Beryllium particulate exposure and disease relations in a beryllium machining plant.

We examined the relationship between exposure to beryllium and the presence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) in a cohort of workers in a beryllium precision machining facility. Twenty workers with BeS or CBD (cases) were compared with 206 worker-controls in a case-control study. Exposure for each job title was measured using cascade impactors placed in the workers' breathing zone to measure total beryllium exposure and exposure to particles < 6 microns and < 1 micron in aerodynamic diameter. Cumulative exposure was calculated as sigma (job title exposure estimate x years in job title). Individual lifetime-weighted (LTW) exposure was calculated as sigma [(job title exposure x years in job title) divided by total years employment)]. Workers in the case group were more likely to have worked as machinists (odds ratio, 4.4; 95% confidence interval, 1.1 to 17.5) than those in the control group. The median cumulative exposure was consistently greater in the cases compared with the controls for all exposure estimates and particle size fractions, although this was not statistically significant. The median cumulative exposure was 2.9 micrograms/m3-years in the cases versus 1.2 micrograms/m3-years in the controls for total exposure, and 1.7 micrograms/m3-years in the cases versus 0.5 microgram/m3-years in the controls for exposure to particles < 6 microns in diameter. With cumulative exposure categorized into low-, intermediate-, and high-exposure groups, the odds ratios were 2.4 (95% confidence interval, 0.7 to 8.2) for the intermediate-exposure group and 1.2 (95% confidence interval, 0.4 to 4.2) for the high-exposure group compared with the low-exposure group. The median LTW exposure was 0.25 microgram/m3 in both groups. The median LTW exposure to particles < 6 microns was 0.20 microgram/m3 in the cases compared with 0.14 microgram/m3 in the controls. The differences in cumulative and LTW exposure were not statistically significant. None of the 22 workers with LTW exposure < 0.02 microgram/m3 had BeS or CBD. Twelve workers (60%) in the case group had LTW exposures > 0.20. In conclusion, increased cumulative and LTW exposure to total and respirable beryllium was observed in workers with CBD or BeS compared with the controls. These results support efforts to control beryllium exposure in the workplace.

Outcome of neurological decompression illness: development of a manifestation-based model.

A significant proportion neurological decompression illness cases remain symptomatic after the first recompression treatment. Currently, the factors that predict an incomplete resolution are poorly defined. In this study, 214 cases of neurological decompression illness were reviewed and classified according to the presenting manifestations and outcome after a standard therapeutic regimen. The neurological manifestations were classified by type (loss of sensory or motor function, or loss of consciousness) and then by either the number of sites involved or the location of each manifestation. Cases with both sensory and motor manifestations were less likely to have complete resolution than those with sensory or motor manifestations alone. Cases with manifestations involving the legs were less likely resolve completely than those with manifestations in the arms, especially if both sensory and motor manifestations were reported. Based on these data, a linear logistic model was developed to predict the probability of incomplete resolution after the first recompression treatment depending on the type and location of the manifestations.

Supraventricular arrhythmias following breath-hold submersions in cold water.

Twelve subjects undertook one submersion into water at 5 degrees C and two at 10 degrees C wearing either a wet or dry suit. During the submersions the subjects held their breath for as long as they could and then breathed through respiratory tubing for a further 10 s before being removed from the water. Bradycardia (heart rate < 60 beats/min) was observed during breath holding in 10 subjects in 28 of the 36 submersions. Ectopic arrhythmias were observed in 11 subjects in 29 of the 36 submersions, a much higher frequency than previously reported. These ectopic arrhythmias included premature atrial and junctional complexes, runs of supraventricular tachycardia, and premature ventricular complexes. They occurred predominantly in the 10-s period of submersion after the cessation of breath holding. The possible etiology of these arrhythmias and their significance are discussed and it is concluded that after breath-hold termination during cold-water submersion there is a short time during which the heart may be particularly susceptible to supraventricular ectopic arrhythmias.

Alpha-fetoprotein glycosylation is abnormal in some hepatocellular carcinoma, including white patients with a normal alpha-fetoprotein concentration.

Lectin-affinity analyses with Lens culinaris agglutinin (LCA) and other lectins have demonstrated that the glycosylation of alpha-fetoprotein (AFP) secreted by hepatocellular carcinomas (HCC) is frequently altered when the serum AFP concentration is increased. To determine if AFP LCA-binding properties are altered in patients with HCC whose serum AFP concentration is normal, the percentage of LCA-binding AFP in serum from white newborns, white normal adults, white patients with chronic hepatitis and hereditary tyrosinemia and white and black patients with HCC were determined. The serum LCA-binding AFP fraction was low in newborns (1-4%) and normal adults (1-8%). There was a significant increase in LCA-binding AFP in patients with chronic hepatitis (10-24%) and hereditary tyrosinemia (5-35%). The AFP LCA-binding fraction was clearly abnormal (greater than 40%) in three of the white patients with an HCC and a normal serum AFP concentration, and the range of values (10-63%) in these HCC patients was similar to that seen in both white and black patients with HCC accompanied by increased AFP concentrations.

Altered glycosylation of alpha-fetoprotein in hepadnavirus-induced hepatocellular carcinoma of the woodchuck.

Altered glycosylation of alpha-fetoprotein (AFP) has been proposed as a marker of hepatocellular carcinoma (HCC) in humans. The lectin-binding properties of woodchuck AFP were investigated to determine if woodchuck hepatitis virus (WHV)-induced HCCs are also accompanied by changes in AFP glycosylation. Ninety-eight to 100% of the AFP from normal, WHV-free woodchucks with physiologic AFP elevations and from WHV-carrier woodchucks with HCC bound to concanavalin A, indicating that virtually all of the AFP was glycosylated. Three percent or less of the serum AFP of normal woodchucks bound to Lens culinaris agglutinin (LCA). In contrast, the AFP from woodchucks with HCC had an increased LCA-binding fraction (range, 8-77%). The increased LCA-binding AFP in WHV-induced HCC is analogous to that which frequently accompanies hepatitis B virus (HBV)-induced HCC in humans. This study corroborates the relationship of altered glycoconjugate synthesis to virus-induced malignant transformation, confirms the importance of AFP glycoforms as markers of HCC, and demonstrates that the WHV-infected woodchuck should be useful in investigating changes in AFP glycosylation during hepadnavirus hepatocarcinogenesis and HCC growth.

Elevated maternal serum alpha-fetoprotein levels and maternal risk factors. Their association with pregnancy complications.

Maternal serum alpha-fetoprotein (MS-AFP) screening programs identify a population of pregnant women with elevated MS-AFP values. When the levels are unassociated with a fetal anomaly, those women have a high incidence of pregnancy complications. Such patients were compared to a population with normal MS-AFP values to determine the incidence of historical risk factors and to ascertain if their presence affected the rate of pregnancy complications. A total of 358 patients were followed prospectively, 23 with elevated MS-AFP levels and 335 with normal levels (control group). Historical risk factors were more frequent in the patients with elevated MS-AFP levels. There was a fourfold increase in the rate of pregnancy complications when a patient had both risk factors and elevated MS-AFP levels as compared with elevated MS-AFP levels alone. In the control group, patients with known risk factors experienced twice the incidence of pregnancy complications as did patients with no risk factors. Using multiple logistic regression analysis, elevated MS-AFP levels were shown to be an independent variable in the risk assessment. The results of this study have wide application in the counseling and follow-up of patients identified by MS-AFP screening programs.

Alterations of the hprt gene in human in vivo-derived 6-thioguanine-resistant T lymphocytes.

Investigations into the extent and significance of somatic gene mutations occurring in vivo in humans have been hampered by the lack of a means of unambiguously defining the mutational origin of in vivo-derived variant cells. Several years ago we proposed that 6-thioguanine-resistant T lymphocytes, present at low frequencies in human peripheral blood, might be useful markers of in vivo somatic mutation. We and others have since described methods for the isolation and study of these unusual cells. The thioguanine-resistant T cell stably lack hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity, suggesting that they are somatic equivalents in normal individuals to cells from individuals with the X-chromosomal hprt Lesch-Nyhan germinal mutation. We now report that in vivo-derived thioguanine-resistant T-cell colonies from a single normal individual show a variety of hprt structural alterations, as determined by Southern blot analysis. This finding demonstrates unequivocally that these cells are genetic mutants and validates their use for fundamental and applied mutational studies in humans.

Effects of carbohydrate-containing and carbohydrate-restricted hypocaloric and eucaloric diets on serum concentrations of retinol-binding protein, thyroxine-binding prealbumin and transferrin.

The effects of diet on the serum concentrations of albumin, transferrin, thyroxine-binding prealbumin (TBPA) and retinol-binding protein (RBP) were studied in 3 groups of obese subjects (Groups I-III) and 1 group of normal weight subjects (Group IV). Group I subjects ate either a 830 kcal carbohydrate-containing diet (CCD) or carbohydrate-restricted diet (CRD), Group II and III subjects ate a hypocaloric CRD. Subjects in Group IV ate a eucaloric CRD. Serum albumin concentrations did not change in any of the 4 groups. Only the subjects in Group II had a statistically significant decrease in serum transferrin concentration 6 wk after starting the hypocaloric, CRD. Group I individuals eating the CRD and the subjects in Groups II, III and IV had significant decreases in the serum concentrations of TBPA and RBP after 1 wk which persisted without further change during the remaining 3-5 wk of the diets. Group I subjects eating the CCD had a significant decrease in TBPA concentration at 1 and 6 wk. The RBP serum concentration was significantly decreased after 1 wk on the diet, but was not significantly different from the control diet period at 6 wk. The magnitude of the decreases in serum concentrations of TBPA and RBP in the Group I subjects eating the CRD were significantly greater than in the Group I subjects eating the CCD. Thus, ingestion of a hypocaloric, CRD by obese individuals results in decreased serum concentrations of TBPA and RBP. Isocaloric substitution of carbohydrate for fat reduces this effect. Dietary carbohydrate apparently modulates the serum concentrations of TBPA and RBP, independently of caloric intake, since ingestion of a eucaloric CRD by normal weight individuals also decreased the serum concentration of the two visceral proteins.

Concanavalin-A-affinity molecular heterogeneity of human hepatoma AFP and cord-serum AFP.

Glycosylation of alpha-fetoprotein (AFP) by human primary hepatocellular carcinoma (PHC) is abnormal. Concanavalin A (Con A)-affinity molecular variant patterns of serum AFP from patients with PHC are different from those of cord-serum AFP. Different patients with PHC exhibit different Con-A-affinity AFP molecular variant patterns, and the pattern remains constant over time in a given individual. The degree of deviation of the AFP molecular variant pattern from the molecular pattern of AFP secreted by neonatal liver cells is independent of the total serum AFP concentration. We propose that analysis of the AFP lectin-affinity molecular heterogeneity will improve the discrimination between malignant and nonmalignant liver disease in cases when the degree of elevation of the serum AFP concentration is nondiagnostic.

Origin of amniocentesis-induced rises of alpha-fetoprotein concentrations in maternal serum.

An elevation of alpha-fetoprotein concentration in maternal serum occurred in 7 of 65 patients (11 per cent) following amniocentesis. Analysis of the molecular heterogeneity of the alpha-fetoprotein by chromatography on concanavalin A-agarose indicated that the source of the alpha-fetoprotein was fetal serum in three patients and amniotic fluid in four patients.

Alpha-fetoprotein concanavalin A-binding variants in the diagnosis of neural tube defects and other communicating fetal abnormalities.

We have extended our initial observations (Smith et al., 1979) on th use of determining the alpha-fetoprotein (AFP) concanavalin A-binding variant patterns in amniotic fluid for the detection of certain fetal malformations. We report here our complete series of amniotic fluids between 14 and 36 weeks of gestation from 52 normal pregnancies and 28 abnormal pregnancies including anencephaly, open spina bifida, Turner's syndrome, omphalocele, osteogenesis imperfecta congenita, meningomyelocele, meningocele, spinal cysts, spontaneous abortion and fetal death. The percentage of the total amniotic fluid AFP which was not reactive with concanavalin A was significantly lower in the presence of a communicating fetal abnormality (mean = 4.8%, P less than 0.001), one in which the fetal/amniotic fluid barrier is defective, than in the presence of a normal fetus (mean = 24.7%) (or of a noncommunicating fetal abnormality. We applied the concanavalin A-binding assay to two of the above amniotic fluids from pregnancies in progress and correctly classified the gestations as abnormal. Our results indicate that measurement of the percentage of concanavalin A-non-reactive amniotic fluid AFP is a valuable adjunct in the diagnosis of a communicating fetal abnormality, especially when the elevation of amniotic fluid AFP concentration is equivocal (between 2 and 5 S.D. above the mean), when gestational aging is uncertain or when the total amniotic fluid AFP concentration and ultrasonographic data are inconsistent.

Reactivity of amniotic fluid alpha-fetoprotein with concanavallin A in diagnosis of neural tube defects.

Alpha-fetoprotein (AFP) concanavallin-A-affinity molecular variant patterns were determined in amniotic fluid samples from 10 pregnancies complicated by anencephaly (6), spina bifida (1), Turner's syndrome (1), osteogenesis imperfecta congenita (1), and fetal death (1) and 20 normal pregnancies between 14.6 and 25.5 weeks of gestation. With the exception of one anencephalic pregnancy, the AFP concentrations in samples from women with a fetal abnormality were more than 5 SD above normal for gestational age. In every case, however, the proportion of total amniotic fluid AFP that was not reactive with concanavallin A was significantly smaller in the presence of a fetal abnormality (mean 2%) than when the fetus was normal (mean 20%). The results suggest that measuring the amount of concanavallin-A-non-reactive amniotic fluid AFP will be a valuable test for diagnosing fetal abnormality, especially when an increase in total amniotic fluid AFP concentration is equivocal or gestational age is uncertain.

Urinary excretion of hydroxyproline, hydroxylysine and hydroxylysine glycosides by patients with Paget's disease of bone and carcinoma with metastases in bone.

Patient's with carcinoma metastases in bone and Pagent's disease of bone have different patterns of collagen metabolite excretion. Both forms of bone disease resulted in an increased excretion of total hydroxyproline and the ratio of glucosylgalactosylhydroxylsine to galactosylhydroxylysine was below normal. The excretion of glucosylgalactosylhydroxylysine and galactosylhydroxylysine was increased in all patients with carcinoma metastases in bone while the excretion of glucosylgalactosylhydroxylysine in patients with Paget's disease. The ratio of total hydroxylysine (free hydroxylysine + glycosylated hydroxylysines) to total hydroxyproline was normal in patients with carcinoma metastases in bone and below normal in patients with Paget's disease bosne. The pattern of urinary collagen metabolite excretion is a more specific indicator of the presence of bone disease than is the measurement of the excretion rate of any individual collagen metabolite. Bone diseases of different etiologies may result in different patterns of urinary collagen metabolite excretion.