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Identification of uroporphyrinogen III synthase (UROIIIS) gene mutations in patients with congenital erythropoietic porphyria (CEP) allows fast and reliable carrier detection and prenatal diagnosis. We describe here the first case of prenatal diagnosis by concomitant measurement of uroporphyrin I in amniotic fluid and direct detection of the gene mutation. A French couple, whose first child was diagnosed with CEP, requested prenatal diagnosis at 16 weeks of gestation. Uroporphyrin I was dramatically increased in amniotic fluid and the fetus was homozygous for the C73R mutation, the most common mutation in this disease. The pregnancy was then terminated.

Summary Biochemical, cytochemical characteristics and electron microscopy subcellular distribution of neutrophil alkaline phosphatase (NAP) were analysed in blood and/or smear samples from 39 trisomy 21 patients (Down's syndrome) aged 11·5-18 years (mean 15·5 years) and 55 normal subjects aged 12-20·5 years (mean 17 years). All patients were karyotyped. NAP cytochemical procedures were carried out on all subjects: biochemical NAP determinations were made in 10 patients and 20 controls: ultrastructural electron microscopy of AP was performed in three patients and four normal subjects. Neutrophil alkaline phosphatase from patients with trisomy 21 displayed the following changes: (1) a significant increase of enzyme activity, (2) a high thermal lability of enzyme. Electron microscope morphology exhibited large deposits of NAP reaction product associated with the plasma membrane and intracellular main organelles, like phosphasomes. The NAP biochemical and cytochemical characteristics suggest that trisomy 21 neutrophils contain a nonspecific AP isoenzyme, closely related to the early placental form.

Immunoreactivity, cytochemical, immunocytochemical characteristics and subcellular distribution of neutrophil alkaline phosphatase (NAP) were investigated in blood and/or smear samples from 18 women aged 23-46 years (mean 32.5 years) with trisomy 21 fetuses (17-21 weeks) and 28 women aged 20-42 years (mean 31 years) with normal fetuses (17-22 weeks). Immunochemical NAP investigations were carried out in 8 pathological and 8 normal pregnancies; cytochemical and immunocytochemical procedures were carried out in 18 pregnant women with trisomy 21 fetuses and 28 controls. NAP from women with trisomy 21 fetuses is characterized by: (1) a significant decrease in reactivity with anti-liver-type alkaline phosphatase (AP) and anti-NAP antisera; (2) low or very slight reactivity with antiplacental or anti-intestinal antibodies; (3) marked dispersion of NAP lead citrate reaction products or anti-NAP antibody colloidal gold-labelling in neutrophil cytoplasms, as detected by electron microscopy. This subcellular AP distribution (extramembranous) is different from that of normal NAP sites associated with plasma membrane, nuclear membrane and secretory vesicles. The NAP immunochemical and cytochemical characteristics suggest that neutrophils of a woman with a trisomy 21 fetus contain two AP isoenzymes: the liver/bone type and an atypical AP.

In this study, we compared the impact of two protein kinase (PK) inhibitors, H-7 and staurosporine, on the normal myeloid progenitors (CFU-GM) and acute myeloid leukemia progenitors (AML-CFU) proliferation measured by in vitro clonogenic assay. H-7 and staurosporine displayed a biphasic dose-effect on both CFU-GM and AML-CFU recovery. At the lowest concentration range (0.1 microM to 20 microM for H-7 and 0.1 nM to 1 nM for staurosporine), we observed growth stimulation whereas higher concentrations induced dose-dependent growth inhibition. Moreover, AML-CFU proved to be significantly more sensitive to the inhibitory effect of both H-7 and staurosporine than CFU-GM (3.16- and 2.12-fold, respectively). These results were further confirmed with comparable murine cell line models (FDC-P1, a hematopoietic cell line generated from normal bone marrow and WEHI, a myelomonocytic leukemia cell line). Furthermore, we report that both H-7 and staurosporine present similar inhibitory effects on proliferation (PE1) as on self-renewal (PEs) of AML-CFU. In an attempt to understand more fully the mechanism of action of H-7 and staurosporine, we investigated their impact (when used at their D50) on the human myelogenous leukemia cell line, K562. H-7 and staurosporine induced a transient decrease of cell growth, between 0 and 24 hours, and produced a transient blockade of K562 cells in the S-phase, either 24 or 48 hours after the addition of staurosporine and H-7, respectively.

In the context of the aetiological investigation of male infertility, the authors stress the place and the contribution of blood karyotype testing in the light of their personal experience based on 1,612 subjects. This examination has an important place, as about 15% of azoospermic subjects and 6 to 7% of subjects with oligospermia less than 10 million spermatozoa per ml, either alone or in combination with other abnormalities of the semen examination, present a congenital chromosomal abnormality. A remarkable constancy of the results was observed according to identical recruitment criteria. The contribution of this examination is also important: the medical and psychological value of detecting the cause of azoospermia, genetic counselling and antenatal chromosomal diagnosis for non-azoospermic subjects with an equilibrated structural abnormality, in whom treatment allows a chance of procreation, genetic counselling for the family of these subjects in order to prevent the appearance of a chromosomally abnormal infant. In conclusion, the authors argue in favour of the routine use of this test in all infertile subjects with at least isolated oligospermia less than 10 million spermatozoa per ml.

This study aimed to evaluate the effect of melphalan on both terminal divisions and self-renewal capacity of acute myeloblastic leukemia (AML) progenitors (colony-forming units, CFU-L) grown in methylcellulose. Terminal divisions and self-renewal were assayed by primary (PE1) and secondary (PE2) colony formation, respectively. Thirteen cases of AML, were tested. Melphalan induced a negative exponential dose-effect on CFU-L survival. Moreover, melphalan was equally effective in inhibiting CFU-L growth in both PE1 and PE2 assays, with D10 values of 1.53 +/- 0.17 micrograms/ml and 1.59 +/- 0.21 micrograms/ml for PE1 and PE2, respectively (p = 0.48). Cytotoxicity of melphalan on CFU-L did not differ significantly from that observed for normal hemopoietic granulocyte-macrophage colony-forming units, erythroid burst-forming units, and granulocyte-erythroid-macrophage-megakaryocyte progenitors. Mafosfamide-lysine, a stable cyclophosphamide congener, strongly inhibited primary colony formation (PE1) with a D10 value of 14.46 +/- 1.76 micrograms/ml, but was much less efficient in the PE2 assay. Our findings suggest that the self-renewal capacity of AML progenitors can be differentially affected by alkylating agents. Moreover, since it is now considered that chemotherapy should be preferentially directed against the self-renewal of leukemic progenitors, melphalan might offer a greater potential than cyclophosphamide or cyclophosphamide derivatives in the therapy of AML.

A comparative study of karyotypes, hematological variables and neutrophil alkaline phosphatase (NAP) was performed in 106 parents (53 couples) of children with free, homogeneous trisomy 21 and of 220

Vergnes H., Colombies P., Hobbe Th. Les pseudocholinestérases sériques : résultats dans les populations du Haut-Languedoc et du Pays Basque.. In: Bulletins et Mémoires de la Société d'anthropologie de Paris, XII° Série. Tome 1 fascicule 2, 1967. pp. 249-256.

Resume Les auteurs rapportent les resultats de l'etude immunologique et cytogenetique d'une observation de double population d'hematies chez deux jumeaux hetero-caryotes.

This report describes a case of lymphoid blast crisis of a chronic myelocytic leukemia with the occurrence of a double chromosomal population carrying a Philadelphia chromosome. Fifty-five % of the cells have 28 chromosomes, and 36% show the exact duplicate of the near haploid chromosome complement. The similarities between this near haploid cell line and those previously reported, as well as the presence of such clones in acute lymphoblastic leukemia, are discussed. In the leukemic lymphoblasts, the association of the Philadelphia chromosomes with a near haploid karyotype described so far in acute lymphoblastic leukemia provides further support for the concept of a pluripotent Philadelphia chromosome-positive stem cell common to both lymphoid and myeloid lines.

Two thousand one hundred and thirty six couples with one or more spontaneous abortions (SAB) before 13 weeks of gestation and with or without one normal liveborn child (NLC) were karyotyped. In 4.31% of the couples one partner was a carrier of a major chromosomal abnormality. Couples with SAB only have 2-fold more chromosomal aberrations than couples with SAB and NLC. A correlation between the frequency of chromosomal abnormalities and the number of SAB was observed. Finally, the various types of chromosome aberrations were analysed.

The authors relate the association XX male and syndrome of Pierre Robin in a child whose father presents a reciprocal equilibrated translocation 46,XY t (16;17) (p13;q21). They discuss the possible relation between these different anomalies and notably the possibility of a genic effect.

Chromosomal anomaly was detected in 7.6% of a cytogenetic survey of 1,444 infertile male azoospermia or oligozoospermia with a sperm count below 20 million/ml. Anomalies are especially of the sex-chromosome and of autosomal robertsonian translocation type. Distribution of these subjects on account of the sperm count has pointed out an increase of chromosomal anomalies in inverse ratio to the sperm count.

The frequency of retinoblastoma was estimated in southwest France (Midi-Pyrénées) during the 1950-1969 period. Twenty-three cases were detected among 507 157 liveborns. After correcting for the probability of ascertainment of patient, the estimated frequency is 1 per 15 849 births. The proportion of unilateral cases is estimated 91 percent after correcting for the higher probability of ascertaining bilateral cases.

A cytogenetic analysis of more than 7000 subjects has been performed in the aetiological screening of infertile couples. This study revealed that infertile couples can be divided into three groups: those with one or more spontaneous abortions before 13 weeks of gestations, those with primary sterility (no gestation for at least 24 months) or those with secondary sterility (after one or more children, no further gestation for at least 24 months). The frequency of chromosomal abnormalities observed in this population is 2,9%, i.e. 1/17 couple. The results, according to sex of subjects bearing the chromosomal abnormality, were then analysed in each of the three groups. From this study, the authors insist on the advantage of systematically performing a chromosome analysis in the case of infertile couples for two main reasons: frequency of chromosomal abnormalities is relatively high in this population, detection of such abnormalities enables some couple to be rapidly directed to other solutions (Artificial Insemination), and others, due to prenatal chromosomal diagnosis, to have offspring in safety.

The authors report an observation of a child with both trisomy 12(pter----q12) and monosomy 21(pter----q21). It is thus possible to detect the clinical signs which can be attributed to trisomy 12p and to monosomy 21ql respectively. The authors point out the originality of the maternal translocation which differs from the translocations affecting these two chromosomes previously described in the literature. Finally, the rarity of the type of adjacent-2 segregation is shown, and discussed according to the literature already published.

Two unrelated patients with partial trisomy 10p due to a paternal balanced translocation are reported. Though the sizes of the trisomic segment are not identical, both patients show: severe growth retardation, important psychomotor retardation and a dysmorphic mouth recalling a "tortois mouth". These observations are compared to twelve others from the literature.

A comparative study of karyotypes and neutrophil alkaline phosphatase (NAP) was carried out for 70 parents (35 couples) of trisomy 21 children and their 35 trisomy 21 children and for 110 control parents (55 couples) and their normal children. In the trisomy 21 families we found a significant increase in NAP: mother P less than 10-4; father P less than 10-4; children P less than 10-9; the NAP level in affected child is approximately equal to the sum of the NAP levels of the two parents (P = 0.80; sigma2 = 5%). In one parent of a trisomy 21 child, a karyotype anomaly was present.

A new case of partial trisomy 13 through unbalanced de novo translocation t(X;13) is reported. In situ hybridization has been used to specify breakage points on the X chromosome. This case is cytogenetically comparable with another reported case; the phenotypical aspect of these two patients is however different. This discrepancy is discussed.

Neutrophil alkaline phosphatase (NAP) from 12 mothers of normal children was investigated and the results compared to those of 7 mothers with trisomy 21 offsprings, in an attempt to determine a parental molecular change in this chromosomal abnormality. The biochemical properties of the enzyme were analyzed by the procedures of isoenzyme characterization, i.e. enzyme assays, thermostability, inhibition patterns and slab gel electrophoresis. Immunological properties were determined on 5 samples from normal mothers and on the same sample number of mothers with affected children. In these latter NAP showed characteristics that were to some extent different from the ones of normal controls. The following changes were observed: highly significant loading of membrane and nucleus pellets in NAP activity, poor effect of inhibitors on thermostable component and immunodepletion measured by a significant decrease of the normal affinity for antiliver and antiplacental alkaline phosphatase antisera. These findings are discussed in the light of our knowledge of alkaline phosphatase isoenzymes.

A biological [karyotype, leucocyte alkaline phosphatase (L.A.P.), haematimetry] and clinical study was performed on three women carriers of a chronic myaloid leukemia during their pregnancy (3 1/2 months, 6 1/2 months), or just after delivery. The results show : (1) a relation between the acuteness of the illness and a higher rate of L.A.P., probably secondary to pregnancy, and (2) a relation between the clinical evolution and the rate of Ph1 (+) cells.

A major chromosomal abnormality was observed in 10.3% of subfertile men in this study. This result is similar to a previous survey using the same criteria for selection of probands. The high frequency of chromosomal abnormalities emphasizes the importance of cytogenetic examination in subfertile men. The detection of such an abnormality should be followed by chromosome analysis in the patient's family. Prenatal diagnosis is indicated if a subfertile man with an abnormal karyotype fathers a child.

The authors studied the karyotype in blood and marrow of 34 patients with Paget's disease and compared the results with those of a control group of the same age. Structural abnormalities are more frequent in the blood than in the marrow, but there is no significant difference in comparison with the abnormalities in the control group. Ionizing radiations and drugs do not seem to be responsible for the abnormalities encountered. The numerical abnormalities are characterized by an increase in the number of hypodiploidies, particularly involving the chromosome groups A, B and D, whereas chromosomal damage affecting the C and G groups is less than normal. These abnormalities were encountered in a limited number of patients. The authors discuss the significance of these chromosomal abnormalities in the more general context of the genetics of Paget's disease.

Two cases of retinoblastoma in two children showing a chromosomal rearrangement in the karyotype were reported. In the first case, a pericentric inversion of chromosome 9 was observed both in the child and his father. In the second case, a reciprocal translocation t (3;12)(q29;q15) present also in the paternal karyotype was identified. A strict connection cannot be established between the tumour itself and the family chromosomal aberrations, but these observations raise the problem of a possible "interchromosomal effect".

Cytogenetic study of bone marrow cells in a child with acute lymphocytic leukemia showed a 27 chromosomes cell-line. Only four pairs appeared to be normal (X, 10, 18, 21). All the others were haploid. This strong hypodiploidy seems to be compatible with the survival and proliferation of these abnormal cells.

In order to give a genetic counsel to the mother and the two twin-sisters of an Hemophilia A boy, a familial investigation has been carried out. The study with the restriction fragment length polymorphism probes together with the hemostasis screening enabled to specify the status of each member of the family with respect to hemophilia A gene. This investigation evidenced the presence of two maternal alleles and one paternal allele in one of the twin-sisters. This led us to assume that she had a chromosomal abnormality in spite of her normal phenotype. The 47, XX, +(X) result of her karyotype confirmed this assumption. Therefore an accurate genetic counsel was provided to the members of this family and more particularly to the triple X subject.

Chromosomal analysis of the bone-marrow aspirate of a five years old girl suffering acute leukemia revealed a cell-line carrying 27 chromosomes. Banding by controlled heating denaturation showed that, in these cells, all chromosomes are haploid, except chromosomes: X, 10, 18, 21. This cell-line, not seen during remission, was found during relapse, in addition to another one with 54 chromosomes. The caryotype of this last clone corresponded to the duplication of the chromosome set found in the first cell-line. The authors discuss two problems: the possible correlations between the clinical evolution and the biological data; the problem raised by the survival and proliferation of such an hypodiploid cell-line.

A comparative study of karyotypes, hematological variables and neutrophil alkaline phosphatase (NAP) was performed in 106 parents (53 couples) of children with free, homogeneous trisomy 21 and of 220 parents (110 couples) of normal children. In the parents of trisomy 21 children we found a significant increase of the NAP (p0.05) and a nonsignificant difference in the number of white blood cells. In 4 cases, we also found an anomaly in the karyotype. A modification of the metabolism of the neutrophils seems possible.

A new case of monosomy 10p without associated chromosomal abnormality is reported. This observation, compared with three others from the literature, shows the following common symptoms: microcephaly, antimongoloid slant of the palpebral fissures, low-set ears, prominent anthelix, congenital heart disease, abnormalities of the limbs. Cranial tomography demonstrates a midline developmental anomaly of the brain (cavum vergae associated with cavum septi pellucidi).