Red cell iron uptake in hereditary microcytic anemia

The iron uptake in vitro of red cells from mice with hereditary microcytic anemia (gene symbol mk) was studied to examine the hypothesis of a generalized impairment of cellular iron uptake in this conidition. Reticulocyte-rich red cells from anemic (mk/mk) and acutely bled normal (+/+) mice were incubated in 59Fe-labeled mouse plasma and the radioiron uptake measured. The 59Fe uptake of the mk/mk and +/+ cells was related in the same way to the reticulocyte concentration, the duration of incubation, and the percentage saturation of the plasma iron-binding capacity. However, under the same conditions, the iron uptake of red cells from normal (+/+) mice was greater than that by red cells from anemic (mk/mk) mice. Furthermore, the cellular loss of radioiron on exposure to EDTA was greater for the mk/mk red cells, although the proportion of the radioiron taken up that was incorporated into heme was the same for mk/mk and +/+ red cells. These results support the hypothesis of a generalized impairment of cellular iron uptake in hereditary microcytic anemia and suggest that there might be a defect in red cell receptor sites for transferrin in this condition.     

Metabolic consequences of intrauterine growth retardation

This review focuses on intrauterine growth retardation (IUGR) occurring spontaneously and without a defined infective, toxic or genetic cause. Such fetal growth retardation is generally thought to be a consequence of inadequate provision of nutritional substrates across the placenta.     

Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone

The effect of rotenone treatment on [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio] acetic acid (WY-14,643) hepatic lesion growth in male B6C3F1 mice was investigated. Following induction of hepatic focal lesions by diethylnitrosamine (DEN) 35 mg/kg twice a week for 8 weeks, mice were placed into one of the four treatment groups: group I, control NIH-07 diet (control diet), group II, rotenone (600 mg/kg diet), group III NIH-07 diet containing WY-14,643 (1000 mg/kg diet), and group IV, NIH-07 diet containing WY-14,643 (1000 mg/kg diet) and rotenone (600 mg/ kg diet). Mice were killed after 30 and 60 days of dietary treatment. The effect of treatment with WY-14,643 and rotenone on hepatic lesion growth was examined by estimating the number of focal lesions per liver and the relative volume of focal lesions. WY-14,643 (group III) increased both the number and the volume of focal lesions. In particular, an increase in number and volume of basophilic lesions was seen. Co-treatment with WY-14,643 and rotenone (group IV) decreased both the number and the volume of the total number of focal lesions and basophilic foci compared with WY-14,643 treatment alone (group II). Alterations in the growth of hepatic focal lesions was further investigated by examining DNA synthesis and apoptosis within individual lesions. WY-14,643 (group III) treatment increased the DNA synthetic labeling index in all foci. Co-treatment of rotenone and WY-14,643 (group IV) decreased focal DNA synthesis and mitosis and increased the incidence of apoptotic hepatocytes. These data suggest that rotenone's ability to inhibit WY-14,643-induced hepatic focal lesion growth was mediated through a decrease in hepatic focal proliferation and an increase in focal apoptosis.      

Long-acting dihydropyridine calcium antagonists. 9. Structure activity relationships around amlodipine

The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated. Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor. Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituent and the DHP receptor. Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity.     

Unintended pregnancies in women delivering at 18 South American hospitals. NFP-ECLAMC Group. Latin American Collaborative Study of Congenital Malformations

Unintended pregnancies are accepted as associated with social, maternal and perinatal risks, but few data exist in South America. In a selected network of hospitals participating in the ECLAMC (Spanish acronym for Latin American Collaborative Study of Congenital Malformations), the frequency of unintended pregnancies was 49.8% in 5155 mothers of normal liveborns, as interviewed in the post-partum period (1992-1994). Compared with the intended pregnancy group, these mothers were more frequently multiparous, conceived easily, had a surprisingly higher mean maternal age, lower educational level, and Black ancestors. The frequency of mistimed pregnancies was the highest among primiparae. No adverse perinatal outcome could be found with regard to low birthweight (< 2500 g), prematurity (< 37 weeks), and early neonatal death. The rates of Caesarean delivery, twinning and sex ratio were similar in intended and unintended groups. Logistic regression analysis showed that maternal education could be a confounding factor associated with other maternal variables. The rate of unintended pregnancies in the present study is significantly higher than that described for other regions. Knowledge of the characteristics of women experiencing unintended pregnancies would allow proper public health strategies.      

Combined and sequential effects of human IL-3 and GM-CSF on the proliferation of CD34+ hematopoietic cells from cord blood

The proliferative effects of recombinant human interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were investigated in semi-solid and liquid cultures of purified CD34+ hematopoietic cells obtained from umbilical cord blood. No important differences in overall cloning efficiencies in response to IL-3 or GM- CSF were observed in semi-solid medium in the presence of erythropoietin (Ep). However, GM-CSF was less effective for the development of erythroid bursts (BFU-E), and only IL-3 was observed to induce significant numbers of mixed-erythroid colonies (E-MIX). Both IL- 3 and GM-CSF also induced proliferation of CD34+ in liquid cultures. Proliferative responses to IL-3 were found to be more rapid and stronger than to GM-CSF, although the number of initial responsive cells as judged by autoradiography were comparable. Enhanced proliferation of CD34+ cells both in semi-solid and liquid cultures was obtained in the presence of combinations of IL-3 and GM-CSF. The responses observed were less than additive, with the exception of the development of eosinophil colonies and clusters, where IL-3 and GM-CSF were found to act synergistically. In secondary cultures, proliferative responses to GM-CSF were strongly enhanced by preculture of CD34+ cells in IL-3 for four to 11 days, and to a lesser extent by preculture in GM- CSF. Finally, responses to IL-3 were not affected by preculture of CD34+ cells in the presence of GM-CSF. Our results indicate that there is a wide overlap of cells capable of proliferating either in response to IL-3 or to GM-CSF within the cord blood CD34+ compartment. However, differences in primary proliferation kinetics and increased responsiveness to GM-CSF following preculture suggest the importance of a sequential action of IL-3 and GM-CSF in the expansion of CD34+ cells.     

Cholangiocarcinoma complicating primary sclerosing cholangitis: cholangiographic appearances

Cholangiograms from 104 patients (and serial cholangiograms in 66 patients) with primary sclerosing cholangitis (PSC) were reviewed. In 13 patients the additional diagnosis of cholangiocarcinoma was made at biopsy or autopsy. Cholangiograms from patients with both PSC and carcinoma were compared with cholangiograms from patients with PSC alone. Marked dilatation of ducts or ductal segments (100% vs. 24%) and the appearance of a polypoid mass (46% vs. 7%) were common findings in the group of patients whose disease was complicated by malignancy. In the malignant group, polypoid masses were larger, measuring 1 cm or greater in diameter. On serial cholangiograms, four of 15 patients with progressive stricture formation and four of five with progressive ductal dilatation proved to have carcinomas. The frequent occurrence of bile duct carcinoma as a complication of PSC in this group of patients indicates that PSC has a strong tendency to undergo malignant degeneration. Cholangiographic findings which suggest malignant degeneration include markedly dilated ducts or ductal segments, presence of a polypoid mass 1 cm or greater in diameter, and progressive stricture formation or ductal dilatation.