Biomedical subjects
Publications and source records attributed to H Hu.
Three diterpenoid compounds were isolated from Rabdosia japonica distributed in the easteur past of Anhui Province and identified as trichorabdal H, shikokianin and macrophyllin B on the basis of spectral evidence. They were obtained from this plant for the first time.
Diphtheria toxin (DT) is often used in the construction of immunotoxins. One potential problem using DT-based immunotoxins is the pre-existing anti-DT antibodies present in human blood due to vaccination. The present study examined the effect of human serum with pre-existing anti-DT antibodies on the toxicity of UCHT1-CRM9, an immunotoxin directed against CD3 molecules on T-lymphocytes. Sera with detectable anti-DT antibodies at 1:100 or greater dilutions inhibited the immunotoxin toxicity. Experiments with radio-labeled UCHT1-CRM9 indicate that anti-DT antibodies partially block its binding to the cell surface as well as inhibit the translocation from the endosome to the cytosol. The inhibitory effect could be adsorbed using a full-length DT mutant or B-subfragment. A C-terminal truncation mutant could not adsorb the inhibitory effect, suggesting that the last 150 amino acids contain the epitope(s) recognized by the inhibitory antibodies. Therefore, an anti-CD3 single-chain immunotoxin, sFv-DT390, was made with a truncated DT. The IC50 of sFv-DT390 was 4.8 x 10(-11) M, 1/16 the potency of the divalent UCHT1-CRM9. More importantly, sFv-DT390 toxicity was only slightly affected by the anti-DT antibodies in human sera.
There is a growing body of evidence indicating that prostate-specific antigen (PSA) may be present in many steroid hormone-stimulated epithelial tissues other than that of the prostate. In particular, breast tumor cell lines treated with steroid hormone receptor agonists, breast tumors, and normal human breast have recently been found by our group to contain PSA. To investigate whether PSA may also be present in other human tumors, we employed a highly sensitive immunofluorometric assay technique to quantify PSA immunoreactivity in tumor extracts. Using a PSA-positivity cutoff value of 0.005 ng per mg of protein, 23 of 43 diverse tumors tested positive for PSA protein. Confirmatory analyses for PSA by a commercially available method (IMx) on six samples demonstrated a high degree of concordance between the two methods. To establish the molecular weight of the immunoreactive species, the most highly positive tumor extracts of each tumor type were fractionated by high performance liquid chromatography. Whereas the majority of tumors had immunoreactivity eluting at both 100 KDa and 33 KDa, corresponding to PSA bound to alpha 1-antichymotrypsin and free PSA, respectively, the colon and parotid tumors displayed immunoreactivity only at the 33 KDa fraction. We conclude that in addition to breast tumors and normal breast, colon, ovarian, liver, kidney, adrenal, and parotid tumors can also produce PSA. The physiological role of PSA in these tumors is currently under investigation.
The effects of intratracheal administration of MKS 492, a selective phosphodiesterase (PDE) III inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 micrograms/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86-99% increases in Rrs) to methacholine without tachyphylaxis. On a separate day, the cats received the same four doses of methacholine after being pretreated with either intratracheal saline or three different doses of MKS 492 (0.17, 1.7, and 17 micrograms/kg). The increases in Rrs with 1.7 micrograms/kg [52.6 +/- 8.4% (SE)] and 17 micrograms/kg of MKS 492 (44.4 +/- 10.1%) were smaller than those with saline pretreatment (88.1 +/- 16.8%) (P < 0.05). There were no treatment-associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine-induced bronchoconstriction in a dose-dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials.
K line x-ray fluorescence (KXRF) measurements of bone lead have emerged as a promising new biological marker of internal lead dose in epidemiological studies. Some disagreements exist, however, over the analysis of data at low levels of bone lead concentration. In this study, we performed 30 serial measurements on each of three phantoms containing spiked amounts of lead. Chemical analysis of these phantoms using an inductively coupled plasma mass spectrometer (ICPMS) indicated that the lead concentrations were 0.30, 5.77, and 11.57 micrograms g-1. Analysis of the data was performed using several definitions of a minimum detectable limit (MDL) to recode data below the MDL, and using all of the continuous point estimates of lead concentration in the phantom (including negative estimates). The results demonstrate that the use of MDLs to recode low-level observations reduces the efficiency of the analysis and the ability to distinguish between the phantoms. Retaining all point estimates of KXRF-measured bone lead concentration provides less bias and greater efficiency in comparing the mean or median levels of bone lead of different populations.
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The suitability of urine specimens from women and men for the detection of Chlamydia trachomatis infection by a ligase chain reaction (LCR)-based assay with plasmid primers was examined with a group of patients attending a sexually transmitted disease clinic in Amsterdam, The Netherlands. Cervical specimens from 15 of 237 (6.3%) women tested positive for C. trachomatis by cell culture. Of the 25 (10.5%) female urine samples that tested positive by the plasmid-LCR assay, 13 were obtained from cervical culture-positive women. Nine of the 12 plasmid-LCR-positive urine samples from cervical culture-negative women were confirmed to be positive by a second LCR assay with primers based on chromosomal DNA. Urethral specimens from 24 of 258 (9.3%) men were positive for C. trachomatis infection by cell culture. Of the 25 (9.7%) urine samples that tested positive by plasmid-LCR, 20 were from culture-positive men. All five of the LCR-positive urine samples from culture-negative men were confirmed to be positive by the LCR with chromosomal DNA primers. Relative to cell culture, testing by plasmid-LCR analysis of male urine samples had a sensitivity of 83.3% and a specificity of 97.9%; after resolution of discordant samples, these values were 86.2 and 100%, respectively. In the study with women, the sensitivities of plasmid-LCR analysis of cervical and urine specimens in comparison with cervical cell culture were 93.3 and 86.7%, respectively. After resolution of discrepant samples, the sensitivities of the plasmid-LCR test for cervical swabs and female urine samples were 96.3 and 92.6%, respectively. These results indicate that the plasmid-LCR-based assay is a very reliable, sensitive, convenient test for the detection of C. trachomatis infection in female and male urine specimens.
Associations between the presence of a constitutional variant of delta-aminolevulinic acid dehydratase (ALAD-2) and lead concentrations in blood and bone, as well as between this allele and indices of kidney function, were investigated among 691 members of a construction trade union. The average blood lead level in this group was 7.78 micrograms/dl. No significant difference was observed in blood lead concentration in ALAD-2 carriers compared to those homozygous for the more common ALAD-1 allele (7.78 +/- 3.62 micrograms Pb/dl vs. 7.73 ( +/- 3.48 micrograms Pb/dl, respectively; p = 0.73). Bone lead was measured in a subset of 122 of the study subjects. Patella minus tibia lead concentrations for each individual averaged 3.35 +/- 11.99 micrograms Pb/g bone mineral in ALAD-1 homozygotes and 8.62 +/- 9.47 micrograms Pb/g bone mineral in ALAD-2 carriers (p = 0.06). Comparisons of blood urea nitrogen (BUN) and uric acid by genotype indicated elevated levels among ALAD-2 individuals (p = 0.03 and 0.07, respectively). In logistic regression models accounting for other variables potentially associated with BUN and uric acid levels, BUN was significantly associated with blood lead levels (p = 0.01). Associations of BUN and uric acid levels with ALAD-2 were of borderline statistical significance in these models (p = 0.06 and 0.07). Taken together, these results suggest that the ALAD-2 genotype may influence the pharmacokinetic distribution and chronic renal toxicity of lead, perhaps due to differential binding of lead to the variant protein.
K-X-ray fluorescence (K-XRF) is a useful tool for assessing environmental exposure to lead in occupationally exposed individuals and older adults. This study explores the possibility of using this technique on young adults with low environmental lead exposure. Twenty-three college students, aged 18-21 years, were recruited for 2 hr of bone lead measurement. Bone lead measurements were taken from the mid-shaft tibia for periods of 30 or 60 min. In the analysis, 30-min measurements were combined so that each subject had the equivalent of two 60-min measurements. The average concentration of two bone lead measurements in this population ranged from -1.5 to 8.2 micrograms Pb/g bone mineral, with a mean of 3.0 micrograms Pb/g bone mineral. In a one sample t-test, this mean was significantly different from 0 (p < 0.0001). A linear trend with age was detected despite the small age range of our population. By doubling the sampling time, the reported measurement uncertainty decreased by a factor of 1.5, resulting in uncertainty estimates below the mean bone lead estimates. Power calculations using the observed variance estimates suggest that with 80% power, differences in bone lead concentration of 2-3 micrograms Pb/g bone mineral can be identified in groups of 100 or smaller. Due to the large within-person variation in young adults, K-XRF may not yet be a useful diagnostic tool for individual subjects, but it may be of great use to environmental scientists trying to characterize long-term lead exposure and dose in the general population or specific subpopulations.
We investigated the cross-sectional and longitudinal relationships between chronic exposure to lead and physical growth among a cohort of children reassessed 13 years after initial examination. We measured weight, height, and dentin lead levels of 270 children in 1975-78. In 1989-1990 we reexamined 79 of these children for measurement of weight, height, and bone lead levels by means of in vivo K X-ray fluorescence. To avoid potential confounding by race and chelation history, analysis was restricted to white subjects without a history of lead chelation therapy. A total of 236 subjects provided complete information for the study of cross-sectional relationship between dentin lead levels and changes in physical growth: 58 subjects for the study of longitudinal relationship between dentin lead levels and changes in physical growth and 54 subjects for the study of longitudinal relationship between bone lead levels and changes in physical growth. Dentin lead levels averaged 14.9 micrograms/g; tibia and patella lead levels averaged 1.2 and 5.0 micrograms/g, respectively. With control for potential confounders including age, sex, baseline body size, and mother's socioeconomic status, log10 dentin lead level was positively associated with body mass index as of 1975-1978 (beta = 1.02, p = 0.03) and increase in body mass index between 1975-78 and 1989-90 (beta = 2.65, p = 0.03). Bone lead levels were not significantly associated with physical growth. This is the first study relating chronic lead exposure to body mass index. The results suggest that chronic lead exposure in childhood may result in obesity that persists into adulthood.
In vivo X-ray fluorescence (XRF) measurement of bone lead concentration (XRF) has emerged as an important technique for future epidemiological studies of long-term toxicity. Several issues germane to epidemiologic methodology need to be addressed, however. First, sources of variability in measurements of bone lead need to be quantified, including imprecision related to the physical measurement itself and the variability of lead deposition over the two main compartments of bones (cortical vs. trabecular) and within each compartment. Imprecision related to the physical measurement can be estimated for each individual measurement based on the variability of the signal and background. Second, approaches to low-level data need to be debated. We argue for using the minimal detection limit (MDL) to compare instruments and interpret individual measurements; however, with regard to epidemiologic studies, we would abandon the MDL in favor of using all point estimates. In analyses using bone lead as an independent variable, statistical techniques can be used to adjust regression estimates based on estimates of measurement uncertainty and bone lead variability. Third, factors that can be expected to modify the relationship between bone lead and toxicity such as gravida history, endocrinological states, nutrition, and other important influences on bone metabolism, need to be identified and measured in epidemiologic studies. By addressing these issues, investigators will be able to maximize the utility of XRF measurements in environmental epidemiologic studies.
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The expanded forehead flap has been used to reconstruct the nose and repair facial defects simultaneously since Sept. 1991. During operation, the expanded flap was divided into two parts: one based on the supratrochlear vessels for nasal reconstruction, the other based on the frontal branch of the superficial temporal vessel for the facial defects, e.g. periorbital or zygomatic area, upper or lower lip. Four patients were treated with this method and satisfactory results obtained.
For accelerating the inflation process of soft tissue expansion, a continuous inflation protocol regarding pain as the criterion of over-inflation, the full-load expansion technique, was introduced. It is carried out by restricting persistently the pressure in the expander near the pain threshold in a state of dynamic equilibrium between the infusing rate and the skin expansion velocity, with a simple and practical assembled device. This inflation is neither at a uniform infusing rate nor at a constant filing pressure. 19 expanders in 13 patients were inflated following this protocol. Their inflations were respectively fulfilled in 5 to 20 days, depending individually on their anatomic regions, total volumes of infusion, areas of the overlying skin and the patient susceptibilities.
In 19 patients with idiopathic dilated cardiomyopathy and symptoms of congestive heart failure, left ventricular (LV) systolic performance and diastolic velocity profiles were assessed by two- dimensional echocardiography and pulsed wave Doppler at rest and during handgrip exercise before and ninety minutes after administration of captopril (mean dose 25 +/- 12mg; range 12.5-50mg). Although heart rate and blood pressure increased similarly during handgrip exercise before and after captopril treatment, both were lower with handgrip exercise during captopril treatment. The results from this study indicated that acute angiotension converting enzyme inhibition with captopril reduces preload and afterload and ameliorates handgrip exercise-induced LV systolic and diastolic filling dysfunction in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy.
Tolerance to allografted hearts in human recipients has been observed both in clinical situations and in in vitro experiments. To elucidate whether a quantitative change of alloreactive CTL is one of the mechanisms accounting for this graft tolerance, CTL precursor (CTLp) frequencies in the peripheral blood of 10 heart recipients were measured against spleen cells from donors and HLA nonidentical third-party persons. In this longitudinal follow-up study, we showed that the rejection reaction(s) in the grafted heart correlated with CTLp frequencies in samples taken before transplantation against the donor spleen cells, but not with the CTLp frequencies against the spleen cells from the third-party persons. The CTLp frequencies against the spleen cells from donors decreased 4-6 months after transplantation, and remained at a low level afterward. However, the CTLp frequencies against spleen cells from third-party persons in blood samples obtained 1 year after transplantation were not significantly different from those before transplantation. Therefore, we conclude that donor-reactive CTLs are important in rejecting allografted heart. The decrease in donor-specific CTLp after transplantation could explain the donor-specific tolerance. The decrease may be due to homing of the specific CTLp to the graft, or by clonal deletion of the donor-reactive CTL caused by chronic alloantigen stimulation in the presence of immunosuppressive therapies.
OBJECTIVE: To determine whether the concentration of lead in bone constitutes a biological marker that is more sensitive for chronic toxicity than blood lead levels. DESIGN: Survey. SETTING: A construction trade union with members who engage in carpentry, demolition, and other construction activities. PARTICIPANTS: Members of the construction trade union. MAIN OUTCOME MEASURES: We measured blood pressure, serum creatinine, hematocrit, and hemoglobin. We measured blood lead by anodic stripping voltametry and used a cadmium 109 K x-ray fluorescence instrument to make in vivo measurements of lead in the tibia (a heavily cortical bone) and the patella (a heavily trabecular bone). Information was also collected on medical history, smoking, and alcohol ingestion. RESULTS: Bone lead levels in the patella were found to be significantly correlated with a decrease in hemoglobin and hematocrit, even after adjusting for age, blood lead, body mass index, cigarette smoking, and alcohol ingestion and removing outliers. Blood lead levels were low (mean = 0.40 mumol/L [8.3 micrograms/dL]) and were not correlated with either hemoglobin or hematocrit. In the final multivariate regression model that corrected for measurement error, an increase in patella bone lead level from the lowest to highest quintile in this study population (37 micrograms/g) was associated with a decrease in hemoglobin and hematocrit of 11 g/L (95% confidence interval [CI], 2.7 to 19.3 g/L) and 0.03 (95% CI, 0.01 to 0.05), respectively. CONCLUSION: We conclude that patella bone lead levels are associated with decreased hematocrit and hemoglobin levels despite the presence of low blood lead levels. This conclusion may reflect a subclinical effect of bone lead stores on hematopoiesis and is the first epidemiological evidence that bone lead may be an important biological marker of ongoing chronic toxicity.