The detection of alpha 1-fetoprotein in patients with viral hepatitis.

PIP: Alpha fetoprotein (AFP) was detected in sera (351 samples) of 128 patients with viral hepatitis by radioimmunoassay. 77 positive tests for AFP were obtained. These positive results were demonstrated on 1 or more samples taken from 40 (31%) of the 128 patients studied; the highest value obtained was 4400 ng/ml. Hepatitis B antigen (HBAg) was positive in 26/40 (65%) of patients in whom AFP was detected during the disease process. However, 58/88 (66%) who were seronegative for AFP also demonstrated HBAg in their sera. Chi-square analysis revealed no significant difference in occurrence of detectable AFP between HBAg seropositive and seronegative patients. Individuals seropositive for AFP had no statistically different concentration of the protein than patients seropositive or seronegative for HBAg. 24 patients' sera were tested serially over a 2-week period. Both the peak glutamic-pyruvic transaminase (GPT) and peak total bilirubin levels were in a higher range in those 10/24 patients seropositive (P .001) for AFP than in the 14/24 who were seronegative. Appearance of AFP was related to the severity of liver tissue destruction, as reflected by serum GPT. However, peak AFP levels were attained 5-16 days after peak serum GPT appeared in the circulation.^ieng

Early appearance of embryonic -globulin in rat serum during carcinogenesis with 4-dimethylaminoazobenzene.

PIP: Heptatic tumors were induced in male Donryo rats by feeding them a 4-dimethylaminoazobenzene diet to study the occurrence of serum alpha globulin (AG) in rats during carcinogenesis. AG was found in rat serum as early as the 3rd week after onset of feeding of the carcinogenic diet; this was designated the early-stage appearance. The embryonic protein was observed in 31 (76%) of 41 rats at the 6th week after diet introduction. Subsequently, concentrations of AG decreased, and by the 11th-12th week it disappeared from serum. After 13 weeks, the developmental protein reappeared in 27/33 rats, designated the last-stage appearance, and 26 of these animals developed hepatomas. Of the 22 rats in which AG appeared in the early stage, 20 (91%) developed hepatomas after 19 weeks. By the 6th week of the carcinogenic diet, the average serum level of AG was 2-4 mg/dl, but after 13 weeks, it reached 60-100 mg/dl, corresponding to the serum level of newborns. Since most of the rats in which AG appeared at the early stage developed hepatomas, the early appearance of the protein may be related to cancerization of liver cells; on the other hand, the early appearance of AG may simply reflect an acute liver lesion caused by the toxicity of 4-dimethylaminoazobenzene. All rats that developed hepatomas were AG positive.^ieng

Radioimmunoassay of rat 1 -fetoprotein.

PIP: A competitive binding radioimmunoassay for rat alpha 1 fetoprotein (AFP) was developed, using Sprague-Dawley rat amniotic fluid. The assay was approximately 20,000 times more sensitive than double-diffusion in agar for AFP detection; the assay threshold was 5 ng. Further purification of apparently pure (by immunodiffusion and immunization) radiolabeled AFP was required for the specific assay. An assay for a previously undetected contaminant(s) was used to check the purity of rat AFP isolated by isoelectric focusing to obtain the purified unlabeled AFP needed to establish the standard inhibition curve. All procedures are outlined.^ieng

Early appearance of serum -fetoprotein as a function of dosage of various hepatocarcinogens.

PIP: A previously reported early appearance of alpha fetoprotein (AFP) in rats fed 3'-methyl-4-dimethylaminobenzene (3-MDAB) which was induced before definite cancers were formed and disappeared on cessation of 3-MDAB administration was further investigated using different doses of 3-MDAB as well as other hepatocellular carcinogens and hepatotoxic agents. AFP was induced after 3 weeks of ingestion of diets with 600 ppm 3-MDAB and appeared after only 2 weeks when higher doses (900 and 1200 ppm) were used. Lower levels of 300 ppm 3-MDAB gave only a transient appaerance of AFP, beginning at the 5th week and remaining detectable for 3 more weeks, but 150 ppm did not induce at all. Immunosuppression with rat lymphocyte globulin extended for 1 week the time during which positive AFP titers were maintained upon cessation of 3-MDAB (600 ppm) intake. A transient appearance of AFP was found when rats were given the carcinogens dimethyl-4-dimethylaminoazobenzene (4-DMAA; 600 ppm), aflatoxin (AFB1; 4 ppm), N-2-fluorenylacetamide (N-2-FAA; 200 and 300 ppm), and N-hydroxy-N-2-fluorenylacetamide (N-OHFAA; 213 and 320 ppm). Lower doses of AFB1 (.2 and 2 ppm), N-2-FAA (150 ppm), N-OHFAA, and diethylnitrosamine (40 ppm) did not induce detectable AFP levels in serum nor did 2'-methyl-4-DMAA (600 ppm) and CCl4 (50 mg intraperitoneally twice a week). Apparently, high levels of liver carcinogens are required to induce the early appearance, within 2-5 weeks, of detectable AFP in serum.^ieng

Alpha-fetoprotein in ontogenesis and its association with malignant tumors.

PIP: The major steps in development of ontogenesis and the role of alpha fetoprotein (AFP) synthesis are outlined. AFP is defined and its physiocochemical characteristics are described including methods of detection and identification. The liver and yolk sac of fetuses are shown as the principle sites of AFP synthesis in ontogenesis, and the dynamics of AFP in ontogenesis from the early embryonic period through midpregnancy to pregnancy termination to AFP shut-down in early postnatal period are displayed. AFP synthesis during regeneration of the liver provides the model for studying the nature of AFP production. The role of AFP in hepatocellular cancer receives a great deal of attention, focusing on the site of AFP synthesis in cancer of the liver; demonstration of AFP in blood of cases of hepatic cancer (and other diseases) by agar-gel precipitation; quantitative aspects of AFP production by liver tumors; and etiologic and pathogenic influences on AFP production by hepatomas. Clinical aspects of the diagnosis of liver cancer are reviewed. The occurrence of AFP with teratocarcinomas is remarked upon. The article's central objective was to emphasize the importance of basic research on AFP, especially the development of an accessible high-sensitivity test for use in broad epidemiological surveys. Experimental approaches to some immediate problems were formulated: 1) Is there any external factor controlling AFP synthesis and determining its intensity? 2) Is synthesis performed only by certain cell types or is AFP production inherent in any hepatocyte? 3) Is control of AFP synthesis accomplished by regulating the intensity of the process in individual cells or by involvement of a varying number of cells? And 4) is AFP synthesis in a tumor due to maintained ability of the stem tumor cell to differentiate or is it the result of dedifferentiation of the mature hepatocyte??^ieng

Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception.

To determine the effect of androgens on body composition and muscle strength, we measured fat-free mass (kg), fat mass (kg), and bone density (g/cm2) by dual x-ray absorptiometry, and muscle strength (Newton meters) by dynamometry in a controlled, prospective study involving 13 nonathletic men receiving testosterone enanthate 200 mg/week in for 6 months and 8 healthy controls. Biochemical markers of bone turnover were measured in the treated subjects at baseline and 6 months. In the treated subjects at 6 months, fat-free mass (mean +/- SEM) increased by 9.6 +/- 1.0% (P < or = 0.01) whereas fat mass decreased by 16.2 +/- 6.7% (P < or = 0.05). Changes in muscle strength ranged from -1.6-19.2%. Only hip adduction increased 19.2 +/- 9.5% (P < 0.05). Changes in bone density ranged from -1.3-5.2%, decreasing significantly at one site and increasing significantly at four of the nine sites measured (P < 0.05). Serum testosterone increased by 91.1 +/- 7.5% (P < 0.01), and testicular volume decreased by 24.0 +/- 3.2% (P < 0.01). Serum osteocalcin increased by 35.7 +/- 17.3% (P < 0.05), serum immunoreactive PTH (iPTH) increased by 41.4 +/- 15.1% (P < 0.05), serum calcium decreased by 2.3 +/- 1.0% (P < 0.05), and serum albumin decreased by 4.5 +/- 1.7% (P < 0.05). There were no detectable changes in fat-free mass, fat mass, muscle strength, or bone density in controls. The administration of testosterone enanthate in pharmacological doses for 6 months resulted in a modest reduction in fat mass and small increases in fat-free mass, muscle strength, and bone density. These changes do not support the use of androgens for enhancing athletic performance.

PIP: In Melbourne, Australia, physicians compared data on 13 healthy, nonathletic, 21-37 year old men receiving an intramuscular injection of 200 mg testosterone enanthate once a week for 6 months with data on 8 age-matched healthy controls to examine the effect of this androgen on body composition and muscle strength and to determine whether it may enhance athletic performance. Dual x-ray absorptiometry measured total body and regional bone density. Dynamometry measured muscle strength. Controls did not experience any detectable changes in fat-free mass, fat mass, muscle strength, or bone density. Between baseline and 6 months of testosterone enanthate treatment, the fat-free mass of cases increased 9.6% (about 6 kg; p .01), while fat mass fell by 16.2% (about 2 kg; p .05). When compared with the literature, however, these changes in body composition were modest. It is not sure whether an increase in lean muscle mass or fluid retention accounted for the increase in fat-free mass. Muscle strength changes varied from -1.6% to 19.2%. Body weight increased by about 5% (around 4 kg). Of the 6 movements, hip adduction was the only significant muscle strength change (increased 19.2%; p .05). Bone density decreased by 1.3% at the skull (p .05), while it increased significantly at the lumbar spine, ribs, pelvis, and femoral neck (p .05). It did not change significantly at the arms, Ward's triangle, trochanter, or legs. The increase in bone density were not enough to reduce the risk of bone fractures. Testosterone enanthate treatment increased serum testosterone levels by 91.1% (p .01), serum osteocalcin by 35.7% (p .05), and the serum immunoreactive parathyrin by 41.4% (p .05). It decreased testicular volume by 24% (p .01), serum calcium levels by 2.3% (p .05), and serum albumin levels by 4.5% (p .05). Based on these findings, androgens, at least in the administered dose range, should not be used to enhance athletic performance.

Anti-estrogens and plasma proteins. II. Contraceptive drugs and gestagens.

PIP: The effects of Ovral (.5 mg norgestrel and .05 mg ethinyl estradiol (EE), and Norlestrin (1 mg norethindrone acetate and .05 mg EE) in women; dydrogesterone alone and with EE in men; and norgestrel, chlormadinone, EE, cyproterone and 17-alpha-methyltestosterone in green monkeys, on plasma proteins and hormones were studied, in an attempt to reverse estrogenic changes. Both contraceptives, given for 2 cycles to 25 women, increased corticosteroid-binding globulin, cortisol, thyroxin, and plasminogen, and Norlestrin increased fibrinogen. 30 or 40 mg dydrogesterone with .01 mg EE did not block the changes induced by estrogen alone in 5 men. Plasma protein and hormone levels in monkeys, tabulated after 2.5 mcg EE, 2 mg norgestrel alone and with 2.5 mcg EE showed that the estrogen effects of EE on corticosteroid-binding globulin and haptoglobin could be reversed by norgestrel. Similarly, 12.5 mg chlormadinone blocked the action of EE on thyroxine. The experiment with cyproterone acetate and methyltestosterone did not yield significant results.^ieng

Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives.

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.

PIP: The effect of oral contraceptives (OCs) on hepatic drug elimination, in this case chlordiazepoxide, was studied in 11 healthy young men, 11 healthy young women, and 7 healthy young women receiving OCs for more than 6 months. Elimination half-life was longer (14.8-8.9 hours) and the protein binding less (95.5 and 97%) in women than in men. When weights were normalized, plasma clearances of total drug did not differ, but clearance of unbound drug was significantly less in women (8.7 ml/min/kg) than in men (15.6 ml/min/kg). Women taking OCs had a lower plasma binding (from 93.6-95.5%) and a higher volume of distribution (from .62-4 1/kg) than women not taking OCs. Elimination half-life was longer (from 23.4-14.8 hours) and clearance of unbound drug lower (from 5.7-8.7 ml/min/kg) in women on OCs than in those not using them, but these differences were not statistically significant.

Lactation and pregnancy in Iran. II. Diet and nutritional status.

Dietary intake in the third month postpartum and nutritional status during pregnancy close to term were assessed in Iranian urban uomen of low and middle socioeconomic status as part of a study investigating nutrition, hormonal status, and lactation in a population where lactation failure is a serious problem. Dietary intake was assessed by the 24-hr-recall method. The greatest differential in food groups consumed was in animal products, fruit, and vegetables. Intake of nutrients equal to or less than 80% of recommendations in both socioeconomic groups were energy, vitamin B6, folacin, calcium, iron, and zinc. In the low socio-economic group, only average intakes of vitamin C, thiamin and protein met the standards. Significant differences were found between the socioeconomic groups in hemoglobin, hematocrit, serum total protein, and protein fractions, but not in weight and height. The only parameters of nutritional status significantly correlated with adequacy of lactation were postpartum weight and percent of standard weight for height in the low socioeconomic group, and hematocrit values in the middle socioeconomic group. Differences between pregnant and postpartum individual values of the blood parameters were in general greater in the middle socioeconomic group than the low socioeconomic group.

PIP: Dietary intake in the 3rd month postpartum and nutritional status during pregnancy close to term were assessed in Iranian urban women of (LSE) low socioeconomic status and (MSE) middle socioeconomic status as part of a study investigating nutrition, hormonal status, and lactation in a population where lactation failure is a serious problem. Dietary intake was assessed by the 24-hour recall method. The greatest differential in food groups consumed was in animal products, fruit, and vegetables. Intake of nutrients = or than 80% of that recommended to both socioeconomic groups were energy, vitamin B6, folacin, calcium, iron, and zinc. In the LSE group, only average intakes of vitamin C, thiamin, and protein met the standards. Significant differences were found between the socioeconomic groups in hemoglobin, hematocrit, serum total protein, and protein fractions, but not in weight and height. The only parameters of nutritional status significantly correlated with adequacy of lactation were postpartum weight and % of standard weight for height in the LSE group, and hematocrit values in the MSE group. Differences between pregnant and postpartum individual values of the blood parameters were in general greater in the MSE group than the LSE group.

Absorption of macronutrients from a rice-vegetable diet before and after treatment of ascariasis in children.

The apparent absorption of nitrogen (N), fat, and total energy from a rice and vegetable diet was measured in 13 children of similar nutritional status but infected with varying loads of Ascaris lumbricoides. Apparent N absorption was modestly decreased initially in subjects with heavy infections as compared to those with light infections (57.2% of intake versus 64.1% of intake, 0.05 < P < 0.1). After antihelminthic therapy there ws a significant improvement in apparent N absorption (P < 0.02), apparent N retention (P < 0.05), and apparent fat absorption (P < 0.05) for the group as a whole, particularly for those with heavy infections. Total energy absorption improved slightly, but not significantly, after treatment, and there was no change in xylose excretion tests. Treatment of ascariasis may be nutritionally advantageous for children with heavy worm burdens and marginal protein availability.

Protein and amino acids of breast milk from Thai mothers.

The protein, amino acids, and nonprotein nitrogen of milk samples obtained from Thai mothers over a period of 0 to more than 270 days postpartum were determined. Protein levels decreased from 1.56% during the 1st wk to a low of about 0.6% from 180 to 270 days and then rose to about 0.7%. The amino acid pattern of the milks suggested a number of differences in their composition and those of samples analyzed in other countries. Nonprotein nitrogen varied from 20 to 40% of the total nitrogen of the milk. It has been concluded that the need for supplementation of breast-fed Thai babies may occur earlier than many nutritionists advocate.

PIP: This study evaluates the effects of prolonged lactation on the quantity of protein and pattern of amino acids in breast milk of 135 Thai women at various times of lactation (from 0 to 270 days postpartum). Breast milk samples were collected approximately 3 hours after nursing at various times during 1978. Total nitrogen, tryptophan and amino acids were respectively analyzed by the methods of Williams, Lorenzo-Andreu and Frandsen and Matheson, and Hitachi Perkin-Elmer Model KLA3B amino acid analyzer. Protein level in breast milk was highest during the 1st week (1.56%) and decreased steadily with time until a level of 0.60% during the period of 180 to 270 days, after which protein content appeared to increase. Ratio of essential to nonessential amino acids was constant throughout the study. Protein or amino acid levels during lactation were not significantly affected by maternal age and parity, although maternal age, parity and socioeconomic factors had been known to affect total milk secretion. Amino acid levels in this study were generally similar to reported values from American and Scottish women, although methionine, valine and tyrosine were lower and tryptophan and lysine were higher. Although breast milk has a nutritional value of the highest quality, it can be argued that the need for supplemental feeding may still occur earlier in life than is often realized. A discussion of the FAO/WHO standards for protein allowances suggests that infants up to 3 months of age require approximately 2 or more g of milk protein per kg daily, while children 60 to 12 months of age require about 1.5 g/kg/daily. Considering that protein content of Thai breast milk is about 0.9% after 3 months of lactation, it is estimated that 1250 ml of milk are needed to supply the protein needs of a 3-month old child, and 950 ml would be insufficient (average daily production of milk varies from 850 ml to 1200 ml). Many Thai and other women who are exclusively breastfeeding may find it difficult to provide the protein needs of their infants, unless supplemental feeding is carried out.

Familial dysfunction of protein S.

We describe a previously unreported defect of protein S characterized by low levels of cofactor activity for activated protein C contrasting with low normal levels of total and free protein S antigen. The distribution of protein S between the free form and the form complexed with the complement component C4b-binding protein was normal on two-dimensional immunoelectrophoresis. The proband developed juvenile deep-vein thrombosis while taking oral contraceptives. Her defect was transmitted in an autosomal dominant fashion from her asymptomatic mother. Other relatives carrying the same laboratory abnormality (mother, maternal uncle, two sisters and one brother) were also asymptomatic. We postulate that the defect is due to a dysfunctional protein S present in plasma in normal amounts and with normal proportions of the free and complexed forms of the protein.

PIP: A case of deep-vein thrombosis in a 23-year old woman 1 month after starting oral contraceptives is described, the 1st known incident of defective Protein S activity with normal levels of Protein S but defective APC cofactor. The woman had no known personal risk factors or family history of thromboembolism. She noticed pain and swelling of her right leg, and on admission to the Institute of Internal Medicine of the University of Milan, bilateral leg venography demonstrated occlusion of the right popliteal, femoral and iliac veins. She was treated with intravenous heparin for 10 days, and then warfarin. Protein S is a vitamin K-dependent plasma protein which binds to platelets and endothelial cells and functions as a cofactor for Protein C in the proteolytic cleavage of the activated forms of coagulation factors V and VIII. Persons with Protein S deficiency are at a high risk for thromboembolism. All coagulation laboratory screens were normal on repeated testing of the proband's plasma before initiating therapy, as well as her family members. In this patient total protein S antigen was low normal by EIA and ELISA. APC-cofactor was the only assay clearly abnormal, in the proband, her mother, siblings and maternal uncle; APC- cofactor activity was restored to normal by adding back pure Protein S.

Effect of oral contraceptives on antithrombin III measurement.

PIP: Various clinical experiments have shown that women taking oral contraceptives have functional values of antithrombin 3 that are less than the values measured with the electroimmunoassay method for antithrombin 3. No final explanation for this occurrence is available. Since tests were performed on the same serum specimens, differences in antithrombin 3 concentrations in plasma and serum do not account for the difference between functional and immunologic values. Electroimmunoassay, unlike radioimmunoassay, does not measure both free and complexed antithrombin 3; therefore, if complexes between thrombin and antithrombin 3 were present, they did not contribute to over- or underevaluation of antithrombin 3. It is possible that an inhibitor is responsible. Results of these experiments point out the importance of measuring both functional properties and protein concentrations together.^ieng

Metabolic effects of oral contraceptives in monkeys fed on adequate and low protein diets.

PIP: Rhesus monkeys were given either high estrogen, low progesterone or low estrogen-high progesterone oral contraceptive agents (OCAs) and maintained on either a 16% protein diet or a 4% protein diet. Both OCAs created a small but significant fall in hemoglobin and serum protein. On both diets, OCAs led to a gradual elevation of serum alkaline phosphatase and serum glutamic oxalic transaminase (SGOT) activities. There were no histologic liver lesions. On the low protein diet, glucose tolerance was impaired between cycles 10 and 11, and on the high protein diet between cycles 16 and 20. Vitamins B-12, A, and thiamine tended to be lower in OCA animals. The conclusion of these experiments is that the hazard of using OCAs is not exaggerated by protein deficiency.^ieng

Alpha-Fetoprotein levels in normal males from seven ethnic groups with different hepatocellular carcinoma risks.

Alpha-Fetoprotein (AFP) levels of 1,335 males (15 years and older) of seven ethnic groups (Chinese, Indians, and Malays from Singapore, Caucasians from Lyon, and Blacks from Nairobi, forest, and the savanna region of the Ivory Coast) were determined by radioimmunoassay. A few elevated levels (up to 30 nanounits/ml) were detected in some normal individuals, especially in the older age-groups. In addition, there was a systematic age-dependency of AFP levels particularly evident in the groups from Singapore-Lyon, in which there was a 50% AFP increase between the ages of 20 and 40. Comparison between Africans on the one hand and people from Singapore-Lyon on the other hand revealed highly significant differences (p less than 0.001), especially in the younger groups, whereas Chinese, Malays, and Indians from Singapore had very similar AFP pattern; this suggests an important role for environmental factors in the regulation of AFP levels. The age dependency of the presumed effect of environmental factors is in keeping with experimental data showing that young animals respond more vigorously to AFP-stimulating factors. Although the incidence of hepatocellular carcinoma (HCC) differs in the three Singapore groups (the highest in Chinese and the lowest in Indians), no relationship was observed in this study between mean AFP level and HCC incidence in Singapore.

PIP: The levels of alpha fetoproteins (AFP) were quantitated in 7 ethnic groups (Chinese, Indians, and Malays from Singapore, Caucasians from Lyon, and Blacks from the Nairobi, forest, and savanna region of the Ivory Coast) by radioimmunoassay. Sera from 1335 men (aged 15 years or older) were assayed. Mean AFP levels increased with age and varied among populations. A few elevated (30 nU/ml) AFP values were detected in normal individuals, mostly from older age groups. The systematic age-dependency was particularly evident in groups from Singapore-Lyon, in which there was a 50% increase in AFP between age 20 and 40 years. When Africans were compared on the one hand and people from Singapore-Lyon were compared on the other, highly significant differences were revealed in AFP patterns (P .001). This was true especially in the younger groups; whereas Chinese, Malays, and Indians from Singapore had very similar AFP patterns, suggesting an important role for environmental factors in regulation of AFP levels. The age dependency observed paralleled experimental data where laboratory animals responded most vigrously to AFP-stimulating factors the younger they were. Although the hepatocellular carcinoma incidence differs in the 3 Singapore groups (Chinese highest and Indians lowest), no relationship was observed bwtween mean AFP level and hepatocellular carcinoma incidence in Singapore.

Evolution of alpha-fetoprotein serum levels throughout life in humans and rats, and during pregnancy in the rat.

PIP: A radioimmunoassay method (RIA) with specific antisera for human and rat alpha fetoprotein (AFP) was used to study the evolution of AFP levels in humans and rats, respectively, throughout the life span. Sera of 66 rats, aged 3-70 weeks, as well as sera of 201 clinically well children, 192 healthy blood donors, and 16 persons aged 70-98 were assayed. In humans, AFP levels decreased steeply during the 1st year of life, reaching a low basal range by the end of the 2nd year which is maintained throughout adulthood. Rats showed a similar pattern, but concentrations were higher at every stage of life. Puberty occurs in rats while AFP is still decreasing, whereas in humans the adult basal level is stabilized long before puberty. Maternal serum AFP was studied in 29 rats, and the levels were found to begin a sharp increase on the 10th-13th day of gestation. From Day 13-19, a deceleration of AFP increase was observed which led to a decrease between Day 17 and 19. From Day 19-21, AFP levels increased sharply again. A significant correlation was observed on Day 21 of pregnancy between the number of rat fetuses and the maternal AFP level. Hemihysterectomy led to a reduction of AFP level that was grossly proportional to the number of remaining fetuses. The stable level of AFP that persists throughout adult life is attributed to the stability of this protein's synthesis. Conversely, in pregnancy the evolution of serum AFP curve is dependent on the fetal synthesis, maternal and fetal catabolism, and permeability of the placental barrier.^ieng

Interactions of contraceptive steroids with binding proteins and the clinical implications.

PIP: There are various complex interactions between combined oral contraceptives (COCs) containing the estrogen, ethinyl estradiol, and a synthetic gestagen and sex hormone binding globulin (SHBG). 1 interaction is that the magnitude of effect of the COC on hepatic synthesis, and thus serum concentration of SHBG, depends on the relative doses of the estrogen and gestagen and on the nature of the gestagen. Next, the interaction between the COC and the SHBG affects the biological activity of the synthetic steroids and influences the binding and the biological activity of the sex hormones produced by the body. The extent of this effect is based on the relative doses of the estrogen and gestagen, on the nature of the gestagen, and the concentration of endogenous sex hormones present. In addition, since women take the COC once/day, serum concentrations of the synthetic estrogen and gestagen fluctuate. Therefore the equilibrium between the synthetic hormones and the endogenous sex hormones also changes. Finally, a broad variation exists in serum concentrations of the synthetic estrogen and gestagen between females using the same COC. Therefore large intersubject variations between SHBG and the endogenous and exogenous hormones are expected.^ieng

Differential lipemic and proteinemic response to oral ethinyl estradiol and parenteral estradiol cypionate.

Oral synthetic estrogen administration to normal women has been shown to result in both a lipemic and a proteinemic response. To determine whether parenteral estrogen administration would have similar results, the effects of intramuscular depo-estradiol cypionate on serum lipids and ceruloplasmin were examined. The oral and parenteral estrogens chosen for this study are frequently used therapeutically and varying doses in the range of those commonly employed clinically were given to the experimental subjects. Following oral ethinyl estradiol (20, 50, and 100 micrograms every 12 hr) comparable and significant increases in triglyceride (73 +/- 6 to 128 +/- 10 mg/dl, p < .001), ceruloplasmin (87 +/- 4 to 188 +/- 11 mg/dl, p < .001), and HDL-cholesterol (60 +/- 2 to 74 +/- 3 mg/dl, p < .001) were observed. In contrast, despite substantial increases in serum estrogens, parenteral estrogen administration (depo-estradiol cypionate, 5 and 10 mg) failed to result in alterations in any of the measured parameters. Thus, the route and/or type of estrogen administered may determine the proteinemic and lipemic effects of estrogen in man.

PIP: This study looked at the effect of a commonly used estrogen preparation, parenteral depo-estradiol cypionate, on several metabolic parameters and compared the results of known alterations which follow oral ethinyl estradiol. The metabolic parameters studied were serum cholesterol, triglyceride (TG), ceruloplasmin, and high-density lipoprotein (HDL) cholesterol. Doses of agents used are common therapeutic ones. After oral ethinyl estradiol (20, 50, and 100 mcg every 12 hours) significant increases in TG (73+ or -6 to 128+ or -10 mg/dl, P .001), ceruloplasmin (87+ or -4 to 188+ or -11 mg/dl, P .001), and HDL-cholesterol (60+ or -2 to 74+ or -3 mg/dl, P .001) were observed. In contrast, despite substantial increases in serum estrogens, parenteral estrogen administration (depo-estradiol cypionate, 5 and 10 mg) failed to result in alterations in any of the measured parameters. Thus, the route of contraceptive agent administration may affect the proteinemic and lipemic responses in humans.

Diagnostic use of meternal serum alpha-fetoprotein levels.

Alpha-fetoprotein (AFP) levels in human maternal serum were elevated in 14 patients when measured by a radioimmunoassay. In 8 patients the elveated serum levels of AFP correlated with increased concentration of AFP in amiotic fluid and were diagnostic of fetal defects. The elevated AFP levels in the remaining 6 patients were shown to be the result of fetomaternal transfusion from either amniocentesis or natural causes. Serum samples drawn after amniocentesis through an anterior placenta may show false-positive elevations. The use of both maternal serum and amniotic fluid samples in pregnancies at high risk for neural tube defects can decrease the risk of diagnostic errors due to mistakes in gestational datind and may increase the diagnostic sensitivity of amniocentesis.

PIP: 14/150 patients studied over a 2-year span had elevated serum alpha fetoprotein (AFP) in the course of pregnancy; fetal abnormality or a source of fetomaternal transfusion was present in each case. The fetomaternal transfusions generally resulted from amniocentesis through an anterior placenta. In 4 cases, fetal demise with fetal maceration occurred. In 3 of these, amniotic fluid AFP concentrations were 10 times the normal for that gestational week. Sequential serum AFP rose to nearly twice the initial value in 1-3 weeks. In 3 cases, the fetuses had neural tube defects, and in each case both amniotic fluid and maternal serum AFP were elevated. In 5 cases with initially false positive serum elevations not accompanied by elevated amniotic fluid AFP, fetomaternal transfusion resulting from amniocentesis was the cause; in all, 7 cases of maternal serum elevation secondary to fetomaternal transfusion were recorded. Analyzing both maternal serum and amniotic fluid samples in pregnancies at high risk for neural tube defects can decrease diagnostic errors caused by mistakes in gestational dating and may increase the diagnostic sensitivity of amniocentesis.

Mannose binding protein deficiency is not associated with malaria, hepatitis B carriage nor tuberculosis in Africans.

We retrospectively studied MBP genotypes in patients with malaria, tuberculosis (TB), and persistent hepatitis B virus (HBV) carriage, in clinics and hospitals in The Gambia. Children under 10 years with cerebral malaria and/or severe malarial anaemia, were compared with children with symptomatic, mild malaria, and controls of the same age and ethnicity. Adult TB cases with smear-positive pulmonary TB were compared with healthy blood donors from the same ethnic groups. Malaria cases and controls were tested for hepatitis B core antibody (anti-HBc) and surface antigen (HBsAg). TB patients were tested for HIV antibodies. Genotyping used sequence-specific oligonucleotide analysis to identify MBP variant alleles. Overall, 46% (944/2041) of patients and controls were homozygous for the wild-type MBP allele, 45% (922/2041) were carriers of a single variant allele and 8.6% (175/2041) had two variant alleles. Neither homozygotes nor heterozygotes for MBP variants were at increased risk of clinical malaria, persistent HBV carriage or TB. The most common mutation in Africans, the codon 57 variant allele, was weakly associated with resistance to TB (221/794 in TB cases and 276/844 in controls, p = 0.037). MBP deficiency is not a significant risk factor for persistent HBV, severe malaria nor pulmonary TB in West Africa.

PIP: Low serum mannose-binding protein (MBP), a calcium-dependent serum lectin that acts as an opsonin to promote phagocytosis, has been characterized as the most common immune deficiency. It has been suggested that MBP acts as a binding protein for mycobacteria and other intracellular pathogens, enabling them to enter host macrophages. The present study investigated the association between variant MBP alleles and malaria, tuberculosis, and hepatitis B virus (HBV) in adults and children in The Gambia. Of the 2041 Gambians screened for MBP mutations, 944 (46%) were homozygous for the wild-type allele, 922 (45%) were carriers of a single variant allele, and 175 (8.6%) possessed 2 mutant alleles. Compared to healthy controls, neither homozygotes nor heterozygotes for MBP genotypes were at increased risk of severe malaria (n = 504), HBV carriage (n = 337), or tuberculosis (n = 397). Stratification of patients by ethnic group did not alter this lack of relationship. However, the most common mutation in Africans--the codon 57 variant allele--was weakly associated with resistance to tuberculosis in both cases and controls. Although MBP deficiency may predispose to recurrent infections, this study failed to provide evidence that such a deficiency is a major risk factor for infectious diseases.