid plate agglutination reaction in the diagnosis of brucellosis in humans]. Using the methods of acid platelet agglutination, agglutination, agglutination with 2-mercaptoethanol, Coombs' reaction, and complement binding reaction, 152 serum specimens taken from patients with diagnosed brucellosis, were subjected to studies. The following per cent of seropositive results was shown: acid platelet agglutination--11.2%, agglutination--40.1%, agglutination with 2-mercaptoethanol--34.4%, Coombs' reaction--42.8%, complement binding reaction--7.9%. The acid platelet agglutination reaction cannot be used for screening for brucellosis in humans.


[Fungal stomach ulcer].

[Fungal stomach ulcer]. Fungal gastric ulcer is a relatively frequent from of gastric mycosis coexisting in 20-30% of cases with peptic ulcer. In such cases fungi were present in patients without other disease and in those with concomitant diseases such as neoplasms, polyps of the stomach, haematological diseases, and in patients treated with cytostatics and H2-blockers. Fungal ulcer differ from common ulcers in greater size and tendency for bleeding. In certain situations "fungal ulcer" requires routine antimycotic treatment especially if operation is planned.


[Acrodermatitis enteropathica--congenital zinc deficiency syndrome]. The importance of the presence of zinc in human physiology and pathology has been analysed. The disturbances in the prostaglandin synthesis in the impaired intestinal zinc absorbtion have been of special interest. It is known that the deficiency of zinc results in the inborn clinical syndrome oh he disease and both its past and present treatment methods.


[Severe exacerbation of chronic hepatitis B following interferon therapy]. A patient with chronic active hepatitis B was treated with interferon alpha. Inhibition of HBV replication was associated with severe exacerbation of hepatitis. Treatment of chronic hepatitis B with interferon may lead to transient decompensation of liver function, especially in patients with high activity of morphological changes.


[Burgdorf's reaction (painful acral erythema) in patients with acute lymphoblastic leukemia following medium-dose methotrexate therapy]. Erythematous changes of the palms with associated oedema, blistering and desquamation were observed in two children during chemotherapy for acute lymphoblastic leukaemia, after methotrexate in doses of 1,000 mg/m2. These changes correspondent to those described in the literature as Burgdorf's reaction. In Poland it was never reported as yet.


[A case of skin reactions to carbamazepine]. A case is described of severe cutaneous complications after carbamazepine administration. Attention is called to the frequency of adverse reactions to this drug.


[A case of side effect of Biseptol].

[A case of side effect of Biseptol]. A case of adverse side effects of co-trimoxazole (Biseptol) was observed, with predominance of neurological changes in the clinical picture. Attention is called to the infrequent occurrence of such side effects of this drug and to the necessity of prompt diagnostic and therapeutic management of such cases.


[A case of non-Hodgkin's lymphoma of the thyroid gland]. A case is reported of centrocytic-centroblastic malignant lymphoma situated in the thyroid and simulating goitre. Attention is called to difficulties in establishing of correct diagnosis.


[Epidemiological analysis of the correlations between selected individual characteristics of patients with primary arterial hypertension]. The purpose of the study was to find the correlations and to evaluate their strength between the progression of hypertension and age, sex, time between the diagnosis of hypertension and the beginning of treatment, body weight and other characteristics. The study was carried out in the population of patients treated in the Cardiology Department, Medical Academy in Lublin in the period 1981-1984. The computer-assisted analysis of the obtained material was carried out in the Department of Epidemiology, Medical Academy in Lublin. The studied population comprised 320 patients with essential hypertension. In the statistical analysis the chi square test was applied for finding of statistically significant correlations and Pearson test was used for estimation of correlation strength. Statistically significant correlations were obtained between the progression of hypertension and age, sex, time between hypertension diagnosis and present treatment and body weight.


[Postoperative complications and mortality; results of skin tests in delayed hypersensitivity]. In 221 patients the test of cutaneous delayed hypersensitivity was done before the operation and 4 days after it, using 3 antigens: tuberculin, distreptase and phytohaemagglutinin. The patients were divided into three groups: I control (109) subjected to minor and moderately serious operations, and study group (II) with peritonitis (IIa 40 cases), digestive tract cancer (IIb 65 cases) and digestive tract diseases (IIc 7 cases). The study showed that in cases with preoperative anergy to antigens the operations were followed significantly more frequently by serious septic complications and mortality from these complications was much higher. No patients with preoperatively normal responses to the antigens died after the operations. The test makes possible preoperative detection of high surgical risk connected with infection, and early treatment reducing postoperative mortality.


[Elaboration of a device for detection of the ovulation period in women]. The results are described of studies for evolving of modern methods for determination of the ovulation time in women. After an analysis of literature reports three methods were chosen based on differences in body temperature measurements and a measuring device for these experiments was designed. The results are presented of preliminary experiments with this method of "measurements of changes in the reactivity of blood vessels". Further studies can be conducted only by physicians, and the paper contains proposals of using this device as well as the literature data.


[Results of the treatment of steroid-resistant and steroid-dependent nephrotic syndrome with pulsed doses of prednisolone]. In 12 children with steroid-resistant and 17 with steroid-sensitive nephrotic syndrome massive doses of prednisolone were used in intravenous infusions ("pulses"). In 8 children with steroid-resistant and 9 with steroid-sensitive nephrotic syndrome very good or good results were obtained. The authors suppose that in a part of the children previous ineffectiveness of this immunosuppressive treatment could have been due to insufficient dosage. Rosette tests before and after pulses demonstrated a reduction of the total number of T-cells after pulses. The change of the ratio of theophylline-resistant to theophylline-sensitive lymphocytes suggests that this reduction was caused mainly by a fall of the number of helper T-cells and non-specific cytotoxic cells.


[Lung cancer among the autochthonous population and among immigrants Upper Silesia in relation to smoking, exposure to harmful factors at work and atmospheric pollution]. By the case-control method 367 patients with lung carcinoma coming from the autochthonous population of Upper Silesia and 253 similar patients from the population of immigrants from other areas were compared (620 cases, in all) treated in the Institute of Oncology in Gliwice in the years 1982-1989. They accounted for about 85% of all male patients with this tumour. In the analysis three zones of Upper Silesia with varying concentrations of atmospheric pollution, where the patients lived, were considered, estimating the risk of this tumour in relation to pollution level, and standardizing the risk for tobacco smoking and considering data related to the exposure to harmful factors in occupational work. The analysis showed that the so called summarized index of relative risk was about 2.5 times greater for the autochthonous as well as immigrant populations in the zone of greatest atmospheric pollution with statistically significant differences in relation to the relatively most favourable zone (accepted as 1.00) However, the risk was progressively rising only in the autochthonous population (in all 3 zones). That showed that the risk of lung carcinoma was increasing in this population with increasing atmospheric pollution. This evident progression of risk was not found in the population of immigrants, although the risk level in this population living in the zone of greatest pollution was similar to that in the autochthonous population.


[Surgical treatment of otosclerosis].

[Surgical treatment of otosclerosis]. The purpose of the study was evaluation of the surgical treatment of otosclerosis by the method of small and large window. On the basis of four conversation frequencies hearing improvement was assessed in 44 ears after operation. Closure of cochlear reserve to 10 dB was obtained in 70.5% of cases. The mean hearing improvement was 29 dB. The best results were obtained with stapedotomy (small window method), particularly at 4 kHz frequencies.


[Endoscopic picture of hemorrhage from the upper digestive tract in elderly patients]. The causes of upper gastrointestinal tract bleeding were analysed in 412 patients dividing them into age groups below and over 60 years. Both groups were compared using endoscopic classification of bleedings by Forrest. In the group aged over 60 years a significantly higher per cent of type II lesion was found, especially non-bleeding vascular stump protruding from the bottom of the ulcer. This lesion was associated in nearly half the cases with recurrence of bleeding. The finding of this endoscopic picture should suggest the necessity of a more radical operation, although the operative risk is higher in patients aged over 60 years.


[Primary sclerosing cholangitis and primary biliary liver cirrhosis as the causes of intrahepatic cholestasis]. Primary sclerosing cholangitis and primary biliary cirrhosis are rarely diagnosed diseases which should, however, be considered in the diagnosis of cholestasis. The authors present an outline of the modern knowledge on these diseases with particular reference to differential diagnosis.


[Non-ulcer dyspepsia].

[Non-ulcer dyspepsia]. The definition, classification, pathophysiology, diagnosis and treatment of functional disturbances of the upper part of the digestive tract called "non-ulcer dyspepsia" are described. Attention is called to the frequency of these disorders, and stress is laid on the role of digestive tract motor function tests in the knowledge of the pathophysiology and effective treatment. In the therapeutic proposals the authors prefer the use of prokinetic drugs, especially metoclopramide, domperidone and cisapridine.


[Decidual prolactin].

[Decidual prolactin]. Human prolactin (hPRL) is a hormone produced by the lactotropic cells of the hypophysis and by the endometrium converted to decidua in pregnancy. Prolactin of decidual origin is identical with the pituitary hormone. Decidual prolactin is released mainly by the extraplacental fetal membranes. Prolactin production was found also in the endometrium in late secretory phase of normal menstrual cycle. It was noted that hPRL production by the decidua in various periods of pregnancy is closely correlated with hPRL concentration in the amniotic fluid. Peak hPRL release into the amniotic fluid is in the 24th week of pregnancy. The most important biological function of decidual prolactin is its effect on water and electrolyte transport for the needs of the fetus, and this transport takes place mainly across the fetal membranes. Moreover, it was found that prolactin affects the synthesis of fetal surfactant, influences calcium absorption in the fetal intestine. Calcium and phosphorus are obtained by the fetus from the amniotic fluid. Many authors suggest that decidual prolactin has a role in the process of implantation and early development of the blastocyst.


[Recurrent acute chylous peritonitis].

[Recurrent acute chylous peritonitis]. A case of acute chylous diffuse peritonitis with recurrences was treated by peritoneal drainage. During the first hospital stay this drainage resulted in cure. After 17 months another recurrence treated in the same way led to death with increasing renal failure, diabetes, cardiorespiratory failure.


[Severe EPH gestosis complicated by development of complete HELLP syndrome]. This is the first in Poland report on fully developed HELLP syndrome complicating severe EPH gestosis. The diagnosis and treatment of the syndrome are discussed in the light of a literature survey.


[4 years' methadone substitution therapy in Austria]. On September 25th 1987 methadone was legalized for therapeutic use in Austria. During the past four years altogether 1828 opiate addicts were admitted to methadone maintenance treatment. 439 females and 926 males were currently being treated in December 1991; their age ranged from 16-59 years, the daily oral d,l methadone dose levels varied between 10 mg and 250 mg per day. Only 406 doctors and 123 pharmacies participate in methadone maintenance treatment, which does not provide complete cover for the area in spite of increased finding. Moreover, the doctors' skills in this treatment have to be improved by requisite training. As Austrian experience shows, methadone treatment offers a first step towards social rehabilitation for drug addicts who have been living as criminals on the fringe of society. Socioeconomic data, as well as criminal behaviour changed dramatically for the better due to this treatment in Austria. Physicians have a clear responsibility to lead the effort on all fronts in the implementation of this treatment modality. Therapeutic drug monitoring should become routine in methadone treatment to ensure compliance and to achieve optimum results, especially in patients who complain of withdrawal symptoms and continue high-risk behaviour and to increase acceptance of substitution therapy. The Austrian treatment model for methadone maintenance treatment is a positive example for other countries who wish to introduce this treatment modality for drug addiction.


The diagnostic impact of magnetic resonance imaging on the evaluation of suspected spinal cord disease. The data from 262 patients studied consecutively for suspected spinal cord disease were analysed to determine the utility of magnetic resonance imaging (MRI) in this clinical setting. Damage to the spinal cord was detected in a total of 188 (72%) patients and was caused by myelocompression in two thirds and by intramedullary lesions in one third of the patients. Misleading sensory levels 5 to 12 segments below the actual lesion site were seen in 26% of patients with both extra- and intramedullary types of abnormality. A negative spinal MRI implied predominantly demyelinating or inflammatory origin of the clinical symptomatology, as was indicated by additional MRI studies of the brain and CSF findings. It is concluded that MRI is the procedure of choice for assessing patients with medullary symptoms. Irrespective of localizing neurologic findings the evaluation of the entire spine and even of the brain may be necessary to obtain maximum diagnostic information.


[Epidemiology of suicide in Austria 1980 to 1990]. This article investigates the suicide rates in Austria from 1980 to 1990 according to age groups and the methods used. In the years investigated the overall suicide rate increased until 1986, followed by a decline until 1990. The suicide rate in women shows a gradual linear increase with age, whilst in men there is a biphasic curve with a steep increase in teenagers and young men in their early twenties, followed by a plateau and a second steep increase as from 65 years of age, whereby the increase from "60-64 years" to the age group "over 85 years" is 134%. Regarding the age groups the decline over the past years in women is biggest in the groups "35-39 years" and "65-69 years", with men a decrease is present in the age groups from 20 to 50 years. Concerning the methods used, hanging is the most common mode of suicide in both women (36.4%) and men (48.8%). Suicide in the elderly--particularly in old men--which has increased internationally over the past few decades is targeted as the major area for vigorous preventive measures in Austria.


[Randomized field study of the etiology of strabismus concomitans]. After an introduction to the problems of binocular vision and an overview of the literature, the authors report on the reasons for undertaking this study and on its practical implications. Up to now, no other randomized study has been undertaken to our knowledge on children of this age group in such a large city as Vienna. All children in primary 3 classes in 20 out of the 256 elementary schools were examined ophthalmologically and orthoptically. It was found that hereditary factors are of statistically significant importance. Especially important for the ophthalmologist is also the statistically significant relation between the diagnosis poor range of fusion, poor fixation, incorrect Worth test for distance and/or proximity, and poor or lacking stereoscopic vision with the occurrence of strabism. The authors were astonished to find a remarkably high percentage of exophoria (58%), in contrast to esophoria (16%). It is interesting for prophylaxis and therapy that children originating from families where spectacles are worn, acted more cooperatively and tended to take the orders of the physician more seriously than those coming from families without eye problems. The promotion of genetic research related to squint and more counselling for couples wishing to have children or confronted with risk factor problems would be desirable, as well as the inclusion of more obligatory ophthalmological examinations in the mother-child medical "passport".


Laminar heterotopic grey matter (double cortex) in a patient with late onset Lennox-Gastaut syndrome. The Lennox-Gastaut syndrome (LGS) is a severe epileptic disorder, characterized by developmental delay, typical electroencephalographic pattern and poor control of seizures. This epileptic syndrome generally presents in early childhood but exceptionally starts at the age of 5 years or later. We describe a patient who was classified as late-onset LGS, with evidence of mild hydrocephalus on CT. MRI added new diagnostic information by demonstrating laminar heterotopic grey matter.


[Neurologic symptoms within the scope of endocrine emergencies]. Functional disturbances of the central and peripheral nervous system can be seen in various internal diseases and it is not unusual that neurological symptoms are the first kind of presentation. The tight anatomical and functional junction between neurology and endocrinology predisposes to the development of neurological derangements such as somnolence, coma, seizures, and focal signs following endocrinological emergencies. In spite of modern imaging and laboratory methods, history and clinical examination are still of great importance to establish the correct diagnosis.


Hemodynamic findings in migraine patients on transcranial Doppler sonography. Forty migraine patients were examined by means of 3D-transcranial Doppler scanning (TCD). The complete circle of Willis was investigated in all patients during headache-free intervals. TCD investigations were repeated in 10 patients during a migraine attack, in one patient twice. Based on the diagnostic criteria of the "headache classification committee of the international headache society" 23 patients were assigned to a "migraine without aura" group and 17 to a "migraine with aura" group. Twenty age-matched volunteers, not suffering from headache or any vascular disease, served as a control group. No significant differences were detected between the hemodynamic data of the control group and the migraine groups both with respect to the headache-free interval and the attack. No hemodynamic changes in keeping with the pathophysiologic hypothesis of vasospasm were found in the proximal segments of the basal cerebral arteries.


[Smoking is a risk factor for spinal diseases. Hypothesis of the pathomechanism]. Epidemiological studies strongly imply that smoking is a risk factor for back problems. The question arises as to the nature of the underlying pathomechanism. Several theories are currently discussed in the literature: it could be due to "unhealthy" life styles associated with smoking, to a rise in intraabdominal pressure caused by frequent coughing, or to osteoporosis of smokers. All of these hypotheses, however, do not stand up to a critical examination of the experimental evidence. A new theory is, therefore, put forward, claiming that smoking leads to malnutrition of the discs, which in turn renders them more vulnerable to mechanical stress. Malnutrition can be brought about by CO-Hb formation, vasoconstriction, arteriosclerotic vessel wall changes, impairment of fibrinolytic activity and changes in the flow properties of blood, all of which are known effects of smoking. The evidence for these pathomechanisms is discussed. Future studies should test the above hypothesis experimentally.


[Perspective in the incidence of Alzheimer's disease in Austria by the year 2050]. Population projections of the Austrian Central Statistical Office show a dramatic increase in the proportion of people of 65 years of age and over in Austria by the year 2050. Since this population group is at higher risk to develop Alzheimer's disease (AD/SDAT), it will be necessary to modify the currently available facilities for social and medical care to meet this increasing demand. Based on official demographic data and epidemiological findings of the "Eurodem" group, our computations show that the number of persons with AD/SDAT aged 65 or over will rise from 48,000 at present to over 113,500 in 2050 (1990: 614/100,000, 2050: 1505/100,000 persons of the total population), equivalent to an increase of 140%. By forecasting the number of persons affected, it should be possible to intensify (and in some areas introduce) long-term health planning with respect to the social, financial and medical care of aged, demented people in Austria.


[Video-endoscopic interventions in thoracic surgery]. Between October and December 1991 we performed videoendoscopic procedures, including resection of lung tissue, on 9 patients in our thoracic surgery unit. A lung measuring 15 x 18 was extirpated in 1 patient and parietal pleurectomy was performed after complicated pneumothorax in 4 patients. In one of these cases it was necessary to close a parenchymal leak and in 3 cases bullae had to be removed. Resection was undertaken in 4 patients for peripheral lung nodules, in one of them for metastases. Two patients proceeded to conventional lobectomy immediately after the frozen section results came through. Closure of lung parenchyma was carried out by means of the new ENDO-GIA stapler. Duration of the procedure was less than one hour except in the case of one patient. In one case it was necessary to use three cannulae. In the other cases two cannulae (one for videoendoscopy and fixating instrument, one for preparation instrument and stapler) sufficed for the operation to be undertaken without difficulty. This new technique brings all the known advantages of minimal invasive intervention to patients requiring thoracic surgery.


[Laparoscopic cholecystectomy--evaluation of a prospective follow-up study]. A report is presented on 105 patients who underwent laparoscopic cholecystectomy because of symptomatic gallstone disease. Preoperative and intraoperative findings, complications and results were prospectively documented. In four (3.8%) patients the laparoscopic procedure had to be converted into open cholecystectomy. There were only minor surgical complications such as wound infection and a subhepatic haematoma. On average, patients were discharged on the second postoperative day. The operating time decreased from a median of 98 minutes in the first half to 73 minutes in the second half of the study, despite augmentation of the number of surgeons and of the indications to include patients with acute cholecystitis (n = 11), previous upper abdominal surgery (n = 7) and cirrhosis (n = 2).


[Anabolic steroids in athletes].

[Anabolic steroids in athletes]. The use of anabolic-androgenic steroids (AS) to enhance appearance as well as physical/physiological capacities has increased dramatically over the past four decades in all age groups from early adolescence to adulthood. Although higher AS use rates are reported by elite and competitive athletes, a significant number of recreational athletes appear to be using AS. The scientific literature is inconsistent and at times at odds with the conventional wisdom and empirical experiences of the athletic community regarding the ergogenic effects of AS. However, individuals experienced in weight training, with an adequate diet, and who continue training during AS administration seem to consistently increase their strength and lean mass over what would have been expected from training alone. Previous research documenting deleterious but transient and mostly asymptomatic acute changes in physiology, risk factors and behavior has been inconclusive regarding the long term health impact. The abuse of AS constitutes a special challenge to society. AS are not euphorigenic or mood altering immediately following administration, as are other illicit drugs; the appetite for AS has been created predominantly by our societal fixations on winning and physical appearance. Consequently any successful intervention in this area must go beyond education, law enforcement and drug testing, and attempt to change a social environment which currently encourages the use of AS.


[Aerobic upper body training. An underutilized potential in training therapy]. Until recently, there was little or no emphasis on aerobic upper body exercise training, despite research strongly supports the inclusion of this type of exercise in cardiac rehabilitation programs and adult fitness. The limited degree of transfer of training benefits from trained limbs to another set of untrained limbs appears to discount the practice of recommending aerobic leg exercise alone. In addition, leg training programs fail to accommodate individuals with specific health problems. There is an increased physiological stress during arm training, if compared to leg training. Exercise intensity derived from a bicycle- or treadmill test would therefore cause an inappropriately target heart rate for upper body exercise. Thus, target heart rate has to be reduced by 10 to 20% to be adequate for aerobic arm training. Finally, an example of a progressive arm exercise training program is shown.


[Females in performance sports from the sports medicine viewpoint]. Especially in the endurance disciplines, the performance of women went up considerably in the course of the past few decades. This seems to be peculiar to the female sex and can be taken as a hint to a higher adaptability of the female organism with respect to the various motor capacities required for strength and endurance. During the past 10 years, however, the rate, with which the performance gap in the endurance disciplines narrowed, has slowed down distinctly. Thus, it seems, that the era during which the women vigorously caught up on the men, is coming to an end in the endurance sports. The different capacity of the sexes with respect to strength is rooted in the differently dimensioned cross sections of the muscle fibres and in the higher activation capability of the skeletal muscles of men. No differences exist with respect to the relative proportions of the ST-, FTa- and FTb-fibres and with respect to the biochemistry of the muscles. Just as in case of men, the adaptation of the cardiovascular system to endurance training manifests in a uniform enlargement of all of the heart's cavities. It is true, that women have a smaller heart volume and lower values for the maximum oxygen uptake, but these differences or by no means related to sex alone. Very often, they are produced by the fact that the endurance training of the women did not go that far. As regards the energy substrates, there is the hypothesis that women have better utilization of free fatty acids under conditions of prolonged and intensive physical work.(ABSTRACT TRUNCATED AT 250 WORDS)


Musculoskeletal pain and work disability. Musculo-skeletal pain caused by neck and back injury, cumulative trauma to the upper extremities, fibromyalgia, and reflex dystrophy is an important cause of worker disability. Physicians are involved not only in the care of injured workers, but in providing independent medical opinions regarding such injuries. Advances in medical knowledge permit better understanding and management of these injuries, and it is the responsibility of all physicians to provide accurate diagnosis, treatment, and information to patients, employers, insurers, and the workers compensation system.


Occupational low back pain: prevention of chronic disability. Work-related low back pain is a major problem for both patients and employers. Although the cause of the pain is often unclear, patients failing to return to work within 3 to 6 months have a poor medical and economic prognoses. This article reviews issues relevant to the need for aggressive management of acute, work-related LBP cases.


Occupational soft tissue disorders of the hand and forearm. Upper extremity work-related diagnoses are becoming more frequent as a source of chronic pain and lost work time for the injured worker. Early directed care toward diagnosis, treatment, and rehabilitation is needed to prevent a protracted course. A review of common regional problems of the upper extremity is presented.


Molecular cloning of a cDNA for rat diabetes-inducible cytochrome P450RLM6: hormonal regulation and similarity to the cytochrome P4502E1 gene. 1. A polyclonal, monospecific antibody to a constitutive, diabetes-inducible and insulin-reversible cytochrome P-450 isozyme (RLM6) was used to screen a male rat liver cDNA library in lambda gt 11. Six clones harbouring the RLM6 cDNA insert were isolated initially from the expression library and three of these were further plaque-purified and sub-cloned. A 1.1 Kb cDNA insert, representing approximately 65% of the expected full length cDNA was characterized by restriction endonuclease mapping and sequenced by the dideoxy chain-termination method. Comparison of the nucleotide sequence of RLM6 cDNA to that of ethanol-inducible P4502E1 rat cDNA showed the two cDNAs to be identical, the RLM6 cDNA corresponding to nucleotides 310-1402 of the P4502E1 sequence. 2. RLM6 cDNA probe was used in Northern blot and RNA dot blot hybridization analysis to demonstrate that both streptozotocin-induced diabetes and fasting significantly elevated the steady-state level of RLM6 mRNA in male rat liver. Increased RLM6 mRNA level in the diabetic rat resulted in increased RLM6 apoprotein synthesis when polysomal RNA was used in a cell-free, protein-synthesizing system, indicating that the elevated RLM6 level observed in diabetic rats was correlated directly with the increased RLM6 mRNA concentration. 3. Daily insulin treatment of diabetic rats reversed the diabetes-dependent increase in RLM6 mRNA in a time-dependent manner, returning to control values after approximately 2 weeks of continuous insulin treatment. This insulin-dependent decrease of the RLM6 mRNA level was paralleled by a similar time-dependent decrease in serum acetone concentration. 4. Treatment of the male diabetic rat with testosterone also resulted in a decrease in both RLM6 mRNA and in vitro translated apoprotein. 5. Modulation of RLM6 mRNA level in the diabetic rat by insulin and testosterone, and the nucleotide sequence similarity with that of P4502E1 confirms that diabetes-inducible P450RLM6 and ethanol-inducible P4502E1 are coded for by the same gene.


Bacterial metabolism of 2,6-dinitrotoluene with Salmonella typhimurium and mutagenicity of the metabolites of 2,6-dinitrotoluene and related compounds. 1. Metabolites produced by the incubation of 2,6-dinitrotoluene (2,6-DNT) with Salmonella typhimurium strains TA 98, TA 98/1,8-DNP6 and TA 98NR were examined. Mutagenicities of bacterial products and related compounds were also examined in the Ames assay using TA 98 and TA 100. 2. 2,6-DNT was converted to 2-nitroso-6-nitrotoluene, 2-hydroxylamino-6-nitrotoluene and 2-amino-6-nitrotoluene, with concurrent spontaneous formation of 2,2'-dimethyl-3,3'-dinitroazoxybenzene, in the incubation with TA 98 and TA 98/1,8-DNP6. Capacity of TA 98NR to reduce 2,6-DNT was much lower than that of TA 98 and TA 98/1,8-DNP6. 3. Bacterial products, including 2,2'-dimethyl-3,3'-dinitroazoxybenzene, showed no mutagenic activity in the Ames assay. 4. Results indicate that the lack of mutagenic activity of 2,6-DNT is not due to low reductive metabolism of 2,6-DNT by bacteria, but due to the lack of mutagenic activity of the bacterial reductive products of 2,6-DNT.


Bioanalytical applications of tandem mass spectrometry in the in vitro metabolism of the anticholinergic drug cimetropium bromide to detect differences in species metabolism. 1. In vitro metabolism of the anticholinergic drug, cimetropium bromide, was investigated using four different animal hepatic microsomal incubates derived from rat, hamster, guinea pig, and mouse livers. 2. Constant neutral loss (CNL) tandem mass spectrometry was used to detect the presence of the N-methylenecyclopropyl-scopine functionality by monitoring loss of 54 daltons (corresponding to loss of methylenecyclopropane) in microsomal incubates. 3. A CNL loss of 46 daltons was used to screen for the presence of ester hydrolysis products. 4. A comparison of the daughter ion spectra obtained on ions detected by CNL scanning, with daughter ion spectra of synthetic standards, determined the presence of ten metabolites of cimetropium bromide. 5. Hydroxylation of the aromatic ring in the ester side-chain was found to be the major metabolic pathway, and ester bond hydrolysis was a minor metabolic pathway. 6. N-Demethylation of the bridgehead nitrogen was observed only in rat and hamster incubates. 7. Using the method of CNL scanning it was possible to screen different animal microsomal incubates without resorting to any major purification procedures such as h.p.l.c. 8. This scanning method revealed differences between species in the metabolic pathways of cimetropium bromide.


Differences in the metabolism of the antitumour agents amsacrine and its derivative CI-921 in rat and mouse. 1. Rats and mice were treated with the antitumour agent CI-921 (I), and parent compound amsacrine, with all biliary metabolites being analysed. 2. In both rat and mouse the major biliary metabolites of amsacrine are the 5'- and 6'-glutathione (GSH) conjugates, with no C9-GSH conjugate being detected. 3. 5'- and 6'-GSH conjugates of I are also formed in both species. However, two additional products were detected and their structures confirmed by liquid secondary ion mass spectrometry and 1H-n.m.r. spectrometry, and by comparison with synthetic standards. 4. Additional metabolites of I are the C9-GSH conjugate and the 4-hydroxymethyl derivative which, either as the aglycone or glucuronide, is the predominant product in rat bile (comprising 56% of the dose eliminated over 3.5 h). 5. Relative amounts of the C9-GSH conjugate to the 5'- and 6'-GSH conjugates to the 4-hydroxymethyl derivatives, were 24:65:10 in mouse bile and 2:8:90 in rat bile. 6. These differences indicate first, likely enzyme involvement in the formation of the C9-GSH conjugate of I, and second, in comparison with amsacrine, alternative pathways which may decrease formation of the reactive quinone diimine intermediate of I and consequent hepatotoxicity.


Interspecies variations in caffeine metabolism related to cytochrome P4501A enzymes. 1. Interspecies (including man, monkey, rabbit, rat and mouse) variations in caffeine metabolism by liver microsomes were studied. While N-3 demethylation was the major pathway in man (81% of total dimethylxanthines), N-7 demethylation was predominant in monkey (89%), and the three demethylation pathways were about equal in mouse, rabbit and rat. 2. Three monooxygenase activities (methoxyresorufin O-demethylase, phenacetin O-deethylase and acetanilide 4-hydroxylase) correlated significantly with the rate of metabolism of caffeine. 3. P4501A1 and 1A2 enzymes were immunodetected in different species. P4501A2 was the only isoform detected in liver of man, rat and mouse, while no polypeptide immunorelated to P4501A was detected in monkey and only a minor band of P4501A1 was detected in rat and rabbit. 4. All in vitro data indicate that paraxanthine formation is mediated mainly by P4501A2 in mammals while theophylline formation is mediated mainly by cytochromes P-450 other than those of the 1A family.


Disposition and biotransformation of pentachlorophenol in the red abalone (Haliotis rufescens). 1. The disposition and biotransformation of pentachlorophenol (PCP) in the red abalone (Haliotis rufescens) have been determined. 2. In a flow-through system, three abalones were exposed to 1.2 mg/l of [U-14C]PCP for 5 h to determine bioconcentration and tissue distribution. Retained residues were quantified from radioactivity, while excreted residues were identified and quantified by h.p.l.c. and determination of radioactivity. 3. The 5-h total concentration factor ranged from 16.0 to 21.5; individual tissue concentrations ranged from 133.4 nmol/g in gill to 17.5 nmol/g in gonad. Due to its large size, the foot muscle received the largest amount of total retained residue (47.4%). 4. During a 13-h recovery period the abalones depurated 72.2% of retained residues; however, residue concentration in gonad increased over 100%. PCP was primarily excreted unchanged (89.3%), but small amounts of pentachloro-beta-D-glucoside (7.9%), pentachloroanisole (1.3%), pentachlorophenylsulphate (0.9%), and tetrachloro-p-hydroquinone (0.6%) were also formed.


Purification and molecular properties of 2-carboxybenzaldehyde (CBA) reductase from phenobarbital-treated rat liver. 1. A rat liver cytosol enzyme, tentatively named CBA reductase, catalyses the conversion of 2-carboxybenzaldehyde (CBA) to 2-hydroxymethyl benzoic acid in the presence of NADH (or NADPH). CBA reductase is useful for exploring the mechanism of in vitro enzyme induction, as the enzyme can be induced by phenobarbital (PB) both in vivo and in vitro. 2. Possible involvement of glutathione (GSH) in gene expression was suggested by a recent study with cultured rat hepatocytes. 3. CBA reductase was purified about 200-fold by a combination of column chromatography and isoelectric focusing in the presence of mercaptoethanol. 4. The ability to form 2-hydroxymethyl benzoic acid was lost when the enzyme was chromatographed on a hydroxylapatite column in the absence of mercaptoethanol; however, it was restored if sulphydryl compounds or bovine serum albumin was added to the eluate from the column. 5. Gel filtration showed the molecular sizes of CBA reductase from the 105,000g supernatant fraction of rat liver extracts and the purified preparation were 64 kDa and 49 kDa, respectively. 6. The results suggest that sulphydryl substances and some proteins play important roles in preserving the molecular and catalytic properties of CBA reductase.


Intestinal metabolism of mephentermine and its biliary metabolites in male Wistar rats. 1. Intestinal metabolites produced in the incubation (0-24 h) of mephentermine (MP), phentermine (Ph), N-hydroxymephentermine (N-hydroxy-MP), N-hydroxyphentermine (N-hydroxy-Ph), p-hydroxymephentermine (p-hydroxy-MP) and p-hydroxyphentermine (p-hydroxy-Ph) with male Wistar rat intestinal contents under N2 were examined by g.l.c. and g.l.c.-electron impact (EI) mass spectrometry. Metabolites produced in the anaerobic incubation of bile from rats given MP, with the intestinal contents were also examined. In addition, urinary and biliary metabolites of p-hydroxy-MP and p-hydroxy-Ph dosed orally to rat were examined. 2. Metabolites in the anaerobic incubation of N-hydroxy-MP and N-hydroxy-Ph were MP and Ph, and Ph, respectively. No metabolites were detected in the incubation of MP, Ph, p-hydroxy-MP and p-hydroxy-Ph. 3. p-Hydroxy-MP and p-hydroxy-Ph (major), and MP and Ph (minor) were detected when bile from rats given MP was incubated with intestinal contents. 4. Unchanged p-hydroxy-MP, and conjugates of p-hydroxy-MP and p-hydroxy-Ph, were detected in the 24-h urine of rats dosed with p-hydroxy-MP, which accounted for about 3, 72 and 1% dose, respectively. Unchanged p-hydroxy-Ph and conjugated p-hydroxy-Ph were detected in the 24-h urine of rats dosed with p-hydroxy-Ph, which accounted for about 4 and 68% dose, respectively. 5. Conjugated p-hydroxy-MP and conjugated p-hydroxy-Ph, which accounted for about 3% doses, were detected in the 24-h bile of rats dosed with p-hydroxy-MP and p-hydroxy-Ph.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man. 1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single i.v. and oral doses of dofetilide or 14C-dofetilide. 2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism. 3. Following i.v. administration, the volume of distribution showed only moderate variation in all species (2.8-6.3 l/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 h), whilst lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 h respectively). 4. After single i.v. doses of 14C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present. 5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide. 6. After oral and i.v. administration of 14C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for greater than 5% of plasma radioactivity.


Stereoselective inhibition of nortriptyline hydroxylation in man by quinidine. 1. Four volunteers phenotyped as extensive metabolizers of sparteine took 25 mg nortriptyline hydrochloride and collected urine for 72-80 h. Total free and conjugated 10-hydroxynortriptyline (10-OH-NT) accounted for 54-58% of the dose and it was reduced to 25-40% when 50 mg quinidine sulphate was ingested on the first and second day. 2. Of the four isomers of 10-OH-NT, (-)-E-10-OH-NT was selectively decreased in quantity by quinidine coadministration, while the (+)-isomer and (-)- and (+)-Z-10-OH-NT were found in unchanged or slightly increased quantities. The contribution of (-)-E-10-OH-NT to total E-10-OH-NT and the E-/Z-ratio in total 10-OH-NT were significantly reduced. 3. The quantity of the phenol, 2-hydroxynortriptyline in urine was decreased by quinidine; the relative amounts of metabolites with a primary amino group were not affected. 4. Liver microsomes from a donor in which cytochrome P450IID6 was shown to be present by in vitro phenotyping metabolized NT to E-10-OH-NT containing 86% of the (-)-isomer. Quinidine reduced the hydroxylation rate in (-)-E-10-position much more than that in (+)-E-10-position. 5. Since quinidine selectively impairs the function of cytochrome P450IID6, it is concluded that this isoform catalyses NT hydroxylation predominantly in (-)-E-10- and in 2-position.


Transgenic animals in the evaluation of compound efficacy and toxicity: will they be as useful as they are novel? 1. Construction of transgenic mice is predicated upon inserting foreign DNA into native host DNA and having this expressed in the germline. This may be accomplished by nuclear injection, retroviral vectors or use of embryonic stem (ES) cells. 2. Expression of novel structural genes may be reasonably directed by the judicious use of an accompanying promoter/enhancer sequence. Insertion of foreign genes may be designed to result in phenotypic expression of a novel trait or ablation of a native gene or gene product. 3. Resulting transgenic mice offer significant utility as models of human diseases and a unique opportunity for investigating immune and metabolic pathways as well as for exploring mechanisms of development, mutagenesis and teratogenesis. 4. Use of transgenic animals in drug development has considerable potential although realization of this potential will take time. Constructing transgenics is only the first step in a complex series of events culminating in understanding the consequences of imposing novel genetic material on an intact, highly integrated living system. Practical use of transgenic animals will depend upon substantial effort being spent in investigating and validating the phenotypic consequences of gene transfer.


Methylation pharmacogenetics: thiopurine methyltransferase as a model system. 1. Methyl conjugation is an important pathway in the biotransformation of many drugs and xenobiotic compounds. 'Pharmacogenetic' variation exists in the activities of many methyltransferase enzymes, and experiments with the drug-metabolizing enzyme thiopurine methyltransferase (TPMT) offer a model for one approach that has proven useful in the study of methyltransferase pharmacogenetics. 2. TPMT catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. This enzyme activity is present in the human red blood cell (RBC), and RBC TPMT activity is controlled by a common genetic polymorphism that regulates also the enzyme activity in all other human tissues that have been studied. 3. Subjects with inherited low levels of TPMT activity are at increased risk for thiopurine drug-induced myelotoxicity, while patients with high TPMT activities may be 'undertreated' with these drugs. 4. TPMT activity in tissue from selected strains of inbred mice also is regulated by a genetic polymorphism. These mice provide an animal model for use in the study of pharmacological or toxicological consequences of inherited differences in TPMT activity. 4. Other methyltransferase enzymes including thiol methyltransferase, catechol O-methyltransferase, and histamine N-methyltransferase also are present in the human RBC, are regulated by inheritance, and are responsible for individual variation in drug metabolism. Enhanced understanding of the pharmacogenetics of methylation may make it possible to understand and predict individual variation in the biotransformation, toxicity and therapeutic effect of compounds that undergo methyl conjugation.


Polymorphisms of N-acetyltransferase genes. 1. A genetic polymorphism of human liver arylamine N-acetyltransferase (NAT) enzyme activity leads to wide variation in the disposition of many drugs and potential carcinogens, resulting in differential susceptibility to chemical-induced toxicity. 2. During studies to determine the biochemical and molecular mechanisms underlying this pharmacogenetic defect, we cloned two human genes, NAT1 and NAT2, which encode the functional acetylating enzymes NAT1 and NAT2. 3. NAT1 and NAT2 are both expressed in human liver cytosol, the latter as two closely related isoforms NAT2A and NAT2B. 4. NAT2 gene locus is the site of the human acetylation polymorphism, because its products NAT2A and NAT2B selectively acetylate 'polymorphic' arylamine substrates (e.g. sulphamethazine), and since the liver content of these isozymes is markedly reduced in genetically slow acetylator subjects. 5. NAT1 shows marked kinetic selectivity for 'monomorphic' substrates (e.g. p-aminobenzoic acid) whose in vivo acetylation rates do not correlate with the acetylation polymorphism. 6. Despite the drastic reduction in NAT2A/B proteins in livers from phenotypically slow acetylators, levels of the NAT2 gene transcript are not altered. 7. Three common mutant alleles at the NAT2 gene locus have so far been identified, which may be detected by restriction fragment length polymorphism (RFLP) analysis on Southern blots or by allele-specific polymerase chain reaction amplification.


Polymorphism in stereoselective hydroxylations of mephenytoin and hexobarbital by Japanese liver samples in relation to cytochrome P-450 human-2 (IIC9). 1. Stereoselective 4'-hydroxylations of R-(--)-mephenytoin and S-(+)-mephenytoin were determined in liver microsomes of 19 Japanese subjects. 2. The content of P-450 human-2 assessed by Western-blots correlated with microsomal S-(+)-mephenytoin 4'-hydroxylation. Antibody raised against P-450 human-2 effectively inhibited microsomal S-(+)-mephenytoin 4'-hydroxylation, but was less efficient for inhibition of R-(--)-mephenytoin 4'-hydroxylation in extensive metabolizers, and 4'-hydroxylation of both mephenytoin enantiomers in poor metabolizers. 3. Similar results were observed on the stereoselective hydroxylations of R-(--)- and S-(+)-hexobarbital. Clear correlations were observed for the content of P-450 human-2 and microsomal R-(--)-hexobarbital 3'alpha-hydroxylation and S-(+)-hexobarbital 3'beta-hydroxylation. 4. Moreover, yeast microsomes expressing P-450 human-2 cDNA showed high stereoselectivities for hydroxylations of mephenytoin and hexobarbital similar to those observed in human liver. 5. Two other cytochromes P-450(IIC 9/10) expressed in yeast, whose cDNA were synthesized by site-directed mutagenesis from human-2 cDNA, showed no stereoselectivity for the hydroxylations of mephenytoin and hexobarbital, in spite of the modification of only two amino acid substitutions or deletions in the whole sequence. 6. Only a cytochrome derived from P-450 human cDNA corresponding to P-450 human-2 was expressed in human livers, the two cytochromes of the three related IIC9/10 forms were not expressed. 7. These findings indicate that P-450 human-2 is the major cytochrome P-450 responsible for the polymorphisms in stereoselective hydroxylations of mephenytoin and hexobarbital.


Applications of stable V79-derived cell lines expressing rat cytochromes P4501A1, 1A2, and 2B1. 1. Chinese hamster V79-derived cell lines, stably expressing cytochromes P4501A1, 1A2, and 2B1 activities, were constructed by genetic engineering in continuation of our work to establish a battery of V79 derived cell lines designed to study the metabolism of xenobiotics. 2. Cell lines XEM1 and XEM2, expressing cytochrome P4501A1, were capable of the O-dealkylation of 7-ethoxycoumarin and the hydroxylation of benzo[a]pyrene. 3. Cell lines XEMd.MZ and XEMd.NH, expressing P4501A2, were shown to hydroxylate 17 beta-estradiol and 2-aminofluorene. 4. Cell line SD1, expressing cytochrome P4502B1, was able to hydroxylate testosterone stereo- and regio-specifically at the 16 alpha and 16 beta positions. 5. Cell lines were validated in mutagenicity, cytotoxicity, and metabolism studies employing benzo[a]pyrene, trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, cyclophosphamide, ifosfamide, and picene. 6. Construction of metabolically-competent V79-derived cell lines be recombinant DNA technology will be a fundamental improvement for the evaluation of the cytotoxic, genotoxic and pharmacological properties of a chemical.


Co-induction of cytochrome P4504A1 and peroxisome proliferation: a causal or casual relationship? 1. The hypothesis that xenobiotic induction of hepatic microsomal cytochrome P4504A1 and peroxisome proliferation are closely-related phenomena has been further investigated. 2. Five rat strains (Gunn, Fischer, Wistar, Long Evans and Sprague Dawley) were all susceptible to xenobiotic induction of both microsomal cytochrome P4504A1 and peroxisome proliferation, and no strain exhibited a dissociation of these phenomena. 3. In comparison to rat, the marmoset was substantially less susceptible to the above hepatic changes. 4. Induction of both cytochrome P4504A1 and peroxisome proliferation by a structural analogue of clofibrate (2-(4-(4-chlorophenyl)benzyloxy)-2-phenyl acetic acid) demonstrated stereochemical selectivity, in that the R(-)-isomer was a more potent inducer of both phenomena than the S(+)-antipode, with the racemic mixture exhibiting an intermediate potency. 5. Cycloheximide inhibition of clofibrate-dependent induction of acyl CoA mRNA, but not cytochrome P4504A1 mRNA has indicated a protein dependency for peroxisome proliferation, not inconsistent with participation of cytochrome P4504A1 in the biogenesis of peroxisome proliferation. 6. Taken collectively, the data described herein provide further evidence for a close linkage between xenobiotic induction of cytochrome P4504A1 and peroxisome proliferation, and possible molecular mechanisms inter-relating these two phenomena are discussed.


Multiple mechanisms in hepatic microsomal azoreduction. 1. Microsomal reduction of azo dyes related to dimethylaminoazobenzene (DAB) is catalysed by at least two types of cytochrome P-450. The first is selectively induced by clofibrate. The second is induced by phenobarbital, beta-naphthoflavone, isosafrole, and pregnenolone-16 alpha-carbonitrile, as well as clofibrate. 2. Azoreduction by the first type of P-450 is insensitive to both O2 and CO and involves dyes with only electron-donating substituents (I substrates). 3. Azoreduction by the second type of P-450 is inhibited by both O2 and CO and involves dyes with electron-withdrawing as well as donating substituents (S substrates). 4. All azo dye substrates exhibit two negative and one positive redox potential, as measured anaerobically by cyclic voltammetry. The negative potentials reflect one- and two-electron reductions while the positive potential permits electron transfer from microsomal P-450, the redox potential for which is reported to be negative (approximately 0.35 V). The positive potential is associated with a polar electron-donating group para to the azo linkage, which is an absolute requirement for microsomal reduction. Dyes without this functional group do not exhibit positive potentials and are not reduced. 5. The first negative potential of S substrates is quenched upon admitting air to the system, whereas this potential is unaffected in I substrates. The relative stability of the one-electron reduced state may be an explanation for the differential O2 sensitivity of I and S substrate reduction.


Glutathione-dependent toxicity.

Glutathione-dependent toxicity. 1. Recent studies show that glutathione conjugate formation is an important bioactivation mechanism for several groups of compounds with implications for organ-selective toxicity and carcinogenicity. 2. Vicinal dihaloalkanes, such as 1,2-dihaloethanes, yield S-(2-haloalkyl)glutathione conjugates that give rise to highly electrophilic episulphonium ions, which are involved in the cytotoxicity and mutagenicity of 1,2-dihaloethanes. 3. Nephrotoxic haloalkenes are metabolized to S-(haloalkenyl)- or S-(haloalkyl)-glutathione conjugates which, after metabolism to the corresponding cysteine conjugates, are bioactivated by renal cysteine conjugate beta-lyase to yield cytotoxic or mutagenic metabolites. 4. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.


The role of the flavin-containing monooxygenase (EC 1.14.13.8) in the metabolism and mode of action of agricultural chemicals. 1. The flavin-containing monooxygenase (FMO) (EC 1.14.13.8) is a versatile enzyme that catalyses the monooxygenation of a large number of xenobiotic soft nucleophiles ranging from inorganic ions to organic compounds with nitrogen, sulphur, phosphorus or selenium heteroatoms. 2. The substrate specificity relative to agricultural chemicals is discussed and compared with that of the cytochrome P-450-dependent monooxygenase system. The relative activity of these two enzymes towards common substrates varies from substrate to substrate and from tissue to tissue as is shown in the case of the insecticide, phorate and the hepatotoxicant, thiobenzamide. 3. The products of FMO action may be chemically different (e.g. nicotine) to those from P-450, or the two enzymes may produce different isomers of the same product (e.g. phorate). 4. Recent studies have demonstrated that, in the rabbit, the FMOs from liver and lung are different gene products which differ not only in primary sequence but also in physical, catalytic and immunochemical properties. These studies are being extended to include other tissues such as skin and brain. 5. Immunocytochemical localization of FMO in lung and skin correlates well with measurements of the oxidation of methimazole, a specific FMO substrate.


Deuterium isotope effect on the metabolism of N-nitrosodimethylamine and related compounds by cytochrome P4502E1. 1. Deuteration of N-nitrosodimethylamine (NDMA) decreases its carcinogenicity, and produces an isotope effect on its metabolism in vivo. Consistent with these results are the observations that deuteration caused a 5-fold increase in the apparent Km, but not the Vmax for the demethylation and denitrozation of NDMA in acetone-induced rat liver microsomes. These microsomes are a good source of cytochrome P4502E1. 2. For demethylation of Z-[2H3]NDMA and E-[2H3]NDMA, the Km values were indistinguishable, and were between the values for those of NDMA and [2H6]NDMA. Almost all the formaldehyde formed was derived from the non-deuterated methyl group, indicating a lack of stereoselectivity in the demethylation of NDMA. 3. NDMA and [2H6]NDMA displayed apparent Ki values of 59 and 441 microM, respectively, for N-nitrosodiethylamine deethylase, showing an apparent isotope effect of 0.13, and displayed an isotope effect of 0.21 in the Ki values for p-nitrophenol hydroxylase. 4. With acetone and deuterated acetone as inhibitors for p-nitrophenol hydroxylase, the isotope effect on the Ki was 0.11. Similar deuterium isotope effects were also observed with acetone and dimethylformamide as competitive inhibitors for NDMA demethylase. 5. In the microsomal oxidation of ethanol, a deuterium isotope effect of about five was observed in the Vmax/Km when carbon-1 was deuterated, but was not observed in the Vmax. 6. Results illustrate a unique deuterium isotope effect on the Km values of reactions catalysed by P4502E1.


Metabolic activation of 1-nitropyrene to a mammalian cell mutagen and a carcinogen. 1. The mutagenicity of 1-nitropyrene metabolites in Chinese hamster ovary (CHO) cells, in the absence of rat liver S9, decreased in the order 6-hydroxy-1-nitropyrene > 1-nitropyrene 9,10-oxide > 1-nitropyrene 4,5-oxide approximately 3-hydroxy-1-nitropyrene approximately 8-hydroxy-1-nitropyrene > 1-nitropyrene. The order of mutagenicity with rat liver S9 was 1-nitropyrene 4,5-oxide approximately 6-hydroxy-1-nitropyrene approximately 1-nitropyrene 9,10-oxide > 3-hydroxy-1-nitropyrene approximately 1-nitropyrene > 8-hydroxy-1-nitropyrene. 2. 1-Nitropyrene 4,5-oxide reacted with calf thymus DNA to give one or several closely related adducts. The same adducts were detected in CHO cells incubated with 1-nitropyrene 4,5-oxide. Inclusion of a nitroreductase, xanthine oxidase, in the incubations with calf thymus DNA resulted in the formation of an additional adduct identified as N-(deoxyguanosin-8-yl)-1-aminopyrene (dG-C8-AP). 3. 1-Nitropyrene 9,10-oxide reacted with calf thymus DNA to give an adduct pattern similar to that observed with 1-nitropyrene 4,5-oxide. Incubation of 1-nitropyrene 9,10-oxide with CHO cells resulted in the formation of the same adducts along with dG-C8-AP. 4. dG-C8-AP and N-(deoxyguanosin-8-yl)-1-amino-x-nitropyrene (x = 3, 6 or 8; dG-C8-ANP) were detected in injection site DNA from Sprague-Dawley rats treated with 1-nitropyrene. In mammary gland DNA, dG-C8-AP and an unidentified adduct were found. dG-C8-ANP was the only DNA adduct detected in the livers of newborn CD-1 mice and the lungs of A/J mice dosed with 1-nitropyrene.


Investigations of mechanisms of reactive metabolite formation from (R)-(+)-pulegone. 1. (R)-(+)-Pulegone is a monoterpene that is oxidized by cytochromes P-450 to reactive metabolites that initiate events in the pathogenesis of hepatotoxicity in mice, rats and humans. 2. Selective labelling of (R)-(+)-pulegone with deuterium revealed that menthofuran was a proximate hepatotoxic metabolite formed by oxidation of the allylic methyl groups of pulegone. Incubations of pulegone with mouse liver microsomes in an atmosphere of 18O2 resulted in the formation of menthofuran that contained only oxygen-18 in the furan moiety. These results are consistent with oxidation of pulegone to an allylic alcohol that reacts intramolecularly with the ketone moiety to form a hemiketal that subsequently dehydrates to generate menthofuran. 3. Studies on the metabolism of menthofuran revealed that it is oxidized by cytochromes P-450 to an electrophilic gamma-ketoenal that reacts with nucleophilic groups on proteins to form covalent adducts. In addition, diastereomeric mintlactones are formed. Investigations with H2(18)O and 18O2 are indicative of a furan epoxide intermediate, or a precursor, in the formation of the gamma-ketoenal and mintlactones.


Metabolic considerations in pyrethroid design. 1. Synthetic pyrethroids, based on the naturally-occurring insecticidal components of pyrethrum extract, emerged in the 1970s as the fourth major chemical class of synthetic insecticides. They are widely used today in the control of agriculture and household pests and disease vectors. 2. Early efforts in the design of synthetic analogues focused on the need to identify novel structural moieties that preserved or enhanced intrinsic insecticidal activity while eliminating known sites of metabolic and photolytic attack in the natural compounds. Subsequent efforts focused on achieving high levels of insecticidal activity while minimizing costs of synthesis and retaining desirable levels of selective toxicity. 3. The synthetic compounds obtained in these efforts constitute a group of insecticides having unprecedented biological activity against target species with low acute toxicity to mammals. 4. The evolutionary development of the pyrethroids illustrates how knowledge of metabolic fate can contribute to the design of novel insecticides with improved insecticidal activity and selective toxicity.


High-performance tandem mass spectrometry in metabolism studies. 1. High-performance tandem mass spectrometry provides unit resolution in both selection of precursor ions and analysis of fragment ions, and extensive and reproducible fragmentation through collisional activation at high energy. 2. Metabolites can be analysed that occur as minor components in h.p.l.c. peaks or other mixtures. Homogeneous isotopic species can be selected for unambiguous analysis of distributions of isotope labels. Fragmentation may be significantly enhanced to provide structural information. Overall, the signal to noise ratio is greatly improved and the spectrum is simplified. 3. These points are illustrated by isotope-labelling studies of the mechanisms of glutathione conjugation of the anti-tumour agent cyclophosphamide, the cytotoxic agent phosphoramide mustard and dimethylbilirubin, an analogue of bilirubin designed to be distinguishable from endogenous bilirubin. Analysis of isomeric mixed disulphides formed between glutathione and a peptide with an internal disulphide bond is discussed. 4. Reaction-induced decomposition is presented as an alternative to collisionally induced decomposition with more efficient energy transfer.


The use of stable isotopes to identify reactive metabolites and target macromolecules associated with toxicities of halogenated hydrocarbon compounds. 1. Halogenated compounds, such as the inhalation anaesthetics, halothane and enflurane, and the chemicals chloroform, carbon tetrachloride, and bromotrichloromethane can cause hepatotoxicity, nephrotoxicity, and inactivation of cytochromes P-450. Each of these toxicities is mediated by reactive metabolites. 2. Stable isotopes of hydrogen, carbon, chlorine and oxygen have been used in conjunction with mass spectrometry and n.m.r. spectrometry to identify the structures of these metabolites, to elucidate the mechanisms of their formation, and to characterize the structures of their macromolecular adducts. 3. In a number of cases, oxidative pathways of metabolism to toxic metabolites have been defined by kinetic deuterium isotope effects. 4. Recently, we have found that the trichloromethyl radical metabolite of bromotrichloromethane can activate myoglobin by causing the covalent cross-linking of haem to protein. The structure of a haem-myoglobin adduct has been defined by the use of stable isotope studies.


Bioanalytical data in decision making: discovery and development. 1. Bioanalysis is traditionally associated with the development phase of drugs; its use in discovery programmes is often ignored but can have a major impact. 2. Pharmacokinetic studies conducted in conjunction with pharmacology screening can provide additional information to that considered in conventional structure activity relationships. Such factors as half-life and bioavailability can be critical in designing improved drugs. 3. Analytical methods in discovery programmes may differ from those used in later development work: for instance bioassay allows a common assay system for a large number of project compounds. Moreover its use, when combined with conventional methods, such as h.p.l.c., allows active metabolites to be readily detected. 4. Bioanalytical data generated in discovery and pre-clinical programmes are a valuable guide to early clinical programmes. Plasma concentration-response data from these programmes can be compared with those obtained in man. Such comparisons are particularly valuable during the phase one-initial dose escalation study. To maximize this it is our practice to generate pharmacokinetic data between each dose increase.


Citrinin.

Citrinin. Citrinin, a nephrotoxic mycotoxin, has been of growing importance also for the "International Agency for Research on Cancer", ever since its presumable role in the occurrence of Balcan endemic nephropathy (BEN) was discussed at the congress on "Mycotoxins, Endemic Nepthropathy and Urinary Tract Tumours" held in Lyon in June 1991 (12). In late 1991, citrinin was therefore also included in the list of toxins to be examined by the screening subcommittees on natural toxins of the International Live Science Institute, European Branch.


[Energy balance in repeated under- and overnutrition in model studies in sows]. In a model experiment eight adult sows were used to examine the effect of successive periods of under- and oversupply of energy (MUMU) on thermogenesis and efficiency of energy utilization in comparison to a constant maintenance supply (NNNN). Each treatment sequence was assigned to each animal according to a change-over design over 8 weeks. Before and after the treatment periods all the animals were fed at maintenance level (N). Energy deficiency (M) was performed by use of a basal diet with 45% of maintenance energy requirements and values for all the other nutrients sufficient for requirements. Normal (N) and excessive (U) intakes of energy was provided with supplements of starch. The total inake of gross energy during the periods MUMU was exactly the same as during NNNN. Complete energy balances were performed for each animal and period as well as during the pre- and post-experimental phase. There was no or little response of altered energy intake on carbon and energy excretion in faeces, urine and methane. However, heat production was significantly decreased by 4.1% on energy deficiency, and increased by 15.1% during energy oversupply. Summed up over the total sequence the animals produced 5.4% more heat on MUMU than during NNNN. This response was associated with a mobilization of 1.1 MJ/d tissue energy and a decrease in body weight by 2.0 kg. The efficiency of utilization of ME was 88% with energy undersupply and 75% during overnutrition. Criteria of energy balance did not differ between the pre- and post-treatment periods. It could be demonstrated that the increase in energy expenditure at oversupply was entirely explainable by the so-called obligatory thermogenesis. At the energy deficiency periods the efficiency of energy utilization reflected both energy costs of ingestion and processing of nutrients as well as a slight reduction in metabolic rate. Finally, there were no residual effects of the treatment on the energy expenditure of the animals at the end of the experiment.


[The nutrition situation of the population in the former East Germany: results of household budget surveys in 1989]. The last representative nutritional surveys in households of the former GDR date back to 1989. Trends towards excessive energy intake have continued, resulting, above all, from high fat consumption. A considerable proportion of employed persons have their meals outside the home. The proportion of food used as animal feed was high in households of members of agricultural cooperatives.


[Intake of trans-isomeric fatty acids--an evaluation on the basis of data of the national consumption study in 1991]. The intake of trans octadecenoic acids is estimated by a national consumption assay. The daily intake in West Germany differs between 3.4 g for women and 4.1 g for men. The consumption of trans fatty acids decreased in the last years, due to the progress in food technology and changes in nutritional habits. The main sources of trans fatty acids are partially hydrogenated vegetable fats just as well as ruminant and dairy fats.


[Common attitudes about the effect of positive and negative mood on task related motivation]. Several theories on emotion and mood have stressed the close relationship between emotion and motivation. However, assumptions on mood contingent motivations have mainly been studied in the field of social behavior, and there are only few studies concerned with mood contingent task motivations, an area in which nit is possible to distinguish between two motivational sets, the deliberative and the implemented mind set. Assuming that positive mood is associated with a stronger task-oriented deliberative mind set, and that negative mood is associated with a stronger self-oriented deliberative mind set, and that implemented mind set should be intrinsically task-oriented during positive mood and instrumentally task-oriented during negative mood. The present paper is concerned with these assumptions from a subjective perspective: The respondents were asked about their lay perceptions of mood influences (positive, elated versus negative, sad mood) on task related motivations. In study I the respondents (N = 40) were asked about their deliberative mind sets during positive versus negative mood and about their general perceptions of mood influences on performance. In study II the respondents (N = 58) were requested to imagine situations which elicit positive, negative or neutral mood, and then to answer questions on deliberative and implemented mind sets during these states; they also hat to answer a general question about mood influences on task performance. Both quantitative and qualitative measures are used in these studies. The findings support the above general notions, and they additionally show that in the respondents' opinions negative mood effects are more variable than positive mood effects; further, that there are quite a few individual differences in assumed mood effects on task-related motivation.


[Slow alpha in the EEG power spectrum as an indicator for conceptual arousal]. Based on previous findings (Bösel et al., 1990) it was assumed that in concept learning tasks generating on hypotheses on a concept which has to be developed is accompanied by increases of the Alpha 1 power (7.5-10 Hz) in the spontaneous EEG activity. In this study 16 subjects performed five problem solving tasks with similar processing requirements. EEG data were analyzed by means of post hoc comparisons of subjects differing in performance quality. Additionally, four control tasks were employed in which, based on previous studies, variations in the Theta frequency range were expected. An effect in the Alpha 1 frequency band was observed in tasks requiring reconstructive recall or testing the usefulness of an mathematical algorithm. The creation of a rank order or mental map is accompanied by power increases in the lower portions of the Alpha 1 frequency band (7.5-8.5 Hz). Moreover a high amount of controlled variance (eta2 up to 34%) was obtained for this effect. Increases in EEG Theta power, which presumably indicate subjects' component analysis, were found before the subjects recognized parts of geometric figures or before relevant features in the "buddhist monk problem" were discriminated. The dynamics of EEG power over time is in examples of frequency/time plots in a figure, illustrated.


[The correlation between coping with stress and blood pressure reaction]. This study explored the relationship between individual strategies of coping and blood pressure responses during and after mental stress. Blood pressure behavior was measured noninvasively and continuously before, during and after a mental stress situation in 27 normotensive subjects. Coping strategies were assessed with the Stressverarbeitungsfragebogen (SVF; coping with stress inventory). Two extreme groups were formed on the basis of the scores in the SVF. Results were: (a) Individuals who used coping strategies characterized by controlling the situation directly and constructively, in contrast to probands not using these strategies, exhibited lower blood pressure during the stress situation and a faster return to baseline levels after cessation of stress. (b) Subjects using a coping behavior characterized by the use of defense mechanisms such as suppression and denial, also showed lower blood pressure during stress but a significantly delayed return to baseline levels of blood pressure after stress was concluded.


[EMG reactions of mimetic muscles after repeated presentation of pictures with positive, negative and neutral content]. Twenty male subjects (Ss) were repeatedly confronted for five seconds to pictures with positive, negative and neutral valence. During the picture presentation facial EMG-reactions of five mimic muscles (m. frontalis lateralis, m. corrugator supercilii, m. orbicularis oculi, m. zygomaticus major on the right and left side of the face) were recorded. In addition, heart rate was measured. It could be shown that during repeated presentation of pictures with positive valence the m. orbicularis oculi and the m. zygomaticus major on both sides of the face yielded enhanced average EMG-reactions as compared to the repeated presentation of pictures with negative and neutral valence. During presentation of pictures with negative valence the m. frontalis lateralis and the m. corrugator supercilii revealed enhanced EMG-reactions as compared to the repeated presentation of pictures with positive valence. Furthermore, it could be shown that during the repeated presentation of pictures with positive valence those facial muscles which mainly react during confrontation with pictures of positive valence showed a continuous decrease of EMG-activity. Facial muscles which mainly react during the presentation of pictures with negative valence do not show a continuous decrease in EMG-activity during the course of the repeated presentation of pictures with negative valence. Additionally, the EMG-activity of the m. zygomaticus major on the right and lift side of the face do not differ with respect to the mean activity and the time course during confrontation of pictures with positive valence. The m. orbicularis oculi yielded enhanced EMG-reactions during the presentation of pictures with positive valence as compared to both m. zygomaticus major muscles. The present results are discussed with respect to psychobiological theories concerning facial expression.


[Change in the event-related skin conductivity: an indicator of the immediate importance of elaborate information processing?]. In recent psychophysiological conceptualizations of the orienting response (OR) within the framework of information processing, the OR is increasingly considered a "call for processing resources", something which is especially inferred from variations in the event-related skin conductance response (SCR). The present study, therefore, was concerned with certain implications arising from this framework or perspective, particularly in regard to the question of whether stimuli eliciting skin conductance responses obligatorily receive/evoke processing priority or not. In order to examine whether these electrodermal responses denote a capturing of attention or merely a call for processing resources, short (1 s) pure sine tones of 65 dB with sudden onset (commonly used as orienting stimuli) were inserted in a reaction time paradigm with an additional memory load. This demand was primarily given because memory processes play a key role in theories of orienting and habituation. The task was run under two different conditions of complexity, factorially combined with a novelty variation of the added auditory stimuli. The results revealed a substantial deterioration of task performance subsequent to the occurrence of the tones, which, however, was dependent on task complexity and on novelty of the tones. The task impairment is particularly remarkable as subjects were asked to avoid distractions by paying attention to the task and as the tones were introduced as subsidiary and task-irrelevant. Together with the missing effects of task complexity on phasic and tonic electrodermal activity, results suggest that information-processing conceptualizations of the OR can only be a meaningful heuristic contribution to theoretical developments about human orienting and its habituation if the setting of processing priority, its conditions, as well as its implications are adequately taken into account. In addition, it seems to be promising to consider the strength of the SCR as an index of urgency of elaborate, attention-demanding processing and not as a peripheral physiological manifestation of the OR, or, respectively, of a call for unspecific processing resources. Such a view would also do justice to the aspect of prioritization. The sufficient conditions for an OR's occurrence could, in this context, be equated with, among others, some of those which activate a mechanism subserving selective attention and, as a possible result, which lead to further and more elaborate processing of potentially important information.


[Gene technology in production of modern drugs]. In the last years gene technology has influenced dramatically medical and biological disciplines. With the help of molecular biology it is possible to produce a variety of proteins in alternative ways. Further, substances can be produced which exist in nature only in trace amounts, and therefore can not be produced with conventional methods. However, there is no other scientific discipline which is discussed so controversially in public like genetic engineering. The "new" biology comprises a multitude of disciplines which are difficult to understand for non experts. Unfortunately, gene technology has become the new symbol for "uncontrolled" technology development. In this review article the basic concepts of genetic engineering will be explained. Further, the production of some recombinant drugs, which are already used in practice, will be demonstrated. Finally, some safety aspects concerning about risk assessment are discussed.


[Therapy of acute lung failure with nifedipine. A study with interventional analysis]. In 24 patients with severe ARDS after major gastro-intestinal surgery the effect of the calcium antagonist nifedipine on pulmonary function was investigated. Besides descriptive statistics and comparison between group means, intervention analysis was employed to assess the treatment effect for the individual patient. The treatment effect could always be assessed after 12 hours. 14 out of 15 patients with initially high PVR showed a significant decrease of PVR followed by an improvement of AaDO2. 8 out of 9 patients with initially normal PVR did not improve in pulmonary function as no significant changes in PVR occurred. No unwanted side-effects on cardio-vascular function (MAP, CI, LVSWI, RVSWI) could be observed. 9 out of 24 patients decreased. Lethality among patients who showed a significant decrease of PVR under nifedipine infusion was 3 out of 15, whereas 5 out of 9 patients died without changes in PVR. Thus nifedipine can improve pulmonary function in ARDS. Especially in the early stages of ARDS with elevated PVR the administration of nifedipine p.i. appears advantageous.