Biomedical subjects

A Cheng

Publications and source records attributed to A Cheng.

At least 73 records · Page 4Linked to original sources

PubMed1999

A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective in nuclear accumulation.

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least eight complementation groups (A-H). Three FA genes, corresponding to complementation groups A, C, and G, have been cloned, but the function of the encoded FA proteins remains unknown. We recently demonstrated that the FANCA and FANCC proteins bind and form a nuclear complex. In the current study, we identified a homozygous mutation in the FANCA gene (3329A>C) in an Egyptian FA patient from a consanguineous family. This mutant FANCA allele is predicted to encode a mutant FANCA protein, FANCA(H1110P), in which histidine 1110 is changed to proline. Initially, we characterized the FANCA(H1110P) protein, expressed in an Epstein Barr virus (EBV)-immortalized lymphoblast line derived from the patient. Unlike wild-type FANCA protein expressed in normal lymphoblasts, FANCA(H1110P) was not phosphorylated and failed to bind to FANCC. To test directly the effect of this mutation on FANCA function, we used retroviral-mediated transduction to express either wild-type FANCA or FANCA(H1110P) protein in the FA-A fibroblast line, GM6914. Unlike wild-type FANCA, the mutant protein failed to complement the mitomycin C sensitivity of these cells. In addition, the FANCA(H1110P) protein was defective in nuclear accumulation in the transduced cells. The characteristics of this mutant protein underscore the importance of FANCA phosphorylation, FANCA/FANCC binding, and nuclear accumulation in the function of the FA pathway.

Amino Acid Substitution↗

PubMed1999

Residential characteristics influence Der p 1 levels in homes in Melbourne, Australia.

BACKGROUND: Exposure to house dust mite (HDM) allergens is an important risk factor for childhood asthma. Knowledge of environmental determinants of HDM allergen levels is essential before designing rational avoidance measures. AIM: To investigate the effect of domestic characteristics on HDM allergen (Der p 1) levels in Melbourne homes. METHODS: Dust was collected from bed and floor of the bedrooms in 485 houses over a period of one year. Dust was analysed for Der p 1 levels using an enzyme-linked immunosorbent assay. Temperature and relative humidity were measured at the visit. Details of residential characteristics were collected using a questionnaire. Statistically significant predictors of Der p 1 levels (P < 0.05) were identified using multiple linear regression. RESULTS: High levels of Der p 1 were observed in the floors (geometric mean 17.2 microg/g fine dust) as well as in the beds (geometric mean 20.3 microg/g fine dust). Der p 1 levels in the floor dust were significantly lower in winter and spring. They were higher in houses built before 1980 and those with central heating, weather board walls, damp bedrooms or fitted old wool carpets. Der p 1 levels in bed dust were significantly higher in houses built before 1980, with wooden floors built on stumps, with high relative humidity, with visible mould in the room, in beds with an old mattress or in beds without a quilt. CONCLUSIONS: We would encourage construction of homes without carpets, wooden floors on stumps or weather board walls.

Allergens↗

PubMed1999

Seasonal differences in risk factors for sudden infant death syndrome. The New Zealand Cot Death Study Group.

The aim of this study was to explore whether the risk of sudden infant death syndrome (SIDS) associated with prone sleeping position and other risk factors varies with season. The study was a large nation-wide case-control study, which compared 485 cases with 1800 controls. Parents of 393 (81.0%) cases and 1591 (88.4%) controls were interviewed. Obstetric records were also examined. Infants dying in winter were older and had lower birthweights than those dying in summer. The increased risk of SIDS associated with prone sleeping position was greater in winter than in summer. In contrast, the increased risk of SIDS associated with excess thermal insulation and bed sharing was less in winter than in summer. Prone sleeping position accounts for about half of the difference between the mortality rate in summer and that in winter. This suggests that some factor related to season modifies the effect of prone sleeping position.

Age Distribution↗

PubMed1999

A reliable and valid home visit report for studies of asthma in young adults.

Validated instruments are not available to assess the residential characteristics. The aim of this study was to assess the reliability and validity of an interviewer-administered home visit report. The validity of 48 items in the Home Visit Report was examined against: observations made by a researcher, measurements of relative humidity, cat allergen, and ergosterol, a biomaker of fungal exposure and a biochemical test. Test-retest reliability of 10 fixed residential characteristics was assessed comparing the responses obtained in the main study with the pilot study, Kappa, ANOVA and Wilcoxon Rank Sum tests were applied to assess the agreement and P < 0.05 was considered as statistically significant. Among 44 items examined for the validity against observations, there was a perfect or almost perfect agreement in 21 (kappa = 0.9-1) and substantial agreement (kappa = 0.6-0.8) in 19. Higher cat allergen levels were observed with cat ownership and cat being allowed indoors. Observed condensation was associated with relative humidity and observed mould was associated with ergosterol levels. The agreement on the type of carpet and the test was substantial (kappa = 0.6). Among 10 items examined for reliability, there was a perfect or almost perfect agreement in 9 (kappa = 0.9-1) and substantial agreement (kappa = 0.7) in one. In conclusion, the Home Visit Report validated in this study provides reliable and valid data.

Adult↗

PubMed1999

Sexual dimorphism in the neonatal gonad.

The neonatal gonad has two distinct forms (i.e., is sexually dimorphic), as judged by morphological and endocrine characteristics. The dimorphic process begins early in embryogenesis. It is well established by the time of birth, by which time the genital ridge has developed into either a testis or an ovary. The mechanisms involved in sex determination involve the Y chromosome, autosomal genes, transcription factors and possibly other unidentified control networks. This review paper describes the morphological changes that occur and the endocrine functions in the developing gonads. It highlights a number of important differences in fetal and neonatal gonadal function. The testis has early histological definition, several determining genes, delayed germ cell maturation, early autonomous steroid secretion, luteinizing hormone (LH) receptor and steroid enzyme expression, high fetal testicular testosterone content, prominent postnatal Leydig and Sertoli cells and high postnatal serum testosterone levels. The ovary has a prolonged monomorphic state, probably one determining gene, germ cells in early meiotic arrest, delayed expression of LH receptor and aromatase, low ovarian oestradiol content, prominent postnatal follicles and low postnatal serum oestradiol levels.

Embryonic and Fetal Development↗

PubMed1999

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome.

OBJECTIVE: To study the value of measuring serum luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in androgen insensitivity syndrome (AIS). DESIGN: Retrospective study of patients on a nationwide register of AIS. PATIENTS: Sixty one cases of AIS with androgen receptor (AR) dysfunction (abnormalities of the AR gene and/or abnormal AR binding) were divided into three age groups: infants, < 1 year old; children, 1-13 years old; and postpubertal, > 13 years old. MEASUREMENTS: Age, dose of human chorionic gonadotrophin (hCG) stimulation, pre-hCG and post-hCG serum testosterone values, serum DHT values, and serum LH and FSH values before and after LH releasing hormone (LHRH) stimulation. RESULTS: In 23 of 30 infants testosterone was within age related reference ranges; six were above this range. The median testosterone rise following variable dosage of hCG was 9.5 times the basal value. The increment was not related to the hCG dose, age, or basal concentration of testosterone. The median basal and stimulated testosterone:DHT ratios were 2.5 and 6.1, respectively. The median increment in DHT was 2.2-fold. Seventeen of 18 FSH and 11 of 19 LH measurements were within age related ranges in infants; in seven patients LH values were above the range. LHRH stimulation performed in 39 patients showed an exaggerated LH in all age groups. The FSH response was not exaggerated in children. CONCLUSION: Although a positive hCG test excludes biosynthetic defects of testosterone, an inadequate response does not exclude AIS. Basal LH and testosterone may not be raised during early infancy. An LHRH stimulation test might be useful for evaluating cases of suspected AIS presenting in mid-childhood.

Adolescent↗

PubMed1999

Minimally invasive direct coronary artery bypass.

BACKGROUND: Minimally invasive cardiac surgery is a new and promising approach to the treatment of coronary artery disease allowing surgery to be performed through smaller incisions with lesser morbidity. METHODOLOGY: From November 1995 to February 1997, ten minimally invasive direct coronary artery bypass (MIDCAB) grafts were performed. The left internal mammary artery was used to bypass the left anterior descending coronary artery (LAD) through a limited left anterior thoracotomy. PATIENTS: There were seven males and three females and their ages ranged from 42 to 72 years (mean = 60 years). Two patients had prior interventional procedures. Cardiopulmonary bypass was used in the first two patients. Two patients were converted to conventional surgery early in the series. RESULTS: There was no mortality nor major morbidity. Mean post-operative hospital stay was seven days. To date, three patients have had post-operative angiography confirming the patency of the left internal mammary artery to LAD anastomosis. CONCLUSION: Early results of the MIDCAB procedure are encouraging. However, the definitive place of such procedures awaits longer term follow-up.

Adult↗

PubMed1999

Integrative approach to the treatment of postherpetic neuralgia: a case series.

OBJECTIVE: To determine if the addition of alternative therapy to conventional medicine enhances the treatment of pain in postherpetic neuralgia (PHN). METHODOLOGY: A review of literature from 1988-1998 was conducted on the MEDLINE database, searching for information on the current treatment of PHN. The literature review found that although many medications have been used to reduce the pain of PHN, no treatments have been completely successful in decreasing pain. Data on pain reduction in PHN following treatment with a multifaceted alternative therapy combined with conventional treatment were compiled from a group of patients in the principal investigator's family medicine practice. RESULTS: The alternative therapy employed in this study, combined with selected medications, showed an average pain reduction of 72.1 percent. There was a 77-percent average pain reduction in patients with herpes zoster (HZ) onset of more than one year and a 68-percent reduction in patients with HZ onset between one month and one year. Almost two-thirds of the 56 PHN patients reported pain reductions of between 75 and 100 percent. CONCLUSION: These preliminary data suggest the combination of alternative therapy and selected conventional medications provides good pain relief for most patients presenting with PHN. Randomized trials with appropriate control groups are needed to validate the effectiveness of this therapy in the treatment of PHN.

Acupuncture Therapy↗

PubMed1999

The effect of fenofibrate on insulin sensitivity and plasma lipid profile in non-diabetic males with low high density lipoprotein/dyslipidaemic syndrome.

Non-diabetic males, particularly those with very low levels of high density lipoprotein (HDL) type cholesterol and high levels of very low density type lipoprotein (VLDL), are associated with insulin resistance and decreased insulin sensitivity. The evidence that elevation of HDL cholesterol and diminution of triglycerides with drugs, with improvement in insulin sensitivity is still lacking. In the treatment of the dyslipidaemic syndromes with hypolipidaemic drugs, the associated metabolic abnormality of insulin resistance/sensitivity has to be addressed. We investigated the degree of decreased insulin sensitivity in 23 patients with low HDL and/or raised triglycerides by measuring the fasting, first and second hour insulin levels during an oral glucose tolerance test (OGTT) and repeated the measurements after a 6-month course of fenofibrate. The insulin levels were correlated with the OGTT, blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides measured before and at the end of the trial. The serum insulin at the second hour of the OGTT fell from 100.79 +/- 42.79 mU/l to 54.56 +/- 25.43 mU/l (P < 0.0005) even though there was no change in the blood glucose level at this point. Our study shows that fenofibrate (Lipanthyl) 300 mg daily significantly raises the pretreatment low HDL cholesterol (from 0.64 +/- 0.1 mmol/l to 0.99 +/- 0.2 mmol/l) as well as lowers the triglyceride level (from 2.17 +/- 1.1 mmol/l to 1.43 +/- 0.64 mmol/l) in patients with low HDL/dyslipidaemic syndrome. The data also support the conclusion that treatment with fenofibrate increases insulin sensitivity as measured by the corresponding insulin levels of the OGTT in the study subjects who presented with very low HDL cholesterol level. There was also a decrease in blood pressure readings in our study subjects. Throughout the trial, there was no significant change in body weight or exercise level in the subjects studied.

Adult↗

PubMed1999

[A pharmacokinetic study of teniposide in intraperitoneal chemotherapy of ovarian cancer].

The objectives of this study were to determine the characteristics of pharmacokinetics of teniposide (VM-26) instilled intraperitoneally with three dosages (100 mg, 150 mg and 200 mg) and to evaluate its toxicity. Twelve patients with ovarian cancer were divided into three groups: teniposide 100 mg i.p., 5 patients; teniposide 150 mg i.p., 5 patients; and teniposide 200 mg i.p., 2 patients. Samples of ascitic fluid, blood and urine were collected after administration of these drugs in 24 hours. Concentrations of teniposide were determined with high-performance liquid chromatographic procedure. The results showed that the data collected from peritoneum and plasma were found to conform to a two-compartment open model. The peak concentration (Cmax) and the area under the curves (AUC) in peritoneal cavity and plasma were dose-dependent. The ratios of Cmax and AUC between peritoneal fluid and plasma varied within 13.46 +/- 1.89 and 7.65 +/- 2.03 respectively. The elimination half-lives (T1/2 beta) in the peritoneum and plasma of teniposide were 5.28 +/- 0.95 and 6.64 +/- 2.73 hours respectively. The volume of peritoneal distribution and its clearance were lower than those of plasma (P < 0.001). The side effects were mild and were not dependent on drug dosage. The results suggest that teniposide as an intraperitoneal therapeutic agent offers some advantages in the treatment of ovarian cancer. The tumor tissues and peritoneal growths could be bathed in a high concentration of teniposide. Teniposide is safe, reasonable in intraperitoneal chemotherapy and shows prospects in the treatment of ovarian cancer.

Adult↗

PubMed1998

Fostriecin-mediated G2-M-phase growth arrest correlates with abnormal centrosome replication, the formation of aberrant mitotic spindles, and the inhibition of serine/threonine protein phosphatase activity.

Fostriecin, a structurally unique phosphate ester, is presently under evaluation in clinical trials to determine its potential use as an antitumor drug in humans. Fostriecin has been reported as having inhibitory activity against DNA topoisomerase type II and protein phosphatases implicated in cell-cycle control. However, the relative contribution of these mechanisms to the antitumor activity of fostriecin has not yet been elucidated. In this study, after confirming that fostriecin is a potent inhibitor of serine/threonine protein phosphatase type 2A and a weak inhibitor of serine/threonine protein phosphatase type 1, we show that fostriecin inhibits approximately 50% of the divalent cation independent serine/threonine protein phosphatase (PPase) activity contained in whole cell homogenates of Chinese hamster ovary cells at concentrations associated with antitumor activity (1-20 microM). Investigations into the cellular effects produced by fostriecin treatment reveal that 1-20 microM fostriecin induces a dose-dependent arrest of cell growth during the G2-M phase of the cell cycle. Immunostaining of treated cells indicates that growth arrest occurs before the completion of mitosis and that fostriecin-induced growth arrest is associated with the aberrant amplification of centrosomes, which results in the formation of abnormal mitotic spindles. The "mitotic block" induced by fostriecin is reversible if treatment is discontinued in <24 h. However, after approximately 24-30 h of continuous treatment, growth arrest is not reversible, and treated cells die even when placed in fostriecin-free media. Correlative studies conducted with established PPase inhibitors reveal that, when applied at concentrations that inhibit PPase activity to a comparable extent, both okadaic acid and cantharidin also induce aberrant centrosome replication, the appearance of multiple aberrant mitotic spindles, and G2-M-phase growth arrest. These studies add additional support to the concept that PPase inhibition underlies the antitumor activity of fostriecin and suggest that other type-selective PPase inhibitors should be evaluated for potential antitumor activity.

Alkenes↗

PubMed1998

A critical evaluation of the planning target volume for 3-D conformal radiotherapy of prostate cancer.

PURPOSE: To determine an adequate planning target volume (PTV) margin for three-dimensional conformal radiotherapy (3D CRT) of prostate cancer, the uncertainties in the internal positions of the prostate and seminal vesicles (SV) and in the treatment setups were measured. METHODS AND MATERIALS: Weekly computed tomography (CT) scans of the pelvis (n=51) and daily electronic portal images (n=1630) were reviewed for eight patients who received seven-field 3D CRT for prostate cancer. The CT scans were registered in three dimensions to the original planning CT scan using commercially available software to measure the center-of volume (COV) motion of the prostate and SV. The daily portal images were registered to the corresponding simulation films to measure the setup displacements. The standard deviation (SD) of the internal organ motions was added to the SD of the setups in quadrature to determine the total uncertainty. Positive directions were left, anterior, and superior. Rotations necessary to register the CT scans and portal images were minimal and not further analyzed. RESULTS: The mean motion for the COV of the prostate+/-the SD was 0+/-0.9 mm in the left-right (LR), 0.5+/-2.6 mm in the anterior-posterior (AP), and 1.5+/-3.9 mm in the superior-inferior (SI) directions. The mean motion for the COV of the SV+/-the SD was 0.3+/-1.7 mm in the LR, 0.7+/-3.8 mm in the AP, and 0.9+/-3.5 mm in the SI directions. For all patients the mean isocenter displacement+/-the SD was 0+/-3.1 mm in the LR, 1.4+/-3.0 mm in the AP, and -0.4+/-2.1 mm in the SI directions. The total uncertainty for the prostate was 3.2 mm, 4.0 mm, and 4.4 mm in the LR, AP, and SI directions, respectively. For the SV, the total uncertainty was 3.5, 4.8, and 4.1 mm in the LR, AP, and SI directions, respectively. CONCLUSIONS: PTV margins of 10 to 16 mm are required to encompass all (99%) possible positions of the prostate or SV during 3D CRT. PTV margins of 7 to 11 mm will encompass the measured uncertainties with a 95% probability. PTV margins of 5 mm may not adequately cover the intended volume.

Humans↗

PubMed1998

Use of angiotensin-converting enzyme inhibitors as monotherapy and in combination with diuretics and calcium channel blockers.

Angiotensin-converting enzyme (ACE) inhibitors have earned an important place in medical therapy since their discovery about two decades ago. This family of drug has grown tremendously since the introduction of captopril in 1981. There are currently more than 14 ACE inhibitors in the world and 9 are available in the United States. Although these agents share many similarities, they differ in their pharmacokinetic properties, approved indications, and cost. This paper provides guidance for selection of ACE inhibitors by examining the pharmacokinetics, pharmacodynamics, drug interactions, adverse effects, and cost of these agents. Combination products of ACE inhibitors with either diuretics or calcium channel blockers also are reviewed.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

A simple mechanical mixer for small viscous lipid-containing samples.

The construction and performance characteristics of a simple device for rapid and convenient hydration and mixing of small volumes (10-500 microliters) of viscous hydrated lipid samples for use in X-ray diffraction/scattering and other applications are described. The mixer has been used successfully over the past several years in studies of the equilibrium properties of lipid mesophases and of the kinetics and mechanism of phase transitions. It is a low dead-volume (3.6-11.2 microliters) device that was built to facilitate maximal transfer of homogeneously hydrated lipid from the mixer into 1 mm diameter X-ray capillaries with minimal loss of water during transfer and sample manipulation. The device consists of inexpensive, commercially available parts, the most important of which are two microsyringes joined by a small-bore coupling needle. Also described in this report is a technique for determining the water content of the small volume, hydrated samples prepared with the mixer and an accessory for conveniently heating and/or degassing samples during mixing. Inadvertent sample heating that occurs during mixing is described.

Lipids↗

PubMed1998

A prospective cohort study of blood donors: methodological issues in the investigation of injuries and chronic diseases.

Blood donors have made important contributions to research, most notably in cross-sectional seroprevalence studies. The proposed New Zealand Blood Donors Health Study is a prospective cohort study of 30,000 New Zealand donors designed to investigate the determinants of common injuries, cardiovascular disease and cancer. While robust from an analytic perspective, the execution of prospective cohort studies in many settings is impeded by methodological, economic and organisational barriers. We examined the operational considerations of implementing a large-scale cohort study at a transfusion centre and evaluated measures taken to optimise data collection procedures. A pilot study of 1,000 participants revealed donor motivation to participate in this research was high (91% response rate). Comprehensive exposure data on lifestyle, behavioural and psychosocial factors were obtained from 95% of participants. Substantial heterogeneity in levels of potential risk factors was noted among respondents. Detailed dietary habit information and a study blood sample were obtained from 67% and 100% of participants, respectively. Study recruitment and baseline data collection was feasible during routine donor visits with minimal interruption to donor centre staff and procedures. We conclude the study design and characteristics of the regional donor program enhance the efficiency and significance of the proposed research.

Adolescent↗

PubMed1998

Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.

The selection of bacterial resistance was examined in relationship to antibiotic pharmacokinetics (PK) and organism MICs in the patients from four nosocomial lower respiratory tract infection clinical trials. The evaluable database included 107 acutely ill patients, 128 pathogens, and five antimicrobial regimens. Antimicrobial pharmacokinetics were characterized by using serum concentrations, and culture and sensitivity tests were performed daily on tracheal aspirates to examine resistance. Pharmacodynamic (PD) models were developed to identify factors associated with the probability of developing bacterial resistance. Overall, in 32 of 128 (25%) initially susceptible cases resistance developed during therapy. An initial univariate screen and a classification and regression tree analysis identified the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC[0-24]/MIC) as a significant predictor of the development of resistance (P < 0.001). The final PK/PD model, a variant of the Hill equation, demonstrated that the probability of developing resistance during therapy increased significantly when antimicrobial exposure was at an AUC[0-24]/MIC ratio of less than 100. This relationship was observed across all treatments and within all organism groupings, with the exception of beta-lactamase-producing gram-negative organisms (consistent with type I beta-lactamase producers) treated with beta-lactam monotherapy. Combination therapy resulted in much lower rates of resistance than monotherapy, probably because all of the combination regimens examined had an AUC[0-24]/MIC ratio in excess of 100. In summary, the selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUC[0-24]MIC ratio of less than 100.

Acute Disease↗

PubMed1998

The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils.

The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcgamma receptor (FcgammaR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk-/- embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcgammaR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcgammaR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcgammaR gamma chain, as well as Erk2 activation, was compromised in Syk-/- macrophages after FcgammaR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcgammaRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.

Abdomen↗

PubMed1998

In vitro and animal validation of bromine-76-bromodeoxyuridine as a proliferation marker.

UNLABELLED: The potential of 76Br-bromodeoxyuridine as a PET tracer for characterizing proliferation potential was investigated in multicellular tumor aggregates and in healthy rats and pigs. METHODS: Bromine-76-bromide was produced by proton irradiation of a 76Se-enriched target using a 17-MeV cyclotron and recovered by thermal diffusion. Bromine-76-BrdU was prepared from the corresponding trimethylstannate by an oxidative bromination. Multicellular aggregates from a carcinoid cell line and two bladder cancer cell lines were co-incubated with 76Br-BrdU and 3H-thymidine and the uptake and DNA incorporation analyzed. About 0.5 MBq 76Br-BrdU were injected in the tail vein of unanaesthetised Sprague-Dawley rats. Two to 36 hr later they were decapitated and the radioactivity concentration and fraction of radioactivity incorporated into DNA determined in five different organs and the blood. Parallel studies were performed in animals pretreated with hydroxyurea. In separate experiments, rats were given an injection of 76Br-bromide and organ uptake was evaluated after 20 hr. PET studies were performed in two pigs and the uptake in different organs was investigated after injection of 76Br-BrdU. In these studies, diuresis was induced by furosemide and mannitol and radioactivity in blood and organs was followed during 10 hr. RESULTS: In the cell aggregates, 30%-90% of the radioactivity was extracted in the DNA fraction. A good correlation was found between 76Br-BrdU and 3H-thymidine with respect to total uptake and DNA fraction. The DNA fraction increased from 2-10 hr after incubation. With in vivo injection in the rat, relatively high uptake of radioactivity was found in all organs, unrelated to the degree of DNA synthesis. However, inhibition by hydroxyurea occurred only in the spleen and intestines, organs which also showed a high degree of incorporation of 76Br-BrdU into DNA. In the pig, the highest in vivo uptake was observed in the red bone marrow and the intestines. In these organs, 70%-80% of the radioactivity was recovered in the DNA fraction. The concentration of radioactivity in the heart, liver and kidney was 3-10 times lower, and here the DNA fraction accounted for 10%-20% of the radioactivity. The decay-corrected radioactivity in blood and nonproliferating organs decreased with diuresis with a half-life of 13 and 16 hr, respectively. CONCLUSION: It is suggested that the radioactivity uptake as seen after the administration of 76Br-BrdU, is constituted by two parts: one relating to incorporation into DNA and one existing as free 76Br- or metabolites of 76Br-BrdU. If sufficient time has passed, 76Br- dominates other metabolites. A correct assessment of DNA-incorporated radioactivity using PET with 76Br-BrdU is not trivial and can only be made with due correction for 76Br-, using either a complementary investigation after hydroxyurea pretreatment (in animal studies) or a separate 76Br-bromide investigation. Alternatively, the free bromide can be eliminated partially through forced diuresis.

Animals↗