The "n-1" model for myelodysplastic syndromes.

Current models of leukaemogenesis tend to visualize this process as consisting of several discrete steps. Since myelodysplastic syndromes (MDS) are, almost by definition, pre-leukaemic disorders, we expect that bone marrow from patients with MDS must contain cells which are one step short of full leukaemic transformation: we designate these cells, for convenience, as "n-1". It should be possible therefore to obtain leukaemic transformation in vitro by introducing into n-1 cells a gene with an appropriate leukaemogenic mutation. We have found, by using as a model system the retrovirus VSN-2 (which carries the neomycin-phosphotransferase gene, neo, which confers resistance to the antibiotic G418), that human bone marrow cells can be successfully transfected in microcultures. Indeed, G418-resistant CFU-CM have been recovered from these cultures for a period of several weeks.     

Electroencephalographic analysis of malignant melanoma patients.

EEGs carried out in 202 patients with melanoma were abnormal in 33%. In the absence of systemic or brain metastasis 14% of the patients had abnormal records. If systemic metastases without brain metastasis were present 45% of the patients had abnormal records and with brain metastasis 88% had abnormal EEGs. Only a third of the patients with abnormal records had brain metastasis but metastatic spread to some organ system was present in 76% of those with EEG abnormalities. The diffuse abnormality was less likely to be a "false positive." Ninety-seven percent of the patients with diffuse EEG abnormality had systemic metastasis but 43% of the patients with focal EEG changes had no detected metastasis.     

Health consequences of obesity.

The recent epidemic of childhood obesity(1) has raised concern because of the possible clinical and public health consequences.(2,)(3) However, there remains a widespread perception among health professionals that childhood obesity is a largely cosmetic problem, with minor clinical effects. No systematic review has yet focused on the diverse array of possible consequences of childhood obesity, though older non-systematic reviews are available.(4,)(5) In addition, no review to date has considered the vast body of evidence on the health impact of childhood obesity which has been published recently. The aim of the present review was therefore to provide a critically appraised, evidence based, summary of the consequences of childhood obesity in the short term (for the child) and longer term (in adulthood).     

BMI distribution changes in adolescent British girls.

Body mass index (BMI) distribution changes were assessed in 2547 relatively affluent English girls, aged 12-16 years, during the UK childhood obesity epidemic (1986-96). An increase in BMI variability was observed only in 12-14 year olds, suggesting that BMI changes for population subgroups were complex, and inconsistent with a generalised increase in BMI.     

Treatment of localized prostate cancer using a combination of high dose rate Iridium‐192 brachytherapy and external beam irradiation: Initial Australian experience

Combination high dose rate brachytherapy (HDRB) and external beam radiation therapy is technically and clinically feasible as definitive treatment for localized prostate cancer. We report the first large Australian experience using this technique of radiation dose escalation in 82 patients with intermediate‐ and high‐risk disease. With a median follow up of 3 years (156 weeks), complications were low and overall prostate‐specific antigen progression‐free survival was 91% using the American Society for Therapeutic Radiology and Oncology consensus definition. The delivery of hypofractionated radiation through the HDRB component shortens overall treatment time and is both biologically and logistically advantageous. As a radiation boost strategy, HDRB is easy to learn and could be introduced into most facilities with brachytherapy capability.     

Mild renal pelvic dilatation is not predictive of vesicoureteral reflux in children

Objective. To determine if mild renal pelvic dilatation at renal ultrasound (RUS) is a reliable sign of vesicoureteral reflux (VUR) at voiding cystourethrogram (VCUG) in children. Materials and methods. All patients less than 10 years of age who had RUS and VCUG on the same day during a 2-year period were identified in a computerized database. The appearance of the collecting system of each kidney was classified into two groups: group 0 – no dilatation (≤ 2-mm anteroposterior diameter of the renal pelvis) and group 1 – 3 to 10-mm AP diameter of the renal pelvis without caliectasis. VUR at VCUG was graded using the International Reflux Study Committee system. Results. Four hundred fifty-five patients (76 boys; 379 girls) with 910 kidneys were included. VUR occurred in 268 kidneys in 174 patients. There were 820 group 0 kidneys and 90 group 1 kidneys. Kidneys classified as group 1 (25.0 % had reflux) were no more likely to have reflux than were kidneys with nondistended (group 0) collecting systems (31.2 % had reflux). There was no statistical difference in the rate of reflux in patients with group 1 renal pelvic distention (39.2 % refluxed) and a normal collecting system (33.3 % refluxed) (P = 0.365). Conclusion. The frequency of vesicoureteral reflux in children with mild renal pelvic distention is not significantly different than in children with no distention. Therefore, mild dilatation of the renal pelvis should not be considered an indication for voiding cystourethrography. Received: 14 April 1997 Accepted: 24 July 1997     

Bacterial and mammalian DNA alkyltransferases sensitize Escherichia coli to the lethal and mutagenic effects of dibromoalkanes

Here we confirm and extend our previous studies demonstrating that the mutagenic potency of 1,2-dibromoethane (DBE) and dibromomethane (DBM) is markedly enhanced (not prevented) in bacteria expressing the O6- alkylguanine-DNA alkyltransferase (ATase) encoded by the Escherichia coli ogt gene. We demonstrate that, in close parallel with mutagenesis, the Ogt ATase sensitizes the bacteria to the lethal effects of these carcinogens, suggesting that one or more of the potentially mutagenic lesions induced by DBE and DBM in the presence of Ogt has additional lethal capacity. We further demonstrate that the sensitization to both lethality and mutagenesis by DBE and DBM is a property shared by other DNA alkyltransferases. This objective was accomplished by quantifying the induction of mutations and lethal events in ogt- ada- E. coli expressing an exogenous bacterial or mammalian ATase from a multicopy plasmid. Mammalian recombinant ATases enhanced the lethal and mutagenic actions of DBE and suppressed the lack of sensitivity of the vector- transformed bacteria to DBM. In most cases the order of effectiveness of the ATases ranked: murine > human > Ogt > rat. Further comparisons included the full-length Ada ATase from E. coli and a truncated Ada version (T-ada) that retains the O6-methylguanine binding domain of the protein. The full-length Ada ATase was effective in enhancing the lethality but not the mutagenicity induced by DBE and DBM. The T-ada ATase provided less sensitization than Ada to lethality by DBE, but of the three bacterial ATases T-ada yielded the highest sensitization to mutagenesis by this compound. T-ada and Ada ATases were in general less effective than the mammalian versions, with the exception of the rat recombinant ATase. The effectiveness of the different mammalian and bacterial ATases in promoting the deleterious actions of dibromoalkanes was compared with the effectiveness of these proteins in suppressing the lethal and mutagenic effects induced by N-nitroso-N-methylurea. The ability to sensitize E. coli to the lethal and mutagenic effects of DBE and DBM seems restricted to DNA alkyltransferase, since overexpression of thioredoxin (Trx) or glutaredoxin (Grx1) in ogt- ada- cells showed no effect, in spite of the reported potential of bioactive dihaloethane- derived species to alkylate Trx.      

Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hydrocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction, tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in strain A/J mouse lung. Groups of mice received a single i.p. injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occurrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days after injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and syn-11,12- dihydroxy-13,14-epoxy- 11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatography. The major adduct was identified as a product of the reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbers of lung adenomas in a dose- dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens including benzo[a]pyrene. As a function of time-integrated DNA adduct levels, DB[a,l]P induced lung adenomas with about the same potency as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar in carcinogenic potency to other PAHs in the strain A/J mouse lung model. Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of codon 12, and A-->T transversions in the second or third base of codon 61, concordant with the DNA adduct profile.