The role of the placenta in fetal nutrition and growth.

The placenta plays a key role in the nutrition of the fetus. It mediates the active transport of nutrients and metabolic wastes across the barrier separating maternal and fetal compartments, as well as modifying the composition of some nutrients through its own metabolic activity. The function of the placenta is essential to the growth of a healthy fetus; it is becoming apparent that the activities of the placenta are in turn modulated by signals originating from the fetus. Communication between placenta and fetus is especially critical in intrauterine growth retardation. The importance of the interaction of factors like insulin-like growth factor and epidermal growth factor with their receptors is becoming increasingly clear.

The failure of parenteral copper therapy in Menkes Kinky Hair syndrome.

In the untreated infant with Menkes Kinky Hair Syndrome, copper concentrations in brain and liver are deficient, while excessive copper accumulates in other tissues. The observed serum ceruloplasmin response after parenteral copper administration is suggestive of an impairment in the incorporation of copper into this metalloprotein. These findings, together with increased urinary copper excretion and the absence of clinical improvement, are compatible with a generalized defect in copper metabolism, transport or storage. The excessive accumulation of copper in many tissues illustrates the potential danger of parenteral copper therapy.

Polyamines in the developing mouse brain.

Polyamine levels were determined during pre- and postnatal development of the male and female mouse brain to assess their possible role during normal brain development. Tissue polyamine levels were increased during periods of neurogenesis and increased cell packing density (assessed by DNA levels) in all brain regions: cerebral cortex, cerebellum, hypothalamus, and rhombencephalon-midbrain. Tissue polyamine levels declined subsequently in a tissue-specific manner toward adult levels. In contrast, the polyamine concentrations per cell were decreased during periods of neurogenesis. A later increase in rhombencephalon-midbrain spermidine levels is consistent with the presumed association of this polyamine with myelin. No sex differences were found in these studies.

Evaluation of a Tay-Sachs screening program on a college campus.

A screening program for Tay-Sachs disease was done on a predominantly unmarried, university student population and later evaluated. Ten carriers were detected among a population of 390 screened. Voluntarily screened individuals were given a questionnaire at the time of screening and after their carrier status was revealed. In addition, individuals in a target population were queried as to why they did not attend the screening. Results of evaluation indicate that both the screened and unscreened students were able to answer approximately two thirds of a set of questions on Tay-Sachs correctly, but there was widespread lack of knowledge regarding the implications of carrier status and inheritance of the disease. In general, respondents to the questionnaires were not opposed to abortion. However, when asked about the family planning alternatives that they would consider if they were carriers, more subjects preferred adoption, artificial insemination, or avoidance of pregnancy to abortion.

Trace metals and hemoglobin metabolism.

Hemoglobin is composed of two pairs of globin chains to which are attached four iron-containing metalloporphyrins. Factors regulating hemoglobin synthesis include the availability of iron and the presence of heme. Heme production occurs by enzymatic synthesis and includes a step mediated by aminolevulinic acid dehydrase, which is zinc-dependent and, thus, susceptible to the toxic effects of other metals. The intake of iron, copper, zinc, cobalt, manganese, cadmium or lead may affect hemoglobin levels by an influence on availability of iron or heme.

Alcaptonuria and sucrase-isomaltase deficiency in three offspring of a consanguineous marriage.

Intestinal brush border membrane hydrolases and HLA lymphocyte antigens have been examined in three siblings with sucrose intolerance and alcaptonuria, and their consanguineous parents. Sucrase-isomaltase activity was absent in the three patients, and corresponded with the gel electrophoresis of SDS-solubilized brush border membranes, which failed to demonstrate the protein band normally associated with sucrase-isomaltase complex. The activities of all brush border membrane enzymes in the mother were normal, while those of the father were generally low. The use of hydrolytic capacity ratios, however, permitted the designation of both parents as heterozygotes. Significant homogentisic aciduria was found only in the three propositi, and no effect of homogentisic acid on the sucrase activities of two normal, unrelated children could be demonstrated in vitro. The HLA lymphocyte antigen profiles of all seven family members demonstrated remarkable histocompatibility in five of them.

Clinical manifestations of hypothalamic tumors.

The regulatory function of the central nervous system encompasses diverse endocrine, metabolic, and behavioral processes. Many of these originate, are integrated, or are coordinated through hypothalamic pathways or nuclei. Thus, tumors affecting areas projecting to the hypothalamus, tumors of the hypothalamus, and tumors invading or compressing the hypothalamus can produce abnormalities of hypothalamic function.

Low dose single weekly injections of growth hormone: response during first year of therapy of hypopituitarism.

Initial year growth responses to single weekly injections of 2.5 units human growth hormone (hGH) in 29 patients with hypopituitarism (130 units/yr/patient) were compared to responses in a series using smaller doses in conjunction with androgen (48 to 112 units/yr); the US collaborative study experience with the standard dose (2 units 3 times/wk = 312 units/yr), and with two size-adjusted doses (0.06 units/kg 3 times/wk = 212 +/- 94 SD units/yr, 0.03 units/kg 3 times/wk = 116 +/- 33 units/yr); and to the British experience with much larger doses (1,040 units/yr). During the first year of hGH treatment our patients grew an average 13% faster than the androgen-supplemented and collaborative study-0.03 units/kg/dose groups. They had a similar pace to the collaborative study-312 units/yr and 0.06 units/kg/dose patients, but grew 15% more slowly than did the British patients. Growth response correlated positively with age and negatively with hGH dose per kilogram of body weight. Of 17 patients with isolated growth hormone deficiency ten developed hypothyroidism with hGH therapy, leading to a policy of routine adjunctive thyroxine replacement.

Cancer of endocrine glands and target organs: genetic considerations.

The pathogenesis of cancer in general is influenced by many factors, genetic and environmental. Epidemiological studies demonstrate familial aggregation of cancer in a significant proportion of cases. Many of these familial cancer syndromes contain endocrine hormone-related components. The etiology of endocrine-related cancers is complex, as is that of other cancers. Tumors of endocrine glands and target organs are subject to the same influences as other cancers; an additional variable is that of hormone-responsiveness.

Medullary carcinoma of the thyroid in the multiple mucosal neuromas syndrome.

The clinical features of the multiple mucosal neuromas (MMN) syndrome permit the recognition of these patients and their potential development of the associated medullary thyroid carcinoma (MTC). The distinctive physical appearance caused by the mucosal neuromas, the Marfanoid habitus and, occasionally, the positive family history aid in establishing the diagnosis. Neurogangliomas are frequently present in the gastrointestinal tract of these patients who may have megacolon, constipation and diarrhea. The third instance of the MMN syndrome is reported in the newborn as intestinal obstruction. It is suggested that the syndrome be considered in the differential diagnosis of Hirschsprung's disease and bowel obstruction in the neonate. Serum calcitonin measurements following stimulation by calcium or pentagastrin infusion reliably detect incipient MTC and may be used to select those MMN patients requiring thyroid surgery. Recognition of patients with the MMN syndrome and subsequent calcitonin screening and early surgical intervention will significantly reduce the chance of their developing terminal MTC. All MMN patients with mucosal neuromas or intestinal neurogangliomas should have such evaluations at least yearly. Relatives who are at risk for inheriting this dominant disease should be similarly evaluated, regardless of their normal appearance.

Inducibility of metallothionein biosynthesis in cultured normal and Menkes kinky hair disease fibroblasts: effects of copper and cadmium.

Metallothionein biosynthesis is not induced by extracellular copper in Menkes Kinky hair disease (MKHD) or in normal cultured fibroblasts under the conditions of these experiments. In the presence of copper, MKHD fibroblasts also incorporated less cysteine than did normal fibroblasts. Extracellular cadmium greatly enhanced the uptake of cysteine in both normal and MKHD cultures. By the technique of polyacrylamide gel electrophoresis, it was demonstrated that metallothionein is induced by cadmium in normal and MKHD-cultured fibroblasts.

Metal-binding studies of metallothioneins in Menkes kinky hair disease.

Two species of metallothioneins were isolated from both normal and Menkes kinky hair disease (MKHD) patient livers. Atomic absorption determination of metals indicated that the patient liver metallothioneins had lower copper and cadmium content than normals. Isotope exchange studies, carried out by incubating native metallothioneins with copper-64 or cadmium-109 demonstrated a decreased affinity for copper and an increased affinity for cadmium in both MKHD metallothioneins. An hypothesis is proposed in which metallothionein functions as an intracellular copper carrier and is responsible for the transport of copper between the cells and the surrounding. Change in the copper affinity of the metallothioneins was suggested to be the major abnormality in MKHD.

Cell culture studies of Menkes kinky hair disease.

The dose response as well as kinetics of uptake and retention of copper and cadmium of normal and Menkes kinky hair disease (MKHD) cultured fibroblasts are described. In basal culture medium, intracellular copper concentration in MKHD fibroblasts was approximately 3 times that of control cultures. The intracellular copper concentration of MKHD cells was significantly higher than that of normal fibroblasts at medium copper concentrations below 20 microgram/ml. Death of MKHD cells occurred at medium copper concentrations between 15 and 20 microgram/ml with an intracellular copper level 3 times that at basal medium. Normal cells died at medium copper concentration above 30 microgram/ml with an intracellular copper concentration 19 times that at basal medium. These observations suggested the existence of a regulatory mechanism for maintenance and control of intracellular copper in normal fibroblasts which is effective at medium copper concentrations below 30 microgram/ml. This system is defective in MKHD fibroblasts. In basal medium MKHD and normal fibroblasts had similar intracellular cadmium concentrations; however, at higher medium cadmium concentrations MKHD cells had increased intracellular cadmium levels. The uptake of both 64Cu and 109Cd was significantly higher in MKHD cells than in normal cells, indicating that the uptake of 64Cu and 109Cd is not impaired in MKHD cells. A higher retention of 64Cu was observed in MKHD cells at both 37 degrees C and 4 degrees C. No obvious trend, however, was observed in the difference of retention of 109Cd between MKHD and normal cells. An impairment of egress of copper in MKHD cells is implicated by these results.

Role of metallothioneins in copper transport in patients with Menkes syndrome.

Fibroblasts from infants with Menkes kinky hair syndrome, which accumulate excessive quantities of copper, are thought to represent a disorder of copper storage or transport. Because of this abnormality, it was thought that they might provide a useful system for investigation of the presumed storage or transport protein metallothionein. Data are presented which are consistent with defective copper efflux from the mutant cells. Because of the more specific role of metallothionein in cadmium detoxification, studies of cadmium metabolism were undertaken which demonstrated abnormal cadmium retention and metallothionein induction in the mutant cells. The association, therefore, of a defect of cadmium metabolism and storage with an abnormality of copper efflux provides evidence implicating metallothionein in copper transport for fibroblasts.

Serum polyamine and octopamine changes following partial hepatectomy and portacaval shunt.

Factors influencing hepatic regeneration following major hepatic resection are poorly understood and often may be modified by associated surgical procedures. Experimental and clinical evidence would suggest that hepatic regeneration may be impaired following hepatectomy performed in conjunction with portacaval shunting. A patient is described who offered a clinical situation in which it was possible to evaluate the effects of complete portal-venous diversion on hepatic regeneration following massive hepatic resection. The usefulness of biogenic amines as a monitor of the course of hepatic regeneration is demonstrated. The potential development of hepatic encephalopathy was evaluated by serial determinations of serum ammonia and the biogenic amine, octopamine, which correlated well with the patient's clinical state.

Intestinal mucosal enzymes in the diagnosis of gastrointestinal metabolic disease.

The small intestinal mucosa is an actively metabolizing, rapidly proliferating, absorptive epithelium with nutritional and homeostatic functions. A metabolic dysfunction of this organ might, therefore, be expected to cause not only gastrointestinal dysfunction, but also systemic symptoms. Several diseases characterized by primary or secondary gastrointestinal metabolic alterations are discussed.

Menkes kinky hair syndrome: Is it a treatable disorder?

A male infant with Menkes Kinky Hair Syndrome was treated with a 3-week course of cupric acetate infusions, which was terminated when he developed aminoaciduria. The lack of improvement seen in this infant is representative of the reported experience with parenteral copper therapy in this condition, and may be attributable to the presence of a clinically significant abnormality in copper metabolism in utero.