Tissue iron deposition in untransfused beta-thalassemic mice.

Homozygous beta-thalassemic mice show many of the features seen in human beta-thalassemia, such as decreased hemoglobin, hematocrit, and red blood cell count as well as increased reticulocyte count. They also exhibit splenomegaly and a decrease in osmotic fragility of red cells. beta-thalassemic mice were examined for spontaneous iron overload at ages ranging from 20 to 595 days. Accumulation of iron was shown to occur in the spleen, liver, and kidneys but not in the heart. Sections of spleen, liver, kidney, and heart were stained for iron and subjectively scored. Image analysis microscopy was used to examine sections of spleen and liver. Nonheme iron in the four tissues was quantitated using the bathophenanthroline sulfonate colorimetric assay. An increase in tissue iron occurred primarily in the spleen, even before weaning, despite the low iron content of milk. Iron accumulation in the absence of blood transfusion is of interest because iron overload is the major cause of death in human beta-thalassemia.

Diminished acquisition of iron by reticulocytes from mice with hemoglobin deficit.

Reticulocyte iron and transferrin uptake was studied in hemoglobin deficit (gene symbol, hbd), an autosomal recessive trait in the mouse characterized by hypochromic microcytic anemia, reticulocytosis, hyperferremia, and increased red-cell-free protoporphyrin. Reticulocyte-rich red cells were incubated in vitro in a mixture of 125I-labeled diferric mouse transferrin and 59Fe-labeled iron-saturated mouse plasma. At 37 degrees C, the uptake of transferrin by reticulocytes from affected animals (15 ng/micrograms RNA) was the same as that of reticulocytes from control animals. However, the uptake of iron by affected reticulocytes (0.11 ng/micrograms RNA) was significantly lower than that by control reticulocytes (0.24). At 4 degrees C, transferrin binding by affected and control reticulocytes was again indistinguishable. The deficiency in the uptake of iron by affected reticulocytes was not observed on incubation at 4 degrees C. Scatchard analysis of transferrin receptors on hbd/hbd and control reticulocytes showed no difference in pKD and a slight elevation in number of receptors per reticulocyte for hbd/hbd animals. These findings suggest that hbd/hbd reticulocytes have a defect in iron acquisition that is distal to the binding of transferrin to the cell membrane receptor. This defect is similar to one already described in the anemia of the Belgrade laboratory rat.

Malignant schwannoma in siblings with neurofibromatosis.

Three brothers with neurofibromatosis (NF) died of sarcoma. The proband tumor had malignant schwannoma. The histologic nature of the sarcoma in the other two brothers was not known, but it seemed likely to be similar to that of the proband. However, the sarcomatous lesions in these two siblings developed in the patients' right lower limbs which showed clinical and radiological evidence of anterior bowing of the tibia. Their mother and two other siblings have neurofibromatosis, but have not developed malignant tumors. The unaffected father died at age 61 of carcinoma of the common bile duct. An unaffected sister developed adenocarcinoma of both colon and lung. Although it is known that patients with NF are at a high risk of developing malignant sarcoma and second primary malignancies, it is not clear whether this association is genetically determined. The family we report has some of the features of a "cancer family" and suggests that sarcomatous transformation in patients with NF may be genetically influenced. This report raises the possibility that the presence of congenital malformation and exposure to irradiation may predispose patients with neurofibromatosis to develop malignant schwannoma.

Studies on the vasoocclusive crisis of sickle cell disease. III. In vitro and in vivo effect of the pyrimido-pyrimidine derivative, RA-233: studies on its mechanism of action.

Red cell deformability was found to be impaired in SS- and SC-genotype and to a lesser extent SA-genotype red blood cells as compared with those of AA-genotype. RA-233 in vitro improved deformability according to a bell-shaped dose-response curve. RA-233 also prevented experimental vasoocclusive crisis in Macaca arctoides. Deoxygenation of SS-genotype red cells resulted in sickle shape transformation, ATP depletion, potassium efflux, and attachment of hemoglobin molecules to the membrane. These changes were prevented by RA-233. Suspending SS-genotype red blood cells in potassium rich tris-buffer also prevented potassium efflux during deoxygenation and also decreased cellular deformability. RA-233 had no effect on osmotic fragility of SS-genotype red blood cells.

Hemoglobin deficit: an inherited hypochromic anemia in the mouse.

The character and pathogenesis of hemoglobin deficit (gene symbol, hbd), an autosomal recessive trait in the mouse, were studied. The main hematological features of hemoglobin deficit are anemia, red cell hypochromia and microcytosis, and reticulocytosis. The absence of raised fecal urobilinogen excretion and frank hyperbilirubinemia and bilirubinuria suggests that excess hemolysis is not the primary cause of the anemia. The raised plasma iron concentration and the failure of the anemia to respond to parenteral iron treatment indicate that the anemia is not due to iron deficiency. The absence of siderocytes and sideroblasts suggests that anemia is probably not due to ferrochelatase deficiency. Thalassemia is excluded by the finding of balanced reticulocyte globin chain synthesis. The markedly elevated levels of free red cell protoporphyrin taken together with the other findings already noted suggest that the anemia of hemoglobin deficit is due to a defect in the erythroid cell iron procurement mechanisms leading in turn to diminished heme and hemoglobin synthesis.

Recurrent pregnancy losses and parental chromosome abnormalities: a review.

A compilation of the cytogenetic results taken from 79 published surveys of couples with two or more pregnancy losses (comprising 8208 women and 7834 men) showed an overall prevalence of major chromosome abnormalities of 2.9%. This is five to six times higher than that of the general adult population. In every group of chromosome abnormalities in the parents a predominance of female to male affected was noted (2:1). Approximately 50% of all chromosome abnormalities detected were balanced reciprocal translocations, 24% were Robertsonian translocations, 12% were sex chromosomal mosaicisms in females, and the rest consisted of inversions and other sporadic abnormalities. Parents with two or more idiopathic pregnancy losses should be karyotyped to aid in management and counselling. When a translocation or other abnormality (e.g. X chromosomal mosaicism) predisposing to an abnormal zygote is found, prenatal diagnosis is indicated in future pregnancies. Even when parental karyotypes are normal, prenatal diagnosis should be considered in subsequent pregnancies of parents with two or more pregnancy losses because of the high incidence of chromosome abnormalities in spontaneous abortions. For the same reason, if a single previous pregnancy loss is known to have been chromosomally aneuploid, parental karyotypes may have to be examined (depending upon the finding in the pregnancy loss), and prenatal diagnosis should also be considered in subsequent pregnancies.

The kinetics of iron uptake by isolated intestinal cells from normal mice and mice with sex-linked anemia.

No significant differences of Km or Vmax could be demonstrated for the initial rate (0-3 min) of iron uptake by preparations of isolated duodenal mucosal epithelial cells from normal or sex-linked anemic (sla) mice. Isolated cells from sla mice do, however, take up significantly more iron than normal cells after 20-min incubation. Upon reincubation with various types of mobilizing agents, the amount of iron released from, and the amount of iron remaining in, cells from sla mice was significantly elevated compared to control values. The percentage of iron released was the same for both types of cells, for all mobilization media employed. The current data, in conjunction with previous studies that showed deficient mucosal to serosal transport of iron in everted duodenal sacs from sla mice, suggest that the lesion in these mice may be located between the mucosal cell and the vascular compartment rather than in the mucosal cell.

The influence of obstetricians on the utilization of amniocentesis.

A study of 173 Western New York State obstetricians was undertaken to study referral patterns for second-trimester amniocentesis in 1974-1978. Referral patterns were analysed in relation to obstetrician age, religion, board certification, hospital affiliation and practice location. Forty-seven per cent of the obstetricians had never referred a patient for amniocentesis. Those referring were overall younger than those not referring and were significantly more often board certified. Obstetrician religion was significantly related to referral with fewer Catholic obstetricians referring. Hospital affiliation (teaching versus non-teaching) and obstetrician practice location (urban versus rural) were not important factors after controlling for religion and board certification. Obstetrician factors account for a small but important part of the variability in referral, and other factors, such as cost and access to laboratory and obstetric care need further investigation.

Offspring of teenage mothers: congenital malformations, low birth weights and other findings.

Teenage mothers were found to have congenitally malformed infants with a significantly higher frequency when compared to a published control population. Low birth weight and perinatal death were common among the infants of mothers 17 and younger. No chromosomal anomalies were found among the infants of this population, but this result does not unequivocally rule out an increased frequency of these disorders.

An infant with trisomy 6q21 leads to 6qter.

A female who died shortly after birth with multiple congenital anomalies corresponding to the clinical picture of partial 6q trisomy is described and the autopsy findings are presented. The patient had an unbalanced chromosome complement with a 6q21 leads to 6qter duplication. Her mother is a balanced 46,XX,t(6;10)(q21;q26) carrier.

Brief clinical report: an infant with duplication of 17q21 lead to 17qter.

Duplication of the distal part of 17q has been reported in 4 patients [1,2]. We are reporting clinical, autopsy, and cytogenetic data on an additional patient whose condition was due to a familial translocation in which the patient's chromosome constitution is 46,XX, der(4),t(4;17)(p16;q21) pat. The phenotype of the five known patients with this duplication is very similar, and their manifestations are distinct enough to be clinically recognizable. Abnormalities common to all five patients are severe growth impairment, craniofacial anomalies with severe hypertelorism, frontal bossing and temporal narrowness, a widow's peak, narrow palpebral fissures, a thin upper lip overlapping a thin lower lip with down-turned corners of the mouth, micrognathia, apparently low-set and deformed ears, short webbed neck, and hyperlaxity of the limbs.

Long survival in trisomy-13-syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old.

The mean survival in Trisomy-13-syndrome patients is reported to be 130 days. We have diagnosed 21 cases of this syndrome in this institution (11 females and 10 males); 15 patients had regular trisomy 13 and 6 had translocation-trisomy 13 karyotypes. The mean survival of the 19 patients who died was 97.05 days; translocation patients survived longer than regular trisomy patients. The oldest living patients with trisomy 13 are a girl 19 and a boy 11 years old. Both are black, have regular trisomy 13 karyotypes and have had most of the manifestations of the syndrome. No mosaicism was detected in repeated cytogenetic studies. The 19-year-old patient is the oldest known living person with regular trisomy 13.

Familial pulmonary atresia. Its occurrence with a ventricular septal defect.

To our knowledge, this is the first reported case of pulmonary atresia with a ventricular septal defect that occurred in a father and his son. A multifactorial mode of determination that resulted from an interaction between genetic predisposition and environmental factors was assumed, since the family history did not show other members with congenital heart defects. Based on the background and on information from the multifactorial theory of inheritance, a counseling plan was formulated for these parents. A similar approach is recommended for the many surgical survivors of previously uncorrectable complex congenital heart defects as they approach reproductive age.