Pediatric automotive restraints, pediatricians, and the academy.

Over 70% of the 192 Southern California Academy pediatricians responding to a survey teach parents about pediatric automotive safety devices but less than 3% do so on every visit. To test two methods of increasing the frequency of teaching, these pediatricians were randomly assigned to either a mailing from the Academy's local chapter (mail group) or a brief presentation by a local pharmaceutical representative at his regular visit (interview group); a follow-up was conducted one month later by mail. Sixty-one percent of the mail group and 49% of the interview group claimed that their teaching on this subject had increased since the original contact. While this difference did not reach statistical significance, it was in the same direction as the preferences for sources of pediatric information expressed by both groups of pediatricians. A special letter from the Academy was ranked most effective and a visit from the pharmaceutical representative was judged least effective. Because of the magnitude of the problem, availability of a solution, proof that pediatricians can influence health behavior related to children and acknowledgment of the Academy's role in pediatric education, an appeal is made for an all-out campaign by the Academy and its members to promote use of appropriate pediatric automotive safety devices.

Fecal alpha 1-antitrypsin and hemoglobin excretion in healthy human milk-, formula-, or cow's milk-fed infants.

There is concern that whole cow's milk feedings may be associated with intestinal abnormalities in infants. We studied this issue by measuring random fecal samples for alpha 1-antitrypsin (FA1AT) and hemoglobin (FH) concentrations in 820 healthy infants up to 12 months of age. Subjects were fed either human milk, formula, or fresh whole cow's milk. Solid foods were given ad libitum. Fecal samples were also tested for occult blood with Hematest reagent tablets. None of the infants younger than 6 months of age were receiving fresh whole cow's milk. We found small but statistically significant differences in mean FA1AT between the three feeding groups (P less than .0001): human milk (n = 354) greater than formula (n = 320) greater than cow's milk (n = 146). The younger subjects fed either formula or human milk tended to have higher FA1AT concentrations than did the age-matched subjects who were not consuming solid foods (P less than or equal to .005). Daily FA1AT excretion, FA1AT concentration, and daily stool output were subsequently determined on a separate group of 40 infants 8 to 12 months of age to ascertain whether differences in total daily FA1AT excretion occur in children fed different types of milk. Total daily FA1AT excretion was similar in the three milk feeding groups. An inverse correlation between FA1AT concentration and daily stool output was also found (P less than .001). The overall rate of detectable FH in 792 stool smears was 2.1% and unrelated to type of milk feeding. Of 705 stool smears, 3.5% had positive Hematest reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of a ghetto school breakfast program.

A program was initiated to provide a free breakfast at a ghetto elementary school. Community support was achieved at the expense of randomization of study subjects. While no significantly greater increase in school attendance or performance was detected in comparison with a control school, none of the students was malnourished and diets of students in the control school were as adequate as those in the breakfast school. Thus, it cannot be concluded that school breakfast programs would not benefit malnourished children or teen-agers who most often go without breakfast.

The molecular biology of hepatitis B virus.

Techniques of recombinant DNA and molecular biology have recently been applied to the study of hepatitis B virus (HBV) in human tissues and have enhanced our knowledge of viral persistence and chronic liver disease. These molecular studies strengthen previous epidemiologic evidence for an association between HBV chronic carriers and hepatocellular carcinoma (HCC). A recently described group of animal viruses with structural and biological properties similar to HBV, termed Hepadna viruses, provides animal models for future studies of hepatitis B virus, especially with regard to the mechanisms for virus replication and persistance and the relationship of these processes to development of HCC.

Splenic replication of hepatitis B virus in the chimpanzee chronic carrier.

Low levels of hepatitis B virus (HBV) replication and serum Dane particles have been commonly observed in chimpanzee chronic HBV carriers. To evaluate the possibility of extrahepatic sites of replication, DNA from various organs of a chimpanzee HBV carrier were evaluated by Southern blot analysis. With cloned, repurified HBV DNA of 3.2 kilobases (Kb) as a hybridization probe under stringent conditions, analysis of liver DNA revealed a diffuse hybridization pattern below 3.2 Kb and full-length double-stranded HBV genomes at 3.2 and 1.8 Kb, the latter representing the supercoiled (CCC) form found in the nucleus. No HBV DNA was found in pancreas, muscle, renal, or adrenal gland. Analysis of splenic DNA revealed diffuse hybridization below 3.2 Kb within the cytoplasmic subcellular fraction, and full-length HBV genomic forms in the nuclear fraction of splenic tissue. Use of (-) and (+) strand-specific HBV DNA and RNA probes demonstrated asymmetric viral replication within the spleen cytoplasm as previously demonstrated in liver. Northern blot analysis of total RNA from chimpanzee spleen and liver revealed HBV RNA sequences in both of these tissues, suggesting active viral gene expression and/or replication in chimpanzee spleen as well as in liver. Elucidation of the splenic cell type supporting viral propagation may serve as a basis for development of a tissue culture system to study molecular events of HBV replication.

Non-A, non-B hepatitis-related hepatocellular carcinoma in a chimpanzee.

Epidemiology has indicated the possible association of non-A, non-B hepatitis (NANBH) with hepatocellular carcinoma (HCC) in man, but there are no means for confirmation. Chimpanzees are recognized models for studying hepatitis B and NANBH, and may become carriers of both. The first case of HCC to be reported in chimpanzees was found after longitudinal study of a hepatitis B-free chimpanzee 7 years after inoculation with human plasma from a patient reported to have chronic NANBH.

Infantile colic and type of milk feeding.

The prevalence of colic with respect to the type of milk feeding in the first 17 weeks of life was assessed by questioning the parents of 964 healthy infants aged 2 to 52 weeks. There was a similar prevalence of colic in infants fed human milk (20%), formula (19%), and formula-supplemented human milk (21%). Intestinal damage, determined by measuring random fecal alpha 1-antitrypsin concentrations in 206 infants aged 2 to 17 weeks and fecal hemoglobin concentrations in 200 of these, was not more likely in infants with colic at the time of study. The occurrence of adverse reactions at the time of introduction of fresh whole cow's milk into the diet of previously colicky infants was uncommon. Our results suggest that dietary protein hypersensitivity is probably not the cause of colic in most healthy young infants.

Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg Vs. anti-HBe positive carriers of hepatitis B virus.

Nine HBeAg+ and 24 anti-HBe+ subjects with chronic hepatitis B virus (HBV) infection were studied for HBV DNA in the serum by molecular hybridization, for HBcAg in the liver by immunofluorescence, and for histologic evidence of liver disease. All HBeAg+ patients had underlying chronic liver disease (chronic persistent hepatitis, chronic active hepatitis, or cirrhosis with or without hepatocellular carcinoma), and all were found positive for both HBV DNA in the serum and HBcAg in the nucleus of hepatocytes. Of the 24 anti-HBe+ individuals, 18 had various forms of chronic liver disease. Six HBsAg+/anti-HBe+ patients had normal liver histology except for numerous "ground-glass" hepatocytes with abundant cytoplasmic HBsAg. All six were negative for nuclear HBcAg and serum HBV DNA, but three showed HBV DNA which appeared to be integrated into unique sites in host liver DNA by hybridization analysis. In contrast, 14/18 (78%) of HBsAg+/anti-HBe+ patients with chronic liver disease were positive for nuclear HBcAg, serum HBV DNA, or both of these markers of HBV replication. It is suggested that in long-term HBsAg carriers with serum anti-HBe and normal liver histology, viral replication is suppressed or inactive and HBV potential infectivity is presumably very low or absent. However, when viral replication is present in HBsAg+/anti-HBe+ carriers (as demonstrated by serum HBV DNA and/or nuclear HBcAg), active liver disease is often found. In these individuals, active chronic liver disease appears to be related to continued replication and secretion of HBV and may occur in a much higher proportion of HBsAg+/anti-HBe+ carriers than was previously suspected.

Liver disease activity and hepatitis B virus replication in chronic delta antigen-positive hepatitis B virus carriers.

Delta antigen is currently thought to reflect superinfection of the liver with a defective RNA virus (delta agent), requiring helper function from hepatitis B virus for its replication. To assess the influence of delta agent on hepatitis B virus replication in patients persistently infected with both viruses and showing chronic liver disease, we measured serum and liver hepatitis B virus DNA in HBsAg-positive chronic liver disease patients who were either positive or negative for delta antigen in the liver. Hepatitis B virus DNA was assayed in the serum of 21 patients with delta antigen-positive/HBsAg-positive chronic liver disease and in 21 patients with delta antigen-negative/HBsAg-positive chronic liver disease matched for HBeAg/anti-HBe status and underlying liver histology. HBcAg and delta antigen in liver was determined by immunofluorescence or immunoperoxidase staining. In delta antigen-positive/HBsAg-positive chronic liver disease, serum hepatitis B virus DNA was detected transiently in 4 of 21 cases (19%) and was present in these patients at low levels (trace to 2+). In contrast, 9 of 21 (43%) delta antigen-negative/HBsAg-positive chronic liver disease patients were serum hepatitis B virus DNA positive, and five of these had high serum hepatitis B virus DNA levels (3+ to 4+). Serum HBsAg and anti-HBc titers were significantly lower in delta antigen-positive cases and correlated with reduced amount of HBcAg in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection and transmission in chimpanzees of hepatitis B virus-related agents formerly designated "non-A, non-B" hepatitis.

Four chimpanzees have been infected with three different inocula containing "non-A, non-B" hepatitis virus(es). After inoculation, serial studies established the presence of antigenemia or viremia (or both) by radioimmunoassay with high-affinity monoclonal antibodies directed toward separate and distinct determinants on hepatitis B surface antigen (HBsAg) and by molecular hybridization analysis using a cloned hepatitis B virus (HBV) DNA probe. In contrast to results observed during HBV infection, elevations in serum alanine aminotransferase values indicate that liver injury preceded antigenemia by several weeks. Thus, the time between inoculation and development of antigenemia (incubation period) varied from 64 to 190 days and, in some cases, single or multiple episodes of antigenemia or viremia occurred in the absence of elevated aminotransferase levels. In this study, two chimpanzees were high-titer positive for antibodies to HBsAg (anti-HBs) from previous infection with HBV, suggesting that the antigenic composition of HBV-related virus(es) is substantially different from that of HBV, since naturally occurring anti-HBs antibodies were not protective. Demonstration of HBV-related virus(es) by the methods used in this study of experimental hepatitis infection in chimpanzees should now permit detection, isolation, and characterization of these previously elusive agents.

Monoclonal radioimmunoassays for hepatitis B surface antigen: demonstration of hepatitis B virus DNA or related sequences in serum and viral epitopes in immune complexes.

High-affinity monoclonal IgM and IgG antibodies (anti-HBs) to hepatitis B surface antigen (HBsAg) have recently been developed and used by us in the construction of highly sensitive radioimmunoassays for the detection of HBsAg-associated determinants in serum. We now report that selected serum samples demonstrating monoclonal immunoreactive material also contain nucleic acid sequences complementary to hepatitis B virus (HBV) DNA by molecular hybridization analysis. In addition, monoclonal radioimmunoassays can detect viral determinants in HBsAg-anti-HBs immune complexes formed in anti-HBs excess; such determinants are undetectable by commercial radioimmunoassay. These and our previous studies suggest that there are HBV or "HBV-related" agents present in human serum that are detected by monoclonal antibodies but are not identified by conventional polyvalent antibodies.

Awareness of pediatric hypertension. Measuring blood pressure.

Surveys of patients at three pediatric teaching hospitals showed a low percentage of blood pressure recordings by the examining physician in the walk-in or emergency clinics. The frequency of blood pressure measurement was higher among inpatients, especially on medical services. A recommendation for obtaining blood pressure measurements is made on three bases: 1. many patients use these ambulatory services as their major source of care, 2. many conditions for which care is sought and many therapeutic agents are associated with hypertension, and 3. unless measurements of blood pressure become customary during training, it is likely that blood pressure recording may not be included as part of routine physical examinations.

Serum HBV-DNA (hepatitis B virus DNA) in acute and chronic hepatitis B infection.

HBV DNA was measured in the sera of 69 patients with hepatitis B virus infections. Sixteen patients had acute hepatitis B, 24 had chronic active hepatitis (CAH), 6 had chronic persistent hepatitis (CPH), 5 had cirrhosis without CAH and 18 were asymptomatic HBsAg carriers. In patients with acute hepatitis B who recovered, HBV DNA was present in the serum transiently early in the illness. HBV DNA persisted in the serum in the two patients who developed chronic hepatitis. Sera of 23 of 24 patients with CAH were persistently positive for HBV DNA. There was no relationship between the quantity of HBV DNA in the serum and the histological intensity of activity. Thirteen of the 24 patients with CAH had histological evidence of cirrhosis in addition to CAH and HBV DNA was detected in the sera of all 13. The sera of 2 of 6 patients with CPH were positive for HBV DNA. In one it was positive only where there was clinical evidence of reactivation of HBV infection. The other patient subsequently developed CAH. Sera of 5 patients with established HBsAg positive cirrhosis but without evidence of CAH were negative for HBV DNA. Two of these patients had hepatocellular carcinoma. Sera of 18 asymptomatic anti-HBe positive carriers with normal ALT were negative for HBV DNA. HBeAg and HBV DNA were not always found in the serum together. In acute hepatitis 5 patients with HBV DNA in the serum were HBeAg positive, but in 6 patients the sera were HBeAg positive inthe absenceof HBV DNA.

Detection of hepatitis B virus DNA directly in human serum by a simplified molecular hybridization test: comparison to HBeAg/anti-HBe status in HBsAg carriers.

A simple, direct molecular hybridization test was employed to detect hepatitis B virus (HBV) DNA sequences in human serum. In 61 HBsAg carriers, many with HBV-related diseases (chronic persistent hepatitis, chronic active hepatitis, or posthepatitic cirrhosis), 28/28 (100%) who were HBeAg+ and 16/32 (50%) who were anti-HBe+ had HBV DNA sequences in their serum. Among 22 South African black patients with hepatocellular carcinoma, 7 (32%) had detectable HBV DNA in their serum but at reduced levels when compared to HBsAg carriers without hepatocellular carcinoma, suggesting that viral replication is suppressed or inactive in many hepatocellular carcinoma patients. Hybridization analysis also distinguished carriers with high, moderate, or low amounts of HBV DNA in serum. Ten to 20% of HBsAg+/HBeAg+ carriers showed high serum levels of HBV DNA but, surprisingly, a similar percentage of HBsAg+/anti-HBe+ carriers also showed relatively high serum levels of HBV DNA. Five patients who had undergone immunosuppression therapy and most of whom were on chronic hemodialysis had very high serum levels of HBV DNA, in the range observed during acute HBV infection. By epidemiologic analysis, two of these individuals were implicated in transmission of hepatitis to other hemodialysis patients, paramedical personnel, or intimate family contacts. Serum HBV DNA hybridization analysis identifies carriers with high serum levels of HBV irrespective of HBeAg/anti-HBe status and may define individuals with potentially high risk of transmitting infection to their immediate contacts.

Interrupted replication of hepatitis B virus in liver tissue of HBsAg carriers with hepatocellular carcinoma.

To search for events underlying reduction of peripheral viremia and integration of hepatitis B virus (HBV) DNA into the liver cell genome in long-term virus carriers with hepatocellular carcinoma, paired samples of liver and tumor tissue were analyzed by molecular hybridization and immunological methods. Most tumor tissues contained integrated viral DNA; in none was extrachromosomal HBV DNA detected. Integrated HBV DNS was also found in peritumor liver tissue in the majority of patients. However, liver of patients either with or without peripheral viremia also contained free HBV DNA and replicative intermediates. In three nonviremic patients with replicative HBV DNA in liver, viral core antigen expression was markedly reduced or absent, whereas viral envelope protein (surface antigen) expression was normal. In one case, replicative intermediates in liver were sensitive to DNase I digestion, indicating that viral DNA was not encapsidated in normal viral core particles. These results suggest that decreased or defective core antigen production can lead to reduced viremia associated with blocked virus assembly/secretion and accumulation of unencapsidated HBV DNA replicative intermediates in the liver cell. Accumulation of such HBV DNA molecular forms in the liver may lead to an increased propensity for HBV DNA to integrate into the host genome, which has been found with high frequency in hepatic neoplasms from patients infected with hepatitis B virus.