Early toxicity from preoperative radiotherapy with continuous infusion 5-fluorouracil for resectable adenocarcinoma of the rectum: A phase II trial for the Trans-Tasman Radiation Oncology Group

Purpose: To assess the toxicity and the efficacy of preoperative radiotherapy with continuous infusion 5-fluorouracil (5-FU) for locally advanced adenocarcinoma of the rectum. Methods and Materials: Eligible patients had newly diagnosed localized adenocarcinoma of the rectum within 12 cm of the anal verge, Stage T3-4, and were suitable for curative resection. Eighty-two patients were treated with radiotherapy-50.4 Gy in 28 fractions in 5.6 weeks, given concurrently with continuous infusion 5-FU, using either 96-h/week infusion at 300 mg/m(2)/day or 7-days/week infusion at 225 mg/m(2)/day. Results: The median age was 59 years (range, 27-87), and 67% of patients were male. Pretreatment stages of the rectal cancer were T3, 89% and resectable T4, 11%, with endorectal ultrasound confirmation in 67% of patients. Grade 3 acute toxicity occurred in 5 of 82 patients (6%; 95% confidence interval [CI], 2-14%). Types of surgical resection were anterior resection, 61%; abdominoperineal resection, 35%; and other procedures, 4%. There was no operative mortality. Anastomotic leakage after low anterior resection occurred in 3 of 50 patients (6%; 95% CI, 1-17%). The pathologic complete response rate was 16% (95% CI, 9-26%). Pathologic Stages T2 or less occurred in 51%. Conclusion: Preoperative radiotherapy with continuous infusion 5-FU for locally advanced rectal cancer is a safe regimen, with a significant downstaging effect. It does not seem to lead to a significant increase in serious surgical complications. (C) 2001 Elsevier Science Inc.

Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P4501B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009

A variety of polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, arylamines, heterocyclic amines, and nitroarenes, were incubated with cDNA-based recombinant (Escherichia coli or Trichoplusia ni) systems expressing different forms of human cytochrome P450 (P450 or CYP) and NADPH-P450 reductase using Salmonella typhimurium, tester strain NM2009, and the resultant DNA damage caused by the reactive metabolites was detected by measuring expression of umu gene in the cells. Recombinant (bacterial) CYP1A1 was slightly more active than any of four CYP1B1 allelic variants, CYP1B1*1, CYP1B1*2, CYP1B1*3, and CYP1B1*6, in catalyzing activation of chrysene-1,2-diol, benz[a]anthracene-trans-1,2-, 3,4-, 5,6-, and 8,9-diol, fluoranthene-2,3-diol, dibenzo[a]pyrene, benzo[c]phenanthrene, and dibenz[a,h]anthracene and several arylamines and heterocyclic amines, whereas CYP1A1 and CYP1B1 enzymes had essentially similar catalytic specificities toward other procarcinogens, such as (+)-, (-)-, and (+/-)-benzo[a]pyrene-7,8-diol, 5-methylchrysene-1,2-diol, 7,12-dimethylbenz[a]anthracene-3,4-diol, dibenzo[a,l]pyrene-11,12-diol, benzo[b]fluoranthene-9,10-diol, benzo[c]chrysene, 5,6-dimethylchrysene-1,2-diol, benzo[c]phenanthrene-3,4-diol, 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene, 5-methylchrysene, and benz[a]anthracene. We also determined activation of these procarcinogens by recombinant (T. ni) human P450 enzymes in S. typhimurium NM2009. There were good correlations between activities of procarcinogen activation by CYP1A1 preparations expressed in E. coli and T. ni cells, although basal activities with three lots of CYP1B1 in T. ni cells were very high without substrates and NADPH in our assay system. Using 14 forms of human P450S (but not CYP1B1) (in T. ni cells), we found that CY1P1A2, 2C9, 3A4, and 2C19 catalyzed activation of several of polycyclic aromatic hydrocarbons at much slower rates than those catalyzed by CYP1A1 and that other enzymes, including CYP2A6, 2B6, 2C8, 2C18, 2D6, 2E1, 3A5, 3A7, and 4A11, were almost inactive in the activation of polycyclic aromatic hydrocarbons examined here.

Validation of the Edinburgh Postnatal Depression Scale for men, and comparison of item endorsement with their partners

Background: The Edinburgh Postnatal Depression Scale (EPDS) has been validated and used extensively in screening for depression in new mothers, both in English speaking and non-English speaking communities. While some studies have reported the use of the EPDS with Fathers, none have validated it for this group, and thus the appropriate cut-off score for screening for depression or anxiety caseness for this population is not known. Method: Couples were recruited antenatally and interviewed at six weeks postpartum. EPDS scores and distress caseness (depression or anxiety disorders) for 208 fathers and 230 mothers were determined using the Diagnostic Interview Schedule. Results: Analyses of the EPDS for fathers using distress caseness (depression or anxiety disorders) as the criterion shows that a cut-off of 5/6 has optimum receiver operating characteristics. Furthermore acceptable reliability (split-half and internal consistency) and validity (concurrent) coefficients were obtained. For mothers the optimum cut-off screening value to detect distress caseness was 7/8. Item analysis revealed that fathers endorsed seven of the ten items at lower rates to mothers, with the most significant being that referring to crying. Conclusions: The EPDS is a reliable and valid measure of mood in fathers. Screening for depression or anxiety disorders in fathers requires a two point lower cut-off than screening for depression or anxiety in mothers, and we recommend this cut-off to he 5/6. (C) 2001 Elsevier Science B.V. All rights reserved.

Cenozoic continental weathering and its implications for the palaeoclimate: evidence from Ar-40/Ar-39 geochronology of supergene K-Mn oxides in Mt Tabor, central Queensland, Australia

One hundred and twenty-five mineral grains from 45 visually pure K-bearing Mn oxide (hollandite group) samples collected from weathering profiles in the Mt Tabor region of central Queensland, Australia, were analysed by the Ar-40/Ar-39 laser probe technique. These K-Mn oxides precipitated mainly through a process of cavity filling (direct precipitation from weathering solution), with botryoidal texture formed by micrometric mineral bands. Well-defined and reproducible plateau ages have been obtained for most samples, ranging from 27.2 +/- 0.8 to 6.8 +/- 0.5 Ma (2 sigma). Statistical analysis of the geochronological results by mixture modelling suggests an episodic mineral precipitation history, with two major peaks at 20.2 +/- 0.22 Ma and 16.5 +/- 0.17 Ma. The geochronological results, when combined with information on paragenetic relationships and mineralogical textures obtained from petrographic, scanning electron microscopy, and electron microprobe investigations, indicate that warm and humid palaeoclimatic conditions favourable to intense chemical weathering prevailed in central Queensland from late Oligocene to middle Miocene, particularly in the early Miocene. These results, in conjunction with previous and ongoing investigations in NW and eastern Queensland, suggest that most of Queensland was dominated by humid climates during the Miocene. (C) 2002 Elsevier Science BN. All rights reserved.

Guideline-discordant care in acute myocardial infarction: predictors and outcomes

Objectives: To determine (i) factors which predict whether patients hospitalised with acute myocardial infarction (AMI) receive care discordant with recommendations of clinical practice guidelines; and (ii) whether such discordant care results in worse outcomes compared with receiving guideline-concordant care. Design: Retrospective cohort study. Setting: Two community general hospitals. Participants: 607 consecutive patients admitted with AMI between July 1997 and December 2000. Main outcome measures: Clinical predictors of discordant care; crude and risk-adjusted rates of inhospital mortality and reinfarction, and mean length of hospital stay. Results: At least one treatment recommendation for AMI was applicable for 602 of the 607 patients. Of these patients, 411(68%) received concordant care, and 191 (32%) discordant care. Positive predictors at presentation of discordant care were age > 65 years (odds ratio [OR], 2.5; 95% Cl, 1.7-3.6), silent infarction (OR, 2.7; 95% Cl, 1.6-4.6), anterior infarction (OR, 2.5; 95% Cl, 1.7-3.8), a history of heart failure (OR, 6.3; 95% Cl, 3.7-10.7), chronic atrial fibrillation (OR, 3.2; 95% Cl, 1.5-6.4); and heart rate greater than or equal to 100 beats/min (OR, 2.1; 95% Cl, 1.4-3.1). Death occurred in 12.0% (23/191) of discordant-care patients versus 4.6% (19/411) of concordant-care patients (adjusted OR, 2.42; 95% Cl, 1.22-4.82). Mortality was inversely related to the level of guideline concordance (P = 0.03). Reinfarction rates also tended to be higher in the discordant-care group (4.2% v 1.7%; adjusted OR, 2.5; 95% Cl, 0.90-7.1). Conclusions: Certain clinical features at presentation predict a higher likelihood of guideline-discordant care in patients presenting with AMI Such care appears to increase the risk of inhospital death.

Development of a fully quantitative approach to the interpretation of stress echocardiography using radial and longitudinal myocardial velocities

Background: Tissue Doppler may be used to quantify regional left ventricular function but is limited by segmental variation of longitudinal velocity from base to apex and free to septal walls. We sought to overcome this by developing a composite of longitudinal and radial velocities. Methods and Results. We examined 82 unselected patients undergoing a standard dobutamine echocardiogram. Longitudinal velocity was obtained in the basal and mid segments of each wall using tissue Doppler in the apical views. Radial velocities were derived in the same segments using an automated border detection system and centerline method with regional chords grouped according to segment location and temporally averaged. In 25 patients at low probability of coronary disease, the pattern of regional variation in longitudinal velocity (higher in the septum) was the opposite of radial velocity (higher in the free wall) and the combination was homogenous. In 57 patients undergoing angiography, velocity in abnormal segments was less than normal segments using longitudinal (6.0 +/- 3.6 vs 9.0 +/- 2.2 cm/s, P = .01) and radial velocity (6.0 +/- 4.0 vs 8.0 +/- 3.9 cm/s, P = .02). However, the composite velocity permitted better separation of abnormal and normal segments (13.3 +/- 5.6 vs 17.5 +/- 4.2 cm/s, P = .001). There was no significant difference between the accuracy of this quantitative approach and expert visual wall motion analysis (81% vs 84%, P = .56). Conclusion: Regional variation of uni-dimensional myocardial velocities necessitates site-specific normal ranges, probably because of different fiber directions. Combined analysis of longitudinal and radial velocities allows the derivation of a composite velocity, which is homogenous in all segments and may allow better separation of normal and abnormal myocardium.

Religious beliefs and practice, and alcohol use in Thai men

Buddhism, the Thai state religion, teaches that use of intoxicants should be avoided. Nonetheless, many Thai people drink alcohol, and a proportion are alcohol-dependent or hazardous or harmful drinkers. This study examines the relationship between Buddhist upbringing and beliefs and alcohol use disorders in Thai men. Three groups, comprising 144 non/infrequent/light drinkers, 77 hazardous/harmful drinkers and 91 alcohol dependents were inter-viewed regarding their early religious life and current religious practices and beliefs. No protective association was shown between early religious life and later alcohol use disorders, indeed, having lived as a buy in a temple for a period was commoner in those with adult alcohol problems. Few subjects reported frequent involvement in current religious activities (9, 8 and 6% in the non/infrequent/light drinkers, hazardous/harmful drinkers, and alcohol dependents respectively). Hazardous/harmful drinkers [odds ratio (OR) = 0.4, 95% confidence interval (0) = 0.2-0.9] and alcohol dependents (OR = 0.5, 95% Cl = 0.2-0.9) were less likely to report being moderately to strongly religious, than were non/infrequent/light drinkers, Understanding the association between religious beliefs and drinking behaviour can potentially assist in the development of prevention and treatment programmes.

Overlarge sets of 2-(11, 5, 2) designs and related configurations

We consider the construction of several configurations, including: • overlarge sets of 2-(11,5,2) designs, that is, partitions of the set of all 5-subsets of a 12-set into 72 2-(11,5,2) designs; • an indecomposable doubly overlarge set of 2-(11,5,2) designs, that is, a partition of two copies of the set of all 5-subsets of a 12-set into 144 2-(11,5,2) designs, such that the 144 designs can be arranged into a 12 × 12 square with interesting row and column properties; • a partition of the Steiner system S(5,6,12) into 12 disjoint 2-(11,6,3) designs arising from the diagonal of the square; • bidistant permutation arrays and generalized Room squares arising from the doubly overlarge set, and their relation to some new strongly regular graphs.

Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Control of ovulation with a GnRH agonist after superstimulation of follicular growth in buffalo: fertilization and embryo recovery

The potential to use a GnRH agonist bioimplant and injection of exogenous LH to control the time of ovulation in a multiple ovulation and embryo transfer (MOET) protocol was examined in buffalo. Mixed-parity buffalo (Bubalus bubalis; 4-15-year-old; 529 13 kg LW) were randomly assigned to one of five groups (n = 6): Group 1, conventional MOET protocol; Group 2, conventional MOET with 12 It delay in injection of PGF(2alpha); Group 3, implanted with GnRH agonist to block the pre-ovulatory surge release of LH; Group 4, implanted with GnRH agonist and injected with exogenous LH (Lutropin(R), 25 mg) 24 h after 4 days of superstimulation with FSH; Group 5, implanted with GnRH agonist and injected with LH 36 h after superstimulation with FSH. Ovarian follicular growth in all buffaloes was stimulated by treatment with FSH (Folltropin-V(R), 200 mg) administered over 4 days, and was monitored by ovarian ultrasonography. At the time of estrus, the number of follicles greater than or equal to8 mm. was greater (P < 0.05) for buffaloes in Group 2 (12.8) than for buffaloes in Groups 1 (8.5), 3 (7.3), 4 (6.1) and 5 (6.8), which did not differ. All buffaloes were mated by AI after spontaneous (Groups 1-3) or induced (Groups 4 and 5) ovulation. The respective number of buffalo that ovulated, number of corpora lutea, ovulation rate (%), and embryos + oocytes recovered were: Group 1 (2, 1.8 +/- 1.6, 18.0 +/- 13.6, 0.2 +/- 0.2); Group 2 (4, 6.1 +/- 2.9, 40.5 +/- 17.5, 3.7 +/- 2.1); Group 3 (0, 0, 0, 0); Group 4 (6, 4.3 +/- 1.2, 69.3 +/- 14.2, 2.0 +/- 0.9); and Group 5 (1, 2.5 +/- 2.5, 15.5 +/- 15.5, 2.1 +/- 2.1). All buffaloes in Group 4 ovulated after injection of LH and had a relatively high ovulation rate (69%) and embryo recovery (46%). It has been shown that the GnRH agonist-LH protocol can be used to improve the efficiency of MOET in buffalo. (C) 2002 Elsevier Science Inc. All rights reserved.

Randomized comparison of the quality of realtime fetal ultrasound images transmitted by ISDN and by IP videoconferencing

We compared the quality of realtime fetal ultrasound images transmitted using ISDN and IP networks. Four experienced obstetric ultrasound specialists viewed standard recordings in a randomized trial and rated the appearance of 30 fetal anatomical landmarks, each on a seven-point scale. A total of 12 evaluations were performed for various combinations of bandwidths (128, 384 or 768 kbit/s) and networks (ISDN or IF). The intraobserver coefficient of variation was 2.9%, 5.0%, 12.7% and 14.7% for the four observers. The mean overall ratings by each of the four observers were 4.6, 4.8, 5.0 and 5.3, respectively (a rating of 4 indicated satisfactory visualization and 7 indicated as good as the original recording). Analysis of variance showed that there were no significant interobserver variations nor significant differences in the mean scores for the different types of videoconferencing machines used. The most significant variable affecting the mean score was the bandwidth used. For ISDN, the mean score was 3.7 at 128 kbit/s, which was significantly worse than the mean score of 4.9 at 384 kbit/s, which was in turn significantly worse than the mean score of 5.9 at 768 kbit/s. The mean score for transmission using IP was about 0.5 points lower than that using ISDN across all the different bandwidths, but the differences were not significant. It appears that IP transmission in a private (non-shared) network is an acceptable alternative to ISDN for fetal tele-ultrasound and one deserving further study.

Cleaner fish drives local fish diversity on coral reefs

Coral reefs are one of the most diverse habitats in the world [1], yet our understanding of the processes affecting their biodiversity is limited [1-3]. At the local scale, cleaner fish are thought to have a disproportionate effect, in relation to their abundance and size, on the activity of many other fish species, but confirmation of this species' effect on local fish diversity has proved elusive. The cleaner fish Labroides dimidiatus has major effects on fish activity patterns [4] and may indirectly affect fish demography through the removal of large numbers of parasites [5, 6]. Here we show that small reefs where L. dimidiatus had been experimentally excluded for 18 months had half the species diversity of fish and one-fourth the abundance of individuals. Only fish that move among reefs, however, were affected. These fish include large species that themselves can affect other reef organisms [2, 7]. In contrast, the distribution of resident fish was not affected by cleaner fish. Thus, many fish appear to choose reefs based on the presence of cleaner fish. Our findings indicate that a single small [8] and not very abundant [9] fish has a strong influence on the movement patterns, habitat choice, activity, and local diversity and abundance of a wide variety of reef fish species.

Hemodynamic and ventilatory effects of manual respiratory physiotherapy techniques of chest clapping, vibration, and shaking in an animal model

Chest clapping, vibration, and shaking were studied in 10 physiotherapists who applied these techniques on an anesthetized animal model. Hemodynamic variables (such as heart rate, blood pressure, pulmonary artery pressure, and right atrial pressure) were measured during the application of these techniques to verify claims of adverse events. In addition, expired tidal volume and peak expiratory flow rate were measured to ascertain effects of these techniques. Physiotherapists in this study applied chest clapping at a rate of 6.2 +/- 0.9 Hz, vibration at 10.5 +/- 2.3 Hz, and shaking at 6.2 +/- 2.3 Hz. With the use of these rates, esophageal pressure swings of 8.8 +/- 5.0, 0.7 +/- 0.3, and 1.4 +/- 0.7 mmHg resulted from clapping, vibration, and shaking respectively. Variability in rates and forces generated by these techniques was 80% of variance in shaking force (P = 0.003). Application of these techniques by physiotherapists was found to have no significant effects on hemodynamic and most ventilatory variables in this study. From this study, we conclude that chest clapping, vibration, and shaking 1) can be consistently performed by physiotherapists; 2) are significantly related to physiotherapists' characteristics, particularly clinical experience; and 3) caused no significant hemodynamic effects.

Novel sesquiterpenes from the fungus lactarius piperatus

Four novel sesquiterpenes, namely 7alpha,8beta,13-trihydroxy-5,13-marasmanolide (2), isoplorantinone (5), 4,8,14-trihydroxyilludala-2,6,8-triene (6), and 8-hydroxy-8,9-secolactara-1,6-dien-5,13-olide (10), together with six known ones, 7alpha,8beta-dihydroxy-5,13-marasmanolide (1), 7alpha,8alpha-dihydroxy-5,13-marasmanolide (3), isolactarorufin (4), blennin A (7), blennin D (8), and lactarorufin (9), were isolated from the ethanolic extract of Lactarius piperatus. The structures of these sesquiterpenes, representing diversified structural types, were determined mainly by spectroscopic methods, especially 2D-NMR techniques. The structure of 6 was further confirmed by a single-crystal X-ray-diffraction determination.

Assessment of bioelectrical impedance analysis for the prediction of total body water in cystic fibrosis

The aim of this study was to compare the measurement of total body water (TBW) by deuterium ((H2O)-H-2) dilution and bioelectrical impedance analysis (BIA) in patients with cystic fibrosis (CF) and healthy controls. Thirty-six clinically stable patients with CF (age 25.4 +/- 5.6 yrs) and 42 healthy controls (age 25.4 +/- 4.8) were recruited into this study. TBW was measured by (H2O)-H-2 dilution and predicted by BIA in patients and controls. The TBW predicted from BIA was significantly different from TBW as measured using (H2O)-H-2 in patients (P