Author Correction: Micronuclei in germ cells of hybrid frogs from Pelophylax esculentus complex contain gradually eliminated chromosomes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Micronuclei in germ cells of hybrid frogs from Pelophylax esculentus complex contain gradually eliminated chromosomes.

In most organisms, cells typically maintain genome integrity, as radical genome reorganization leads to dramatic consequences. However, certain organisms, ranging from unicellular ciliates to vertebrates, are able to selectively eliminate specific parts of their genome during certain stages of development. Moreover, partial or complete elimination of one of the parental genomes occurs in interspecies hybrids reproducing asexually. Although several examples of this phenomenon are known, the molecular and cellular processes involved in selective elimination of genetic material remain largely undescribed for the majority of such organisms. Here, we elucidate the process of selective genome elimination in water frog hybrids from the Pelophylax esculentus complex reproducing through hybridogenesis. Specifically, in the gonads of diploid and triploid hybrids, but not those of the parental species, we revealed micronuclei in the cytoplasm of germ cells. In each micronucleus, only one centromere was detected with antibodies against kinetochore proteins, suggesting that each micronucleus comprises a single chromosome. Using 3D-FISH with species-specific centromeric probe, we determined the role of micronuclei in selective genome elimination. We found that in triploid LLR hybrids, micronuclei preferentially contain P. ridibundus chromosomes, while in diploid hybrids, micronuclei preferentially contain P. lessonae chromosomes. The number of centromere signals in the nuclei suggested that germ cells were aneuploid until they eliminate the whole chromosomal set of one of the parental species. Furthermore, in diploid hybrids, misaligned P. lessonae chromosomes were observed during the metaphase stage of germ cells division, suggesting their possible elimination due to the inability to attach to the spindle and segregate properly. Additionally, we described gonocytes with an increased number of P. ridibundus centromeres, indicating duplication of the genetic material. We conclude that selective genome elimination from germ cells of diploid and triploid hybrids occurs via the gradual elimination of individual chromosomes of one of the parental genomes, which are enclosed within micronuclei.

Metabolism of cardiac glycosides studied in the isolated perfused guinea-pig liver.

1. Metabolic degradation of tritiated ouabain, digoxin, and digitoxin has been investigated quantitatively using the isolated perfused guinea-pig liver. The cardiac glycosides and their metabolites have been extracted from the plasma, liver, and bile by different solvents and identified as far as possible by radio-chromatographic analysis.2. The total metabolic activity in the experimental system was localized in the liver.3. The hydrophilic glycoside ouabain could not penetrate into the metabolically active compartment of the liver and was, therefore, not degraded. The more lipophilic compound digitoxin, however, was completely degraded due to its high affinity for the metabolically active sites. The unchanged digitoxin cannot enter the aqueous bile fluid in contrast to its more hydrophilic metabolites.4. The only detectable metabolic degradation of digoxin was a conjugation with glucuronic and/or sulphuric acid, but a cleavage of sugar molecules seemed not to occur.5. In the case of digitoxin the metabolic processes are more complicated: sugar cleavage, conjugation, and C-12 hydroxylation take place simultaneously. An immediate hydroxylation of digitoxin leading to digoxin was not observed. After administration of digitoxin conjugation products as well as digoxigenin-bis-and digoxigenin-mono-digitoxosides were present in each of the compartments investigated, but the digitoxosides of digitoxigenin were intermediates in concentrations too low to be determined indicating a very high rate of conjugation and/or C-12 hydroxylation as compared with the cleavage of the digitoxoses.6. A scheme for the metabolic pathways of the cardiac glycosides based on experimental results is presented. The metabolic behaviour of each of the three compounds involved is closely related to their physicochemical properties, especially the lipid solubility.

Plasma concentration, uptake by liver, and biliary excretion of tritiated cardiac glycosides in the isolated perfused guinea-pig liver.

1. Investigations were carried out on isolated perfused guinea-pig livers. Different doses of tritiated ouabain, digoxin, and digitoxin were added to the perfusion medium and the subsequent plasma elimination, hepatic uptake, and biliary excretion quantitatively measured. After the perfusion, extracts of liver, bile and plasma were subjected to thin layer chromatography in order to detect the radioactively labelled glycosides and their metabolites.2. The ouabain concentration in the plasma approached the equilibrium stage within 45 minutes. At this time 40% of the administered dose had been taken up by the liver, and no further elimination occurred. The elimination curve for ouabain followed a simple exponential function. After 1 h the tissue medium (T/M) ratio was approximately 3. In bile hardly any radioactivity could be detected. Ouabain was therefore not excreted by the liver.3. Up to 80% of the digitoxin was eliminated from the plasma within 4 hours. The elimination of radioactive material for the dose range studied could be described by a hyperbolic function. The T/M ratio in the liver varied with time. At the beginning it was as high as 10 and after 4 h reduced to approximately 3. After 45-60 min the concentration of radioactive material in the bile was 500 times as high as that in the plasma. Almost 70% of the administered radioactivity was excreted with the bile within 4 hours. At the end of the perfusion almost all the identifiable substances in plasma and bile were polar metabolites, as shown by thin layer radiochromatography.4. Digoxin behaved similarly to digitoxin.5. The findings led to the following hypothesis: uptake of cardiac glycosides into the liver cells occurs by a passive diffusion process and is related to their lipid solubility. On the other hand excretion in the bile occurs in general if polar metabolites are formed in the liver cells.

Return to work after myocardial infarction/coronary artery bypass grafting: patients' and physicians' initial viewpoints and outcome 12 months later.

Nonmedical factors play an important role in determining whether patients resume their work after myocardial infarction or CABG. The main questions dealt with in this study are: What is the respective basis of physicians' and patients' judgements as far as vocational disabilities are concerned, and what are the decisive factors that facilitate a prediction as to who will return to work and who will not? 132 male patients participating in a cardiac rehabilitation program served as subjects. The age group was limited to patients between 40 and 59 yr of age. The work situation 12 months following rehabilitation is known for 119 subjects; 74 had resumed their occupations. Results of regression analyses show that patients' and physicians' views on disabilities and re-employment are based on different factors. The physicians derive their estimates mainly from medical variables (cardiac status and comorbidity), whereas the patients' views are based on the overall health status, their former job status, job satisfaction, and negative incentives for the return to work. Three variables were found that allow a prediction to be made as to re-employment in 85% of all cases: (1) age, (2) patients' feelings about the extent to which they are disabled by their cardiac problem, and (3) the physicians' views on the extent to which the patient is vocationally disabled by his overall medical situation. Medical variables (e.g. cardiac status) had little relevance to re-employment. The results are discussed with regard to the consequences for cardiac rehabilitation.

[Rehabilitation, social medical evaluation and counselling in HIV-infected patients]. / Rehabilitation, sozialmedizinische Beurteilung und Beratung bei HIV-infizierten Patienten.

An inpatient rehabilitation programme for HIV-infected patients is described. Since the early nineties some 1,200 patients with HIV infection have been treated in our internal and orthopaedic rehabilitation clinic. Beside internal and orthopaedic diagnostics, supporting compliance with antiretroviral therapy, motivating the patients for regular moderate exercises and specific nutritional counselling are major issues of the programme. From the psychological point of view, the patients are offered to aquire relaxation and stress coping techniques, to take part in non-smoking courses and to use individual psychological counselling in case of depression or panic. In addition, all HIV-infected patients are offered individual advice on their disease and necessary changes in lifestyle. Finally, the programme includes social medical evaluation and counselling. As the majority of the patients are still working or are of working age, evaluating the capacity for work and potential introduction of occupational rehabilitation measures are prominent. Almost 70 percent of the HIV-infected patients who had been treated in our clinic over the last few years were fully capable of returning to their previous occupation. Our experiences demonstrate that statements such as rehabilitation of AIDS patients being useless because of its missing prospects of success, are not up-to-date any longer. Since introduction of combination antiretroviral therapy many patients with HIV infection are able to return to their previous occupation if they receive the necessary medical und psychosocial support.

[Interaction between alcohol and drugs (author's transl)]. / Wechselwirkungen zwischen Arzneimitteln und Alkohol

The interaction of ethanol with drugs becomes more and more important because of a constant increase of the consumption of both. While most of the commonly used drugs do not alter the elimination of alcohol there exist a number of drugs which influence the degradation of ethanol by inhibition of the acetaldehyddehydrogenase. In combination with alcohol these drugs lead to an antabus-like reaction. In respect to the influence of ethanol on the metabolic degradation of drugs it must be destinguished between acute and chronic effects of alcohol. Upon acute influence of ethanol we observe an increased efficiency of many drugs. Chronical influence of ethanol on the other hand leads to a reduced action of drugs by enzyme inhibition. Besides the interaction on the level of biotransformation the interaction on the receptor-level is important. This mechanism especially leads to an increased efficiency of drugs which influence the central-nervous system.

[The "alcohol-syndrome" from internal medical view (author's transl)]. / Das "Alkoholsyndrom" aus internistisher Sicht

A distict alcoholic withdrawal syndrome in chronic alcoholics cannot only be induced upon withdrawal of alcohol or dose reduction but also occurs upon continuous and long lasting consumption of larger quantities of alcohol. In the latter case we deal with an alcoholic predelirium which is characterized by simultaneous occurence of neurologic, vegetative and gastrointestinal disturbances as well as mental symptoms like anxiety, increased irritability and disturbance of sleep. In parallel to this alcoholic withdrawal syndrome from internal medical view a characteristic symptomatology can be observed in patients with chronic alcohol abuse. In most cases younger patients are concerned who, concomitantly with predelirant symptoms frequently display a labile hyperlipidemia and additional obesity, fatty liver, hyperlipidemia and often also hyperuricemia. Based on ten typical cases the combination of symptoms as described above is introduced. This combination can according to Feuerlein be defined as "alcohol-syndrome". The difficulties of diagnosis are shown because in many cases not the alcohol abuse but primarily vegetative and other functional disturbances dominate the clinical appearance. Additionally the pathogenetic connection between the described symptoms and alcohol abuse are discussed.

[Taste disorders and liver parenchymal damage after administration of thiamazole (author's transl)]. / Geschmacksstörungen und Leberparenchymschäden bei der Behandlung mit Thiamazol

Marked, and in some cases long-lasting, taste disturbances occurred in three patients on thiamazole. In addition, all three had a rise in serum transaminases and alkaline phosphatase levels, due to associated liver parenchymal damage. Cause of these changes was the high thiamazole dosage (160 and 120 mg/d). Reduction in dosage restored normal taste sense in all three, but in two the drug had to be discontinued because of persisting high transaminase levels.

[Digitoxin in hepatorenal insufficiency]. / Digitoxin bei hepatorenaler Insuffizienz.

Serum digitoxin levels were measured during maintenance treatment with digitoxin, 0.1 mg daily i.v., in 12 patients under intensive postoperative care who had hepatorenal failure resulting from multiple organ failure. Thirteen patients in intensive care with comparable basic diseases served as controls; they had developed predominantly renal failure. Serum digitoxin levels in the two groups were no different and remained within therapeutic range during the total period of observation of 8-40 days. During this time toxic serum digitoxin levels were measured in 2.9% of patients in renal failure and 2.7% of patients with hepatorenal failure. The pathogenesis of the liver failure and the severity of the underlying disease did not influence serum digitoxin levels. Digitoxin was tolerated similarly in the two patient groups.

[Drug interaction during therapy with tolbutamide. The influence of some commonly used drugs on plasma level and half life in diabetic out-patients (author's transl)]. / Arzneimittelwechselwirkungen bei der Therapie mit Tolbutamid Beeinflussung von Serumspiegel und Halbwertzeit durch einige gebräuchliche Pharmaka bei Altersdiabetikern.

Tolbutamide belongs to those drugs responsible for the majority of drug interactions. E.g. Tolbutamide metabolism has been shown to be inhibited by coumarole derivatives. We determined plasma-tolbutamide levels in diabetic out-patients for one year. The results obtained indicate no difference in patients additionally treated with either digoxin or digoxin and alpha-methyldopa, or buformin and phenprocumone as compared with control groups. Interactions with respect to biotransformation should not be expected as far as digoxin, alpha-Methyldopa, or buformine were concerned, since these compounds do not share a common metabolic pathway with tolbutamide. In a different group of patients the elimination half life of tolbutamide under the influence of phenprocoumone was additonally determined. Differences could not be detected. This finding can be explained by means of enzyme-kinetic considerations, since phenprocumone, in contrast to dicoumarole, becomes metabolized according to a first order reaction. Competitive enzyme inhibition with tolbutamide which is metabolized similarly to phenprocoumone, therefore appears improbable.

[Color perception disorders in therapeutic glycoside serum concentrations]. / Farbsinnstörungen bei "therapeutischen" Glykosid-Serumkonzentrationen.

Vision deficiencies are dominant symptoms from digitalis intoxication. Twenty-nine and twenty-eight patients have been examined by the Farnsworth-Munsell-100-Hue-test under common maintenance therapy with digitoxin respectively digoxin or beta-acetyldigoxin. This was done to prove how glycosides may create colour vision disturbances even in "therapeutic" glycoside serum concentrations, and in which degree the lipophile digitoxin differs in its effect from the less lipophile digoxin. To exclude any congenital colour vision deficiencies the study was restricted to females. No definite difference in the total error score has been found among patients treated with digitoxin and digoxin. Our results and further new investigations have pointed out that colour vision in digitalized patients is influenced even under common maintenance therapy. It can also be stated that digitoxin does not influence colour vision other than digoxin.

[Serum level of digoxin and digitoxin and glomerular filtration rate in hyper- and hypothyroidism]. / Serumspiegel von Digoxin und Digitoxin und glomeruläre Filtrationsrate bei Hyper- und Hypothyreose.

In a comparative prospective study the serum levels of digoxin and digitoxin and the glomerular filtration of the kidneys were determined radioimmunologically in thyroid function disorders using the endogenous creatinine clearance and the 51Cr-EDTA clearance. Compared to a euthyroid control group 17 patients with hyperthyroidism showed a decreased and 5 patients with hypothyroidism showed a largely toxic digoxin level, both groups being on a maintenance therapy of 0.25 mg digoxin b. i. d. During an oral maintenance therapy of daily 0.1 mg digitoxin unchanged therapeutic serum levels were found in 35 hyperthyroid and 18 hypothyroid patients when compared to a euthyroid control group. Assessment of clearances showed that glomerular filtration rates were clearly increased in the hyperthyroid and lowered in the hypothyroid patients. Renewed assessment of the clearance in four hyperthyroid patients and three with hypothyroidism after thyroid recompensation showed a marked decrease of clearance values in hyperthyroidism and an increase in hypothyroidism. Increased clearance values in hyperthyroidism were associated with lowered digoxin serum levels. In contrast, lowered clearance values in hypothyroidism were accompanied by increased serum digoxin levels. There was no such association detectable for digitoxin.

Interaction of pentobarbital, diphenylhydantoin and digitoxin with ethanol in the isolated perfused guinea-pig liver.

In the isolated guinea-pig liver the interactions of ethanol with the metabolism of three drugs (14C-pentobarbital, 14C-diphenylhydantoin, and 2H-digitoxin) has been investigated. The disappearance of ethanol could be described by zero-order kinetics and was not influenced by the three drugs. In the case of 14C-pentobarbital and 14C-diphenylhydantoin after a short period of distribution disappearance of radioactivity was faster under the influence of ethanol, whereas radioactivity in liver tissue was increased. The radioactivity accumulated in the liver tissue predominantly represented the unchanged drugs suggesting that the inhibition of drug metabolism by ethanol was the cause of the altered distribution. In the case of 3H-digitoxin ethanol did neither significantly influence the distribution of radioactivity nor the pronounced biliary excretion. However there exists some evidence for a minor inhibition of 3H-digitoxin's metabolism by ethanol.

Effect of physical activity on serum concentrations of digoxin and digitoxin.

OBJECTIVE: To study the influence of moderate physical activity on serum concentrations of digoxin, digitoxin and albumin. METHODS: Blood samples were drawn from 10 consecutive mobile patients on digoxin and 12 patients on digitoxin therapy before and following a 10-min walking period. Digitalis serum concentrations were determined by radioimmunoassay, and albumin serum concentrations by laser nephelometry. RESULTS: Following physical activity, digoxin serum concentrations dropped immediately to 79% of baseline values and remained significantly decreased for 20 min. Digitoxin concentrations did not change significantly. CONCLUSION: In contrast to digoxin, the effect of physical activity the serum concentration of digitoxin can be disregarded.

[Disorders of color perception in subtoxic and toxic digoxin and serum digoxin concentrations]. / Farbsinnstörungen bei subtoxischen und toxischen Digoxin- und Digitoxinserumkonzentrationen.

Using the Farnsworth-Munsell 100-hue test, investigations were carried out in 14 patients with subtoxic to toxic serum concentrations of digoxin (greater than 2.0 ng/ml) and 13 patients with subtoxic to toxic serum concentrations of digitoxin (greater than 30 ng/ml), in order to detect color vision deficiencies related to serum levels of digitalis. As compared to the control group (n = 24) the total error scores were significantly increased for both glycosides and all serum level ranges. No evidence was found indicating that digoxin and digitoxin influence color vision differently. The FM 100-hue test indicated definite improvements in the digoxin group within one day of discontinuing the glycosides, while the digitoxin group only started to normalize a week later. The results are discussed, taking the different pharmacokinetics of the two digitalis glycosides into account.