Phenotypic heterogeneity associated with defective apolipoprotein B-100 and occurrence of the familial hypercholesterolemia phenotype in the absence of an LDL-receptor defect within a Canadian kindred

Of 163 individuals with a diagnosis of heterozygous familial hypercholesterolemia (FH), only one subject was found to be positive for familial defective apo B-100 (FDB). The eight-member kindred ascertained through this subject who presented with both a clinical phenotype of FH and the FDB apo B-100 (Arg₃₅₀₀→-Gln) mutation was studied. Plasma lipid and lipoprotein profiles, apo E phenotypes, apo B gene markers at the 3′ hypervariable region and LDL-receptor haplotypes (ApaLI, PvuII, NcoI), were determined, together with LDL-receptor activity on freshly isolated blood lymphocytes. The FDB mutation, present in four relatives, was associated with three different phenotypes: FH and severe hypercholesterolemia, moderate hypercholesterolemia and normolipidemia. The FH phenotype occurred in the absence of any functional LDL-receptor defect. In homozygotes for the absence of the PvuII cutting site who had the apo B mutation, LDL-cholesterol levels were low in the presence of the apo E3/2 phenotype and high in the presence of the apo E4/4 phenotype. None of the major known environmental influences accounted for the wide range of variation in LDL-cholesterol among the affected members. Further observations in the spouse and offspring of the normolipidemic FDB subject confirmed the association of apo E4, the FDB mutation and the PvuH(-/-) genotype with high cholesterol levels. It is concluded that the phenotypic expression of the FDB mutation may vary widely as a function of the genetic environment within a family. The presence of phenotypic heterogeneity among individuals with the same apo B mutation may result from epistatic interaction of the apo B locus with genetic factors regulating cholesterol homeostasis, including possible involvement of the apo E and the LDL-receptor gene loci. This study also confirms that the clinical diagnosis of FH is not necessarily associated with an LDL-receptor defect.     

Effect of iron on serum 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations.

In 13 of 17 infants (aged 10.5 +/- 4.3; mean +/- SD mo) with iron-deficiency anemia, the serum 24,25-dihydroxyvitamin D concentration was below the normal range and in 9 of these 13 the serum 25-hydroxyvitamin D concentration was below the normal range despite the fact that these infants received 10 micrograms vitamin D/d from the age of 1 mo. The infants were treated with intramuscular iron dextran (Imferon). The iron-dextran treatment increased the hemoglobin and serum iron concentrations as well as 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations. It is known that iron deficiency impairs fat and vitamin A intestinal absorption. Therefore, it is suggested that absorption of vitamin D may also be impaired. This may contribute to the development of vitamin D deficiency. Iron supplementation may have improved the absorption of vitamin D in the small intestine and hence increased the vitamin D concentration in the plasma.     

Fluorescence polarization immunoassay and HPLC assays compared for measuring monoethylglycinexylidide in liver-transplant patients.

We compared fluorescence polarization immunoassay (FPIA, x) and HPLC (y) for measuring monoethylglycinexylidide (MEGX) concentrations in 119 serum samples from 61 liver-transplant donors and recipients. The correlation between the two methods was y = 1.48 micrograms/L + 0.8x (r = 0.89). The bias (mean difference) was 12 micrograms/L (0.055 mumol/L) through the MEGX concentration range measured (0-250 micrograms/L, 0-1.136 mumol/L). We observed a major difference between the two methods in samples from four recipients and one donor. Cross-reactivity in FPIA with lignocaine and two of its metabolites (glycinexylidide and 2,6-xylidine) was < 3%. Samples with high bilirubin concentrations (> 200 mumol/L) required dilution before assay of MEGX by FPIA. Although there was an increase in apparent MEGX concentrations in some samples with increased bilirubin concentrations, the relationship was not constant. Increased plasma concentrations of cholesterol and triglyceride resulted in relatively small increases in apparent MEGX concentrations.     

Laryngomalacia: a cause for early near miss for SIDS

Six infants had recurrent apnea of infancy episodes (near miss sudden infant death syndrome) during their neonatal period. Physical examination and laboratory investigation were normal. Polygraphic sleep monitoring revealed recurrent obstructive sleep apnea. These infants underwent fiberoptic endoscopy which showed that airway obstruction occurred at the laryngeal orifice as a result of laryngomalacia. It is suggested that laryngomalacia may be a cause for early apnea of infancy.     

Efficacy of SIV/deltaB670 glycoprotein-enriched and glycoprotein-depleted subunit vaccines in protecting against infection and disease in rhesus monkeys

Immunization with an inactivated whole-virus vaccine is highly effective in preventing lentivirus infection. The viral protein(s) essential to the induction of protective responses, however, have not been identified. To define the role of virion components in the induction of protective immunity, we evaluated the efficacy of glycoprotein-enriched and glycoprotein-depleted simian immunodeficiency virus (SIV) subunit vaccines prepared by lentil-lectin affinity chromatography of gradient-purified virions using the immunization and challenge regimen previously found successful with an inactivated whole-virus vaccine. Infection was determined by successful recovery of virus, the induction of SIV-specific antibody responses, and infection of naive recipients by inoculation with lymph-node-derived lymphocytes from the vaccinates. Immunization with the glycoprotein-enriched preparation prevented infection in two out of four monkeys, whereas the glycoprotein-depleted vaccine failed to prevent infection in all four vaccinates tested. However, the glycoprotein-depleted vaccine appeared to moderate the progression of SIV-induced disease compared with non-immunized infected control monkeys inoculated with the same challenge dose. These data suggest that subunit vaccines containing sufficient quantities of viral glycoproteins can protect against SIV infection, whereas subunit vaccines composed predominantly of viral core proteins cannot. The development of effective vaccines against HIV infection should include studies on the optimum presentation of the viral envelope glycoproteins to produce long-term broadly protective immune responses.     

Activity of natural killer cells and granulocytes in peripheral blood and separated cells]

The natural killing of K 562 cells by whole blood from normal subjects was comparable with that shown by separated mononuclear cells. In order to establish the conditions for a reliable natural killer assay by using very small numbers of effector cells in whole blood, the isotope uptake of target cells was increased by a modified labelling method, which permitted the use of fewer target cells in the assay. The natural cytotoxicity of whole blood was augmented by interferon to the same extent as observed with separated mononuclear cells. The chemiluminescence of granulocytes in whole blood comparable with that of separated granulocytes. Taken together, these methods are considerably less tedious than the conventional methods, technique is also economical, and the results may reflect in vivo cytolytic processes much better.     

A comparative study of pepsinogen (PG) and lactic acid dehydrogenase (LDH) activities and isoenzyme patterns in tissues from human primary gastric cancer, gastric cancer xenografts in nude mice and gastric cancer cell lines]

Tissue and cell homogenates were prepared for PG and LDH study from 20 samples of histologically proven gastric cancer (GC), 6 samples of gastric cancer xenografts (THPGC-1) of different passages (GCXG) and cultured cells of 3 different gastric cancer cell lines (GCCL). Normal gastric mucosa (NGM) was also obtained from the resected stomach far distant from the primary tumor and histologically tumor free. The results indicated that the expression of PG isoenzymes was low or absent and the PG activities were significantly decreased in GC, GCXG and GCCL as compared to NGM. The activity of LDH was also significantly increased in GC, GCXG and GCCL. In addition, there was a change in isoenzyme pattern in GC and GCXG in which isoenzyme type M was observed whereas isoenzyme type H was preponderent in NGM. The results show that the human gastric cancer xenograft, THPGC-1, has biological properties very similar to those of the primary tumor suggesting that THPGC-1 is a reliable model for the study of the molecular biology of human gastric cancer.     

A study on personal information system using movable media for effective welfare services]

A data system which enables utilization of individual patient data by public health nurses, physicians and home helpers, is required both for the continuous and comprehensive monitoring of the various needs of the aged receiving care services at home in the local district and for facilitating welfare services. Therefore, an experimental and comprehensive system for public health, medical services and welfare was put into practice for district public health services for the aging society. The results of this trial system shows that this system is useful indeed for the welfare services, though it also has several problems.     

Studies on the retention of the mucous-membrane-adhesive anticancer agent hydroxypropylcellulose doxorubicin.

Incorporation of hydroxypropylcellulose (HPC-)doxorubicin, which we developed as a mucous-membrane-adhesive drug preparation, was instilled into the urinary bladder in 10 clinical cases. Tumor of the urinary bladder was a single tumor in all 10 cases, and preclinical histology showed transitional cell carcinoma, grade 1 or 2, and a lower stage than T1. HPC-doxorubicin, 20 mg/20 ml, was administered in 5 cases, and the other 5 cases received the conventional aqueous doxorubicin, 20 mg/20 ml by way of a catheter and the urethra. Cold punch biopsy was performed after 3 days of instillation, and the incorporation of doxorubicin into both tumorous and normal tissue was measured by high-pressure liquid chromatography. After 3 days, it was found that in the HPC-doxorubicin-administered group, doxorubicin was detected in both tumorous and normal tissue, but it was not detected in either tissue after aqueous doxorubicin administration. In 5 cases of the HPC-doxorubicin group, doxorubicin levels in the tumorous and normal tissue were examined, and it was found that significantly more doxorubicin was detected in the tumorous tissues. Thus, it may be said that our HPC-doxorubicin remained longer within the urinary bladder than the conventional aqueous doxorubicin preparation. Instilled HPC-doxorubicin is more highly concentrated in the tumorous tissue than in the normal bladder tissue, and thus, HPC-compounded anticancer drugs may be therapeutically more useful.