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B Modell

Publications and source records attributed to B Modell.

At least 37 records · Page 2Linked to original sources

Impact of public health on human genetics.

It is often thought that the incidence of genetic disease is rising, because improved medical care is increasing the survival, and therefore the cumulative number of affected people. This examination of the genetic implications of recent demographic change in Europe suggests that the incidence of genetic disease is in fact falling, for several reasons, most of which are indirect consequences of improved primary care. There seems to be no evidence that improved care for the handicapped will have long-term deleterious effects on the human gene pool.

Consanguinity

Changes in circulating alphafetoprotein and human chorionic gonadotrophin following chorionic villus sampling.

Chorionic villus sampling (CVS) is rapidly becoming established as a routine procedure for first-trimester fetal diagnosis. The technique can result in fetomaternal haemorrhage and this might sensitize Rhesus-negative mothers and on occasion lead to spontaneous abortion. Serial sampling indicates that there is a rapid rise in alphafetoprotein (AFP) levels following CVS; however, this is not reflected by raised levels at 16-18 weeks and does not influence the subsequent pregnancy outcome. Unlike AFP, alterations in hCG levels are small and variable. Anti-D prophylaxis for non-sensitized Rhesus negative mothers should be given after CVS and the procedure may be contra-indicated in patients who are already sensitized.

Chorionic Gonadotropin

The frequency of consanguineous marriage among British Pakistanis.

An enquiry answered by 100 randomly selected British Pakistani mothers in the postnatal wards of two hospitals in West Yorkshire showed that 55 were married to their first cousins, while in only 33 cases had their mother been married to her first cousin. This suggests an increasing rate of consanguineous marriage in this relatively small group, by contrast with the decreasing rate observed in some other countries. The genetic implications merit further study.

Consanguinity

Distribution and control of some genetic disorders.

The health burden of genetic disorders varies between ethnic groups within the same country or between countries to a large extent because of genotypic differences at the population level. Genetic services should recognize this variability in need and be developed within the traditional context of medical care. All practical approaches require a sound epidemiological basis and underline the importance of early diagnosis for both prevention and treatment. Effective control is now possible for some Mendelian conditions and some congenital malformations and should be incorporated into general health care. The development of genetic services within any country depends on the optimal utilization of available resources, both financial and intellectual.

Chromosome Aberrations

Two unusual cases of first trimester prenatal diagnosis of cystic fibrosis using DNA probes.

There are now several DNA probes which localize the cystic fibrosis mutation (CF) to chromosome 7q2.2-q3.1. The most tightly linked probes, pJ3.11 and met, are useful for first trimester prenatal diagnosis for many families provided that there is at least one living child affected by CF (Farrall et al., 1986). We describe here two families seeking prenatal diagnosis for CF which present unusual counselling problems. The first is an extended family in which there is no living affected member with CF; the second, a consanguinous marriage at risk both for cystic fibrosis and beta-thalassaemia. In both cases first trimester chorionic villus sampling and DNA haplotype analysis predicted that the fetus is a carrier for CF, and in the doubly affected family a carrier for beta-thalassaemia as well. Both pregnancies resulted in live births and subsequent immunoreactive trypsin estimations were both in the normal range.

Chorionic Villi

Association of thalassaemia intermedia with a beta-globin gene haplotype.

We have identified 14 Asian patients with homozygous beta zero thalassaemia who had a mild clinical disorder related to an augmented production of haemoglobin F. None of their parents had an elevated level of Hb F. Restriction fragment length polymorphism analysis of the beta-globin cluster of these patients and a control group of Asian thalassaemia major patients showed that 6/14 of the thalassaemia intermedia patients were homozygous for a particular 5' beta-globin haplotype (-+-++), in contrast to 1/42 of the thalassaemia major patients. Furthermore, the -+-++ beta haplotype is also associated with amelioration of disease severity in beta thalassaemia in an Italian population. This beta haplotype is linked to a DNA sequence variation 5' (at position -158) to the G gamma globin gene which can be detected by the presence (+) of an Xmn I restriction enzyme site. The possible role of the Xmn I-gamma polymorphism in relation to this variant HPFH is discussed. We conclude that much of the observed clinical variability of beta thalassaemia can now be explained by the inheritance of beta thalassaemia chromosomes with different propensities for fetal haemoglobin production.

Adolescent

Human fetal lymphocytes require T cell growth factors for cytotoxic responses.

Lymphocytes isolated from the blood of 17 human fetuses, varying in gestational age between 16 and 26 weeks, were tested for their capacity to generate specific cytotoxic cells after mixed lymphocyte culture (MLC) with allogeneic cells in the presence or absence of exogenous T cell growth factor (TCGF). Blood cells from seven fetuses, distributed throughout the age range, failed to generate cytotoxic cells even when TCGF was added in MLC, whereas six others gave positive responses but only when exogenous TCGF was present during the sensitisation phase. The maturation induced in the latter was not caused solely by a direct, non-specific effect of the TCGF, for control responder cells incubated with TCGF in the absence of allogeneic stimulator cells always responded less strongly or not at all. Fetal blood lymphocytes from the remaining four fetuses gave significant cytotoxic responses that were not augmented by TCGF. It is concluded that there can be a clear dichotomy between proliferative and cytotoxic responses to alloantigens and that the inability of human fetal blood lymphocytes to mount cytotoxic responses at this stage of development might be due to deficiencies in helper cells, cytotoxic precursors or both. For three fetuses it was possible to study, additionally, cytotoxic responses of spleen, liver and thymus with and without TCGF. None of them made specific responses even when TCGF was added, though cells from two spleens and one thymus responded directly to TCGF. To ascertain whether the absence of cytotoxic responses might have been caused by a failure of blood, spleen, thymus or liver cells to proliferate, their mixed lymphocyte reactivity, as detected by the uptake of 3H-thymidine, was studied without exogenous TCGF. Whereas thymus cells from only one of five fetuses responded, cells from all other tissues (including blood) responded consistently.

Adult

First-trimester fetal diagnosis for haemoglobinopathies: report on 200 cases.

First-trimester prenatal diagnosis by DNA analysis was found to be possible in 224 (80%) of 281 families at risk of having a child with beta-thalassaemia major. 200 prenatal diagnoses, mainly for beta-thalassaemia or sickle-cell anaemia, were made by means of chorionic villus sampling and fetal DNA analysis. The overall fetal loss rate was 6.7%, the majority being in the first half of the programme. There was one misdiagnosis. Prenatal diagnosis was also carried out successfully for both pairs of twins in two pregnancies. Comparison of these results with 53 prenatal diagnoses made with DNA prepared from amniotic fluid suggests that the first-trimester procedure is more reliable. If further experience confirms that chorionic villus sampling has an acceptably low risk for both mother and fetus it will largely replace other methods for prenatal diagnosis of the haemoglobin disorders and other single-gene conditions.

Amniotic Fluid

Meiotic recombination between two polymorphic restriction sites within the beta globin gene cluster.

Analysis of beta globin gene haplotypes for prenatal diagnosis of beta thalassaemia has revealed a recombination event within the beta globin gene cluster. Both a change in the AvaII polymorphic site within the beta globin gene and a change in the phenotype of the beta globin gene were observed. Paternity was established by the pedigree analysis of hypervariable 'minisatellite' DNA polymorphisms and the most probable explanation of the recombination event is a crossover between the psi beta globin gene and the beta globin gene. The data provide direct evidence in support of a DNA region 3' to the beta globin gene with a recombination frequency much higher than expected, and have important implications for the prenatal diagnosis of beta thalassaemia by linked restriction fragment length polymorphisms.

Alleles

Antenatal search for fetal beta-thalassaemia in a twin pregnancy.

The antenatal search for fetal beta-thalassaemia in a twin pregnancy is described. Thalassaemia major was correctly excluded in both fetuses, and some of the problems of identifying patients at risk are outlined as well as those of obtaining fetal blood in the second trimester of pregnancy.

Adult

Antenatal diagnosis of thalassaemia major.

Haemoglobin synthesis was studied in fetal blood samples obtained at 17 to 20 weeks' gestation in 22 women at risk of carrying a fetus with homozygous beta-thalassaemia. A presumptive diagnosis of homozygous beta-thalassaemia was made in four cases, and the pregnancy was terminated. An inconclusive answer was obtained in one case, and the patient also chose to have her pregnancy terminated. Two fetuses were lost as a result of the procedure. Of the remaining 15 pregnancies, 13 proceeded to term and two to 36 weeks; in each case a normal infant or one heterozygous for beta-thalassaemia was delivered. Current efforts should be directed towards improving the blood sampling technology so that fetal blood sampling can be used widely in those countries where thalassaemia is a major problem.

Abortion, Eugenic

Presence of gene for beta globin in homozygous beta0 thalassaemia.

In one southern Italian and one Pakistani patient with homozygous beta0 thalassaemia in which no detectable beta-globin synthesis occurs and no beta-globin messenger RNA is found, the gene for beta globin has been shown to be present using complementary DNA. This demonstrates that for these patients the imbalance in chain synthesis is not attributable to a gene deletion.

DNA