Social mechanisms in the population genetics of Tay-Sachs and other lethal autosomal recessive diseases: a computer simulation model.

A computer simulation model was developed to study the effects of various feudal social customs on the incidence of lethal autosomal recessive genes. Populations of 500 individuals were created in which each person was characterized by sibship, genotype, and sex. The numbered sibships were sorted into numerical order. Each individual then sought a mate from 6 or 12 sibships on either side of his or her own sibship. The resulting couples were sorted in order of the husband's sibship number, after which the couples produced children in accordance with the prevailing birth rate. This ordering of sibships made the probability of a gene remaining in one locality higher than the probability of it drifting to distant localities. A lethal autosomal recessive gene was introduced into populations at a starting carrier rate of 10%. This fell after 20 generations to 2.54 +/- 0.17% (SEM) which was significantly less than the 5.00% carrier rate predicted by a deterministic model in which random mating occurred in an infinite population. The excessive loss of the lethal gene was caused by the high incidence of consanguineous marriages and by the occurrence of random inequalities in the distribution of the gene. The avoidance of sib marriages raised the final carrier frequency (3.28 +/- 0.19%) as did reproductive compensation (4.33 +/- 0.26%). The combination of the incest taboo and reproductive compensation raised the final carrier rate to 5.05 +/- 0.28%. It is concluded that the social factors which may have operated over a period of many centuries in the past have had a significant effect on the population genetics of lethal autosomal recessive genes.

Treosulfan in the treatment of advanced ovarian cancer: a randomised co-operative multicentre phase III-study.

BACKGROUND: In August 1988 a randomised phase III multicenter trial was started in order to compare cisplatinum/treosulfan (PT) with standard cisplatinum/cyclophosphamide (PC) in advanced ovarian carcinoma, aiming at lower toxicity and maintained efficiency. PATIENTS AND METHODS: Five hundred and nineteen patients were enrolled into the protocol. Final evaluation after a median observation time of more than five years was made in July 1996 and included 398 eligible patients, of whom 366 were evaluable regarding efficiency and 290 in respect of toxicity. The tumour stages were classified as FIGO II in 53, FIGO III in 244 and FIGO IV in 68 patients. The patients were stratified regarding post-operative tumour burden. RESULTS: Hematological and gastrointestinal toxicity WHO > = 3 were comparable between the two study arms though a significant difference could be demonstrated regarding alopecia (PT 8% vs. PC 47% after six cycles). The median time to progression as the main efficiency item was in favour of the study schedule (PT 20.6 vs. PC 15.1 months) while significant differences were neither observed in the whole study group nor in the analysed subgroups (R0, < 2 cm, > = 2 cm). The same held true for overall survival. CONCLUSION: PT may be recommended as a less toxic substitute for the former standard PC. After the acceptance of paclitaxel/cisplatin as a new standard, the role of treosulfan should be investigated regarding adjuvant therapy in patients without residual tumor, as a potential partner in triple or sequential treatment and in second-line treatment.

ENDO-LAB: an integrated, portable endocrinology laboratory software system.

ENDO-LAB is an IBM PC-based system which performs calculations and record-keeping for the Vanderbilt University Medical Center Endocrinology Laboratory. It manages maintenance and quality control, and prints reports for regulatory agencies. The system was designed to minimize paperwork without changing laboratory procedures in any way. Key features of ENDO-LAB include a uniform user interface, and error detection mechanisms. The system is designed to detect data which has been incorrectly entered. In addition, where the efficacy of a test can be determined on the basis of limited data, preliminary graphs are screened as soon as possible, so that the user can terminate lengthy calculations whose outcome would be invalid or inconclusive. ENDO-LAB is an integrated system in that the same statistical and calibration programs can be applied to all of the analyses. The system is both extensible and portable; it has been successfully implemented outside Vanderbilt.

Pooled historical MRI data as a basis for research in multiple sclerosis--a statistical evaluation.

Pooled data from placebo groups of different trials can serve as historical control for ongoing or future therapeutic studies and as a reference for power calculations. In order to assess their usefulness for this purpose, we investigated the degree of heterogeneity of placebo arm data from 14 controlled studies included in the database of the Sylvia Lawry Centre for Multiple Sclerosis Research. Since different criteria for the inclusion/exclusion of patients were used in these studies, an attempt was made to adjust the distribution of magnetic resonance imaging (MRI) measures for the differences in the study populations. The analyses showed that, even after adjustment, significant differences remained. This heterogeneity does not reduce the usefulness of the database for statistical analysis of inter-relationships between variables, provided that it is explicitly taken into account as a stratification factor. However, care must be taken when trying to compare the results of a newly treated group with the patients of this pool. Heterogeneity in some MRI variables was greatly reduced when only studies from the same image analysis centre were compared.

Tay-Sachs disease and the role of reproductive compensation in the maintenance of ethnic variations in the incidence of autosomal recessive disease.

Several deleterious and lethal autosomal recessive genes appear to exist in equilibrium with their normal alleles at a variety of stable, or near stable frequencies of considerable antiquity. One person in 25 is, for instance, a carrier of the Tay-Sachs gene among Ashkenazi Jews, compared with 1 in 300 among Sephardic and Oriental Jews and non-Jews. The explanations offered for this phenomenon have generally not been entirely satisfactory. It has been shown that parents replace fortuitous infant and childhood deaths with, on average, approximately two surviving sibs each. When mutation rates are low, this practice, which has also been shown to occur among other animals, can maintain considerable variations in the stable incidence of autosomal recessive disease, should such ethnic polymorphism arise through genetic drift, the founder effect or hitch-hiking. High mutation rates would appear to preclude ethnic variations in the stable incidence of genetic disease.

On the perpetuation of relic genes having an inviable homozygote.

Reproductive compensation may be prezygotic or postzygotic. Prezygotic compensation is the replacement of inviable infants by one or more additional births. When the marital fertility rates are greater than necessary to replace the parents, however, many traditional societies ensured that any surviving progeny in excess of two (on average) did not marry, or married only if they replaced an older sib as heir to the family estate. We call this postzygotic compensation. We show that the coefficient of biologically effective compensation approximates unity when normal and genetic-disease-affected sibships were both sufficiently large to ensure that, on average, two or more sibs survived to the end of the reproductive period, irrespective of the level of prezygotic compensation. The impact of these types of compensation on the population genetics of Tay-Sachs disease and cystic fibrosis is discussed.

Duration of breastfeeding and associated factors in Western and Eastern Germany.

UNLABELLED: Ten years after the German political reunification, specific lifestyle habits still vary between the former Western (FRG) and Eastern (GDR) sectors of Germany. We have analysed data from the first nationwide SuSe Study on breastfeeding 1997-1998 (n = 1593 healthy, term German infants) stratified in a Western (80.3%) and Eastern (19.7%) subgroup. In the Eastern subgroup, breastfeeding was higher for the first 2 wk but decreased more rapidly thereafter. The adjusted relative risk (odds ratios, OR) for short-term breastfeeding was strongly associated (OR >2) with maternal age, supplementary feeding, single parent status, maternal educational status, breastfeeding problems and partner's attitude towards breastfeeding. In the multivariate model, not the geographical location where the mother grew up but the different distribution of risk factors was associated with short-term breastfeeding. Moreover, mothers from both the Western and Eastern sectors mentioned different reasons for giving up breastfeeding. CONCLUSION: More breastfeeding promotion is necessary for women from the former GDR.

A reappraisal of the use of the phi-coefficient in multiple choice examinations.

The phi-coefficient of an item in a multiple choice question (MCQ) examination is often used to determine whether that item is suitable for re-use in future examinations. In order to be of value in this regard, the coefficient must be shown to be an objective and consistent index of the discriminating power of an MCQ item. The behaviour of the phi-coefficient (phi) was investigated in two one-from-five MCQ and two true/false examinations. It is shown that the magnitude of the phi-coefficient for the items in any examination is a function not only of the discriminating power of the items, but also of the magnitude of the countermark for incorrect responses, of the proportion of 'don't know' responses in the examination, and of how the 'don't know' responses are handled in the analysis. It is further shown that the reproducibility of the phi, when calculated for any pair of randomly selected portions of a class of students, is very poor. We conclude that the error of estimation of the phi is of the same order of magnitude as the phi's normal operative range.

Tay-Sachs disease and the persistence of lethal autosomal recessive genes in human populations.

Several lethal autosomal recessive genes have stable carrier frequencies of about 1:20-30 in certain communities, while being exceedingly rare in other, biologically equally successful communities sharing the same environment. It is shown that this situation could persist indefinitely, without invoking the concepts of heterozygote advantage or epistasis, if the parents of affected offspring replace such children with additional sibs. We believe that this could be an important biological mechanism which ensures the maintenance of genetic diversity in the face of natural selection.

Penalties in multiple-choice and true-false questions.

In multiple-choice and true-false (T-F) questions a student expresses his ignorance by leaving questions unanswered, guessing randomly, answering according to some predetermined formula, or, in T-F tests, by marking all those which are unknown as 'true' or all as 'false'. Each of these no-knowledge strategies should, on average, yield the same score. It is shown that partial knowledge is awarded part-marks in multiple-choice question and T-F tests, since the chance of guessing correctly is greater when students possess some knowledge than when they guess randomly. There is a constant relationship between the score obtained by the informed guesser and the minimum, maximum and random-guessing scores, this relationship being independent of the scoring system. Modifications of the scoring system (i.e. of the magnitude of the penalty for incorrect responses) affect only the reward for unanswered questions: in the absence of a penalty the reward for unanswered questions equals the minimum score--a score which is unattainable by random guessing; with a large penalty the reward for unanswered questions approaches the maximum score obtainable.

Marital mores as a mechanism for the maintenance of ethnic variations of lethal gene frequencies.

A computer simulation model was developed to study the effects of various marital mores on the incidence of lethal autosomal recessive genes in populations that are subdivided into small isolates. The problem was studied in isolates where initial generation size was 30, 40, and 50 individuals. In each of these, the mean fertility rate was varied from 2.3 to 2.7 surviving (to adulthood) children per couple whose marriage had been contracted in accordance with the prevailing convention: marriage between first cousins and siblings prohibited; marriage between siblings prohibited; marriage allowed between any individuals; marriage prohibited between siblings but encouraged between cousins; and marriage encouraged between siblings. In all cases, the mean gene frequency in generation 20 was lower than that predicted by the deterministic model with random mating in an unsubdivided population of infinite size, due to gene loss through random drift (to zero) in many of the isolates. The mores that encouraged consanguineous marriages had the lowest final lethal-gene frequencies. Random mating produced intermediate values, and the restrictive mores, the highest final frequencies. The deterministic model (assuming infinite population size and random mating) predictions of the final gene frequency were exceeded only if there was reproductive compensation. It is concluded that restrictive marital mores significantly reduce the selective pressures on lethal recessive genes in small isolates, but that this is counteracted by the increased rate of gene loss through random drift.

Quinoline 2-oxidoreductase and 2-oxo-1,2-dihydroquinoline 5,6-dioxygenase from Comamonas testosteroni 63. The first two enzymes in quinoline and 3-methylquinoline degradation.

The enzymes catalysing the first two steps of quinoline and 3-methylquinoline degradation by Comamonas testosteroni 63 were investigated. Quinoline 2-oxidoreductase, which catalyses the hydroxylation of (3-methyl-)quinoline to (3-methyl-)2-oxo-1,2-dihydroquinoline, was purified to apparent homogeneity. The native enzyme, with a molecular mass of 360 kDa, is composed of three non-identical subunits (87, 32, and 22 kDa), occurring in a ratio of 1.16:1:0.83. Containing FAD, molybdenum, iron, and acid-labile sulfur in the stoichiometric ratio of 2:2:8:8, the enzyme belongs to the molybdo-iron/sulfur flavoproteins. Molybdopterin cytosine dinucleotide is the organic part of the pterin molybdenum cofactor. Comparison of N-terminal amino acid sequences revealed similarities to a number of procaryotic molybdenum-containing hydroxylases. Especially the N-termini of the beta-subunits of the quinoline 2-oxidoreductases from Comamonas testosteroni 63, Pseudomonas putida 86, and Rhodococcus spec. B1, and of quinoline-4-carboxylic acid 2-oxidoreductase from Agrobacterium spec. 1B showed striking similarities. Further degradation of (3-methyl-)2-oxo-1,2-dihydroquinoline proceeds via dioxygenation at the benzene ring, i.e. at 5,6-position [Schach, S., Schwarz, G., Fetzner, S. & Lingens, F. (1993) Biol. Chem. Hoppe-Seyler 374, 175-181]. 2-Oxo-1,2-dihydroquinoline 5,6-dioxygenase was partially purified; NADH and oxygen are required for the reaction, and the enzymic activity is enhanced 1.5-fold by addition of Fe2+ ions. Unexpectedly, this aromatic ring dioxygenase did not separate into distinct protein components, but is apparently a single-component enzyme. The molecular mass was estimated to be about 260 kDa. 2-Oxo-1,2-dihydroquinoline 5,6-dioxygenase is very thermolabile. However, dithioerythritol and low concentrations of substrate had a moderately stabilizing effect. 2-Oxo-1,2-dihydroquinoline 5,6-dioxygenase is inhibited by sulfhydryl-blocking agents, by metal-chelating agents, and by the flavin analogues quinacrine and acriflavin.

Microbial metabolism of quinoline and related compounds. XVII. Degradation of 3-methylquinoline by Comamonas testosteroni 63.

A bacterial strain which utilizes 3-methylquinoline as sole source of carbon, nitrogen and energy was isolated from activated sludge. On the basis of its morphological and physiological characteristics, this isolate was classified as Comamonas testosteroni. Four metabolites of 3-methylquinoline degradation were isolated from the culture supernatant and identified as 3-methyl-2-oxo-1,2-dihydroquinoline, 6-hydroxy-3-methyl-2-oxo-1,2-dihydroquinoline, 5,6-dihydroxy-3-methyl-2-oxo-1,2-dihydroquinoline and 2,5,6-trihydroxy-3-methylpyridine. Based on these results, a degradation pathway for 3-methylquinoline is proposed.

Misconceptions and miscarriages in multiple choice questions.

A modification of the standard format of multiple choice question (MCQ) examinations, recently introduced in certain medical schools in this country, is decribed. The scheme allows for the variation of marks allocated to different in the paper, depending upon the relevance, importance and degree of difficulty of each question. However, the manner in which this new system is being implemented in some cases transgresses some fundamental principles of MCQ examinations. The consequence of this is that the average mark for the class is unintentionally low, with the good students separated from the main body of the class by a disproportionate number of marks. In addition, the examination lends itself to abuse by the enterprising student who is familar with the system of mark allocation.

[Quality of primary medical care after in-patient stroke rehabilitation]. / Versorgungsqualität von Patienten nach Schlaganfallrehabilitation. (Hausärztliche Nordbaden-Schlaganfallnachsorgestudie [HANS]).

PURPOSE: Since only insufficient information concerning the further development of patients after stroke and rehabilitation is currently available, and since the quality of care provided by family doctors is often classified as insufficient, this quality of care was to be examined on the basis of the rehabilitation results. Of particular interest were the co-operation, the therapeutical quality standards and the risk management, as well as the quality of life and compliance of the patients. METHODS: In 2000, all 223 stroke patients were asked prior to their discharge from three large rehabilitation clinics in North Baden, and subsequently their 210 family doctors, whether they were prepared to participate in this follow-up study. The participating patients were examined at their discharge from the clinic as well as 6 and 18 months later using a standardised documentation package, and quality circles for family doctors were initiated. RESULTS: All patients with atrial fibrillation were treated to prevent thrombosis. Smoking showed a positive trend. Quality of life and knowledge of the sickness trend to increase, depressiveness decreases. 60 % of the contacted family doctors participated in the study, 29 % (33 out of 114 physicians at the end of the study) contributed to improve interdisciplinary co-operation. Although 87 % of the patients said to be well informed, 25 % were dissatisfied with their own compliance. CONCLUSION: The quality of care of stroke patients by family doctors as assessed by indicators for secondary prevention and quality of life is satisfactory under present conditions. Apart from the hypertension control there was no negative trend. However, participation of GPs was insufficient. Co-operative after-care by GP can relatively easily stabilise health conditions following inpatient rehabilitation.

[Age-dependent accumulation of lead in teeth]. / Altersabhängige Kumulation von Blei in den Zähnen.

Teeth from people aged 5-73 years old, who differ in their occupational type of exposure to lead and who live in different areas of Dortmund, were collected in 1980/81 and were investigated by means of flameless atomic absorption spectrometry. The major result obtained from the 163 permanent and 22 deciduous teeth studied was a statistically significant dependence of the lead content of the permanent teeth on the donor's age. This was superior to all other influences, showing an increase of 3.4% per year of life. There were no sex specific differences, and no correlations with height and body weight were found. To find different lead concentrations within samples of teeth of various living areas and various occupational types of exposure would have required more variation in these variables than was available in the population of our study. It must be emphasized that the reliability of the measured values of dental-lead concentration greatly depends upon the methodical and analytical procedures used, especially because of the overall lead contamination. The analytical method we finally used is described. The factors which influence the dental lead concentration are discussed. The investigation of whole teeth is tolerable. The age-dependent values of the lead content of teeth could be a useful indicator of the overall lead uptake especially in continuous low level lead exposure. Under the conditions described, at least 150 permanent teeth are needed to compare samples of different regions or periods.

Classification of psychoactive drugs by visually evoked potentials in rabbits by means of multiple discriminant analysis. A possible way of predicting the clinical efficacy of new psychoactive drugs.

The influence of representatives of various groups of antipsychotic drugs on the visually evoked potential (EP) was investigated with the aid of a modified recording and evaluation technique for the rabbit EEG from cortical and subcortical structures. The starting point was the hypothesis that changes in the EP in animal experiments caused by representative members of these "substance groups" (neuroleptics with predominantly antipsychotic or predominantly sedative effect, and antidepressants with predominantly mood-brightening or predominantly sedative main components) make predictions of the clinical efficacy of "unknown" substances possible on the basis of clinical therapeutic principles of classification. Experiments were carried out with haloperidol and fluphenazine, chlorpromazine, amitriptyline and doxepin, and with imipramine and clomipramine, as representatives of these classes of substances. The hypothesis was checked by attempts to assign amitriptyline and chlorprothixene in varying dosage, haloperidol, benzperidol and mianserine to appropriate classes. As classification and assignment procedure we used stepwise multiple discriminant analysis (SWDA) according to our modification of the BMD 0 7 M Program. The purpose of the latter program, and its applicability to our studies, are described and discussed. It was found 1. that with EP data from animal experiments it is possible to classify various groups of psychoactive drugs on the basis of clinical therapeutic findings, using SWDA; 2. that assignment of "unknown" compounds can be based on this classification; 3. that hence with some caution predictions of the clinical effect of newly developed substances may be made on the basis of findings in animal experiments. The EP variables which contain most information for making up the separation formula and hence are of special importance, are investigated with respect to their possible neurophysiological evidential value, and their significance is discussed. It was found that the EP from the visual cortex are of particular significance for the separation of groups in the form presented here.

[Frequency of medical consultation as reflected in 2 representative surveys: DHP-Survey and EVaS-Study (German Cardiovascular Disease Prevention and Survey of Ambulatory Care)]. / Die Häufigkeit der ärztlichen Inanspruchnahme in Spiegel zweier Repräsentativerhebungen: DHP-Survey und EVaS-Studie.

The frequency of patient-doctor contacts in outpatient care is determined via two representative inquiries supplying complementary perspectives. They concern, on the one hand, a sample of contacts in the consultation room, and, on the other hand, contacts as stated in a population-based survey. In the 25-69 years age bracket, both surveys yielded a contact incidence of 2 to more than 5 contacts per person and quarter of a year. The figure is higher in women than in men. Both surveys agree very well if the consultation-room survey is limited to personal contacts between the doctor and the patient. The distribution of contacts over specialties is similar in both surveys. Compared to other countries, the frequency of outpatient consultations is high in the Federal Republic of Germany. Periodic surveys help to get insight into frequency and structure of medical services.