Search

We have analyzed predicted helical twist angles in the 21-bp repeat region of the SV40 genome, using a semi-empirical model previously shown to accurately predict backbone conformations. Unexpectedly, the pattern of twist angles characteristic of the six GC-boxes is repeated an additional five times at positions that are regularly interspersed with the six GC-box sequences. These patterns of helical twist angles are associated with a second, imperfectly-repeated sequence motif, the TR-box 5'-RRNTRGG. Unrelated DNA sequences that interact with trans-acting factors (p53 and GABP) exhibit similar twist angle patterns, due to elements of the general form 5'-RRRYRRR that occur as interspersed arrays with a spacing of 10-11 bp and an offset of 4-6 bp. Arrays of these elements, which we call pyrimidine sandwich elements (PSEs), may play an important role in the interaction of trans-acting factors with DNA control regions. In 13 human proto-oncogenes analyzed, we identified 31 PSE arrays, 11 of which were in the 5'-flanking regions of the genes. The most extensive array was found in the promoter region of the K-ras gene. Extending over 80 bp of DNA, it contained 16 PSEs that showed an average deviation from the SV40 criterion pattern of angles of only 1.2 degrees.

The management of prolonged pregnancy still remains controversial, although most now accept that perinatal mortality and possibly morbidity are increased when pregnancy exceeds 42 weeks gestational age. Accurate diagnosis must commence with the first prenatal visit, since retrospective documentation is impossible. Except for elective induction of a few special high risk pregnancies, the problem can be well managed with the use of frequent urinary estriol determinations and selective amniocentesis. Careful monitoring and detection of fetal distress with early intervention are essential in eliminating this problem with elective cesarean section in a selected few. A combination of low estriols and prolonged pregnancy should always be an indication for maternal X-ray to eliminate anencephalic monsters.

Right lobe living donor liver transplantation is an effective treatment for selected individuals with end-stage liver disease. Although 1 year donor morbidity and mortality have been reported, little is known about outcomes beyond 1 year. Our objective was to analyze the outcomes of the first 202 consecutive donors performed at our center with a minimum follow-up of 12 months (range 12-96 months). All physical complications were prospectively recorded and categorized according to the modified Clavien classification system. Donors were seen by a dedicated family physician at 2 weeks, 1, 3 and 12 months postoperatively and yearly thereafter. The cohort included 108 males and 94 females (mean age 37.3 +/- 11.5 years). Donor survival was 100%. A total of 39.6% of donors experienced a medical complication during the first year after surgery (21 Grade 1, 27 Grade 2, 32 Grade 3). After 1 year, three donors experienced a medical complication (1 Grade 1, 1 Grade 2, 1 Grade 3). All donors returned to predonation employment or studies although four donors (2%) experienced a psychiatric complication. This prospective study suggests that living liver donation can be performed safely without any serious late medical complications and suggests that long-term follow-up may contribute to favorable donor outcomes.

Sulfur mustard (bis-(2-chloroethyl)sulfide) has been used in chemical warfare since World War I and is well known as an acutely toxic vesicant. It has been implicated as a carcinogen after chronic low-level exposure and is known to form interstrand cross-links in DNA. Sulfur and nitrogen mustards are currently of interest as potential chemical threat agents for terrorists because of ease of synthesis. Sulfur mustard and monofunctional analogues (half-mustards, 2-[chloroethyl] alkyl sulfides) react as electrophiles, damaging cellular macromolecules, and thus are potentially subject to scavenging by nucleophilic agents. We have determined rate constants for the reaction of four purine derivatives that contain nucleophilic thiol moieties with several sulfur-half-mustards. Three of these compounds, 2,6-dithiopurine, 2,6-dithiouric acid, and 9-methyl-6-mercaptopurine, exhibit facile reaction with the electrophilic mustard compounds. At near neutral pH, these thiopurines are much better nucleophilic scavengers of mustard electrophiles than other low molecular weight thiols such as N-acetyl cysteine and glutathione. Progress curves calculated by numerical integration techniques indicate that equimolar concentrations of thiopurine provide significant reductions in the overall exposure to the episulfonium ions, which are the major reactive, electrophiles produced when sulfur mustards are dissolved in aqueous solution.

Sulfur mustard (bis-(2-chloroethyl)sulfide) is a well-known chemical warfare agent that induces debilitating cutaneous toxicity in exposed individuals. It is also known to be carcinogenic and mutagenic because of its ability to damage DNA via electrophilic attack. We previously showed that a nucleophilic scavenger, 2,6-dithiopurine (DTP), reacts chemically with several electrophilic carcinogens, blocking DNA damage in vitro and in vivo and abolishing tumor formation in a two-stage mouse skin carcinogenesis model. To assess the potential of DTP as an antagonist of sulfur mustard, we have utilized monofunctional chemical analogues of sulfur mustard, 2-chloroethyl ethyl sulfide (CEES) and 2-chloroethyl methyl sulfide (CEMS), to induce toxicity and mutagenesis in a cell line, NCTC2544, derived from a human skin tumor. We show that DTP blocks cytotoxicity in CEMS- and CEES-treated cells when present at approximately equimolar concentration. A related thiopurine, 9-methyl-6-mercaptopurine, is similarly effective. Correlated with this, we find that DTP is transported into these cells and that adducts between DTP and CEES are found intracellularly. Using a shuttle vector-based mutagenesis system, which allows enumeration of mutations induced in the skin cells by a blue/white colony screen, we find that DTP completely abolishes the mutagenesis induced by CEMS and CEES in human cells.

A search for 6.668-GHz A + -methanol masers towards all Galactic star-forming regions lying in the longitude range 260° to 359° with OH masers and no known methanol masers has been completed. Forty new A-methanol masers have been detected above a 3 σ detection limit of 5 Jy. This brings the total number now detected to 143

The effects of intravenous elgodipine, a new second-generation dihydropyridine calcium antagonist, on hemodynamics and coronary artery diameter were investigated in 15 patients undergoing cardiac catheterization for suspected coronary artery disease. Despite a significant decrease in systemic blood pressure, elgodipine infused at a rate of 1.5 micrograms/kg/min over a period of 10 minutes did not affect heart rate and left ventricular end-diastolic pressure. The contractile responses during isovolumic contraction showed a slight but significant increase in maximum velocity (56 +/- 10 to 60 +/- 10 seconds-1; p less than 0.005), whereas the time constant of early relaxation was shortened from 49 +/- 11 to 44 +/- 9 ms (p less than 0.05). Coronary sinus and great cardiac vein flow increased significantly by 15 and 26%, respectively. As mean aortic pressure decreased, a significant decrease in coronary sinus (-27%) and great cardiac vein (-28%) resistance was observed, while the calculated myocardial oxygen consumption remained unchanged. In all, 69 coronary segments (including 13 stenotic segments) were analyzed quantitatively using computer-assisted quantitative coronary angiography. A significant increase in mean coronary artery diameter (2.27 +/- 0.53 to 2.48 +/- 0.53 mm; p less than 0.000001), as well as in obstruction diameter, (1.08 +/- 0.29 to 1.36 +/- 0.32 mm; p less than 0.02), was observed. The results demonstrate that elgodipine, in the route and dose described, induces significant vasodilatation of both coronary resistance and epicardial conductance vessels, without adverse effects on heart rate, myocardial oxygen demand and contractile indexes.

To establish the cardiovascular profile of nicorandil in patients with coronary artery disease, we recently conducted three studies at our institution. In two groups of patients undergoing cardiac catheterization, the effects of 20 mg nicorandil sublingually (s.l.) on, first, left ventricular hemodynamics (n = 10) and, second, coronary vasodilatation (n = 11) were investigated. In the first group, despite a significant decrease of 12% in left ventricular systolic pressure, heart rate did not increase significantly after nicorandil. Both left ventricular end-diastolic pressure (-43%) and the time constant of early isovolumic relaxation (-11%) decreased, whereas peak Vce and Vmax increased (+19%) (all significantly). In the second group, as mean aortic pressure decreased (-13%, p0.05), coronary sinus blood flow did not change significantly, and calculated coronary vascular resistance tended to decrease (-10%). Myocardial oxygen consumption decreased significantly by 14%. Quantitative coronary angiography confirmed a significant increase in the mean diameter of nonstenotic coronary artery segments (+ 14%, n = 43) and, importantly, in mean obstruction diameter of stenotic segments (+ 14%, n = 7) after s.l. nicorandil. In a third continuing study, the effects of intracoronary (i.c.) nicorandil (6 micrograms/kg) and isosorbide dinitrate (2 mg) on the epicardial coronary arteries were investigated in 10 patients undergoing coronary angioplasty. In nonstenotic coronary artery segments, mean coronary diameter increased significantly after either nicorandil (+ 12%) or isosorbide dinitrate (+ 17%). In stenotic segments, however, where the increase in obstruction diameter (+ 20%) after i.c. nicorandil was significant, the 8% increase of isosorbide dinitrate was not.(ABSTRACT TRUNCATED AT 250 WORDS)

A search for 6.668-GHz A + -methanol masers in the 19 star-forming regions known to contain 12.2-GHz E-methanol masers and lying at declinations below −42° has led to the detection of masers in every object. This supplements the results of Menten who found A-methanol masers towards all the northern hemisphere E-methanol masering regions

The pyrene-like fluorescence of adducts derived from the covalent binding of (+/-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene [+/-]-anti-BPDE] to DNA increases in intensity by factors of 20 or more as the temperature is lowered from ambient to approximately 100 K. This effect is primarily associated with the strong quenching of the pyrene-like fluorescence of BPDE-deoxyguanosyl adducts at room temperature, and the suppression of the electron-transfer quenching mechanism at 100 K. In contrast, the fluorescence of BPDE-deoxyadenosyl adducts is not quenched at ambient temperatures, and the fluorescence yields of (+/-)-anti-BPDE-poly(dA-dT).(dA-dT) adducts increases by only a factor of 2 in this same temperature range. Utilizing an internal fluorescein fluorescence standard to correct for differences in light scattering and variations in instrumental factors, a fluorescence method is described for quantitatively determining the levels of benzo[a]pyrene diolepoxide derivatives covalently bound to cellular DNA at 100 K. The method is illustrated with (+/-)-reverse-BPDE [(+/-)-trans-9,10-dihydroxy-anti-7, 8-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene]. Adduct levels as low as 10 pmol in a 400 microliters sample volume can be detected and identified from their excitation and fluorescence emission spectra using a conventional and commercially available fluorometer. In the case of modified DNA extracted from BPDE-treated Chinese hamster ovary cells or from mouse skin (approximately 1 BPDE residue/20,000 bases), such an analysis requires only 100 micrograms of DNA. Conformationally different adducts derived from the binding of the isomeric (+/-)-anti-BPDE, (+/-)-reverse-BPDE or (+/-)-syn-BPDE to cellular DNA can be distinguished by their low-temperature fluorescence excitation spectra. Specifically, the quasi-intercalated site I BPDE adducts (believed to be associated with cis-addition stereochemistry) can be distinguished from site II adducts situated at external BPDE binding sites (trans-addition stereochemistry). These results suggest that the fates of these conformationally different BPDE-DNA adducts, e.g. due to enzymatic repair, can be monitored as a function of time in DNA extracted from intact, functioning cells.

The Memory Test Experiment is a space test of a ferroelectric memory device on a low Earth orbit satellite. The test consists of writing and reading data with a ferroelectric based memory device. Any errors are detected and are stored on board the satellite. The data is send to the ground through telemetry once a day. Analysis of the data can determine the kind of error that was found and will lead to a better understanding of the effects of space radiation on memory systems. The test will be one of the first flight demonstrations of ferroelectric memory in a near polar orbit which allows testing in a varied radiation environment. The memory devices being tested is a Ramtron Inc. 512K memory device. This paper details the goals and purpose of this experiment as well as the development process. The process for analyzing the data to gain the maximum understanding of the performance of the ferroelectric memory device is detailed.

The initiation of carcinogenesis by carcinogens such as 7 r ,8 t -dihydroxy-9,10 t -oxy-7,8,9,10-tetrahydrobenzo[ a ]pyrene (BPDE-I) is thought to involve the formation of DNA adducts. However, the diastereomeric diol epoxide, 7 r ,8 t -dihydroxy-9,10 c -oxy-7,8,9,10-tetrahydrobenzo[ a ]pyrene (BPDE-II), also forms DNA adducts but is inactive in standard carcinogenesis models. We have measured the formation and loss of DNA adducts derived from BPDE-II in a DNA-repair-proficient line of Chinese hamster ovary (CHO) cells, AT3-2, and in two derived mutant cell lines, UVL-1 and UVL-10, which are unable to repair bulky DNA adducts. BPDE-II adducts were lost from cellular DNA in AT3-2 cells with a half-life of 13.8 h; this was about twice the rate found for BPDE-I adducts. BPDE-II adducts were also lost from DNA in UVL-1 and UVL-10 cells, but at a much slower rate. When purified DNA was modified in vitro with BPDE-II and then held at 37°C, DNA adducts were removed at a rate identical to that seen in UVL-1 and UVL-10 cells, suggesting that the loss in these cells was not due to enzymatic DNA-repair processes but to chemical lability of the adducts. Mutant frequencies at the APRT and HPRT loci were measured at BPDE-II doses that resulted in > 20% survival, and were found to increase linearly with dose. In the DNA-repair-deficient cells, the HPRT locus was moderately hypermutable compared with AT3-2 cells (about 5-fold); the APRT locus was extremely hypermutable, giving about 25-fold higher mutant fractions in UVL-1 and UVL-10 than in AT3-2 cells at equal initial levels of binding. When we compared the mutational efficiency of BPDE-II at both loci in AT3-2 cells (the mutant frequency in mutants/10 6 survivors at a dose that resulted in one adduct per 10 6 base pairs) with our previous studies of BPDE-I, we found that BPDE-II was 4–5 times less efficient as a mutagen than BPDE-I. This difference in mutational efficiency could be explained in part by the increased rate of loss of BPDE-II adducts from the cellular DNA, part of which was due to an increased rate of enzymatic removal of these lesions compared with the removal of BPDE-I adducts.

Gene targeting by triplex-forming oligonucleotides (TFOs) has proven useful for gene modulation in vivo. Photoreactive molecules have been conjugated to TFOs to direct sequence-specific damage in double-stranded DNA. However, the photoproducts are often repaired efficiently in cells. This limitation has led to the search for sequence-specific photoreactive reagents that can produce more genotoxic lesions. Here we demonstrate that photoactivated pyrene-conjugated TFOs (pyr-TFOs) induce DNA strand breaks near the pyrene moiety with remarkably high efficiency and also produce covalent pyrene-DNA adducts. Free radical scavenging experiments demonstrated a role for singlet oxygen activated by the singlet excited state of pyrene in the mechanism of pyr-TFO-induced DNA damage. In cultured mammalian cells, the effect of photoactivated pyr-TFO-directed DNA damage was to induce mutations, in the form of deletions, approximately 7-fold over background levels, at the targeted site. Thus, pyr-TFOs represent a potentially powerful new tool for directing DNA strand breaks to specific chromosomal locations for biotechnological and potential clinical applications.

Significant progress in the description of quasar variability has been recently made by employing SDSS and POSS data. Common to most studies is a fundamental assumption that photometric observations at two epochs for a large number of quasars will reveal the same statistical properties as well-sampled light curves for individual objects. We critically test this assumption using light curves for a sample of $\sim$2,600 spectroscopically confirmed quasars observed about 50 times on average over 8 years by the SDSS stripe 82 survey. We find that the dependence of the mean structure function computed for individual quasars on luminosity, rest-frame wavelength and time is qualitatively and quantitatively similar to the behavior of the structure function derived from two-epoch observations of a much larger sample. We also reproduce the result that the variability properties of radio and X-ray selected subsamples are different. However, the scatter of the variability structure function for fixed values of luminosity, rest-frame wavelength and time is similar to the scatter induced by the variance of these quantities in the analyzed sample. Hence, our results suggest that, although the statistical properties of quasar variability inferred using two-epoch data capture some underlying physics, there is significant additional information that can be extracted from well-sampled light curves for individual objects., Comment: Presented at the "Classification and Discovery in Large Astronomical Surveys" meeting, Ringberg Castle, 14-17 October, 2008

607 Background: Since 2005 seven new agents were approved for metastatic renal cell carcinoma (mRCC), demarcating a transition from the cytokine to the targeted therapy era. Trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) pre-2005. However, upfront versus delayed CN relative to targeted therapy has not been reported in the trial arena. We hypothesized that upfront CN confers a survival benefit in the targeted therapy era. We analyze survival in a population based cohort exposed to targeted therapies with upfront CN compared to deferred CN. Methods: Patients from SEER registries (2005-2011) with mRCC were categorized into: 1.) CN followed by targeted therapy or 2). initial targeted therapy. Additional exclusions were age < 66, due to chance of uncaptured non-Medicare care, competing non-renal stage IV cancer and non-clear cell histology. Targeted therapy was identified from Medicare Part D files (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib, temsirolmus, everolimus) and duration of use. Clinical data, including co-morbidities, were obtained from Medicare inpatient and outpatient files, and cancer data from Medicare-linked SEER files. Unadjusted and multivariable Cox proportional hazards regression determined association between survival in the two groups. Propensity matching with bootstrapping was performed to control for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases screened, 491 met the inclusion criteria. Median survival in the initial CN group (N = 194) was 20 months (IQR 12-32) compared to 14 months (IQR 6-27) in the initial targeted therapy group (N = 297, p < 0.01). On multivariable analysis upfront CN was associated with improved survival (HR 0.57 95% CI 0.44, 0.74). On propensity matched analysis the survival advantage (average treatment effect on the treated, ATT) for upfront CN was 7.4 months (95% CI 3.86, 11.21). Conclusions: This study population closely resembles the treatment groups in ongoing randomized trials on the surgical management of mRCC in the targeted therapy era and demonstrates a survival advantage for upfront CN.

615 Background: Many patients with metastatic kidney cancer (mRCC) are ineligible for trials due to non-clear cell histology. Efficacy of targeted therapy agents in non-clear cell mRCC is still being investigated. We hypothesized that sequencing CN upfront is associated with improved overall survival. We analyze a population-based cohort of non-clear cell mRCC patients in the targeted therapy era. Methods: Patients from the SEER-Medicare files (2005-2011) with non-clear cell mRCC were categorized as having received upfront targeted therapy or upfront CN. Additional exclusions were age < 66 to avoid confounding by uncaptured non-Medicare coverage, and competing stage IV cancer. Targeted therapy was identified through Medicare Part D files. Cox proportional hazards regression determined association between treatment groups, clinical and cancer-related characteristics, and the main outcome, median overall survival (OS). Propensity matching controlled for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases, 528 met inclusion criteria of whom 433 (82%) received targeted agents and 172 (33%) underwent CN. Of those not having CN, 74% were diagnosed by biopsy, 10% by cytology, and 16% radiographically (confirmed at autopsy). Thirteen percent received CN then targeted therapy (OS 14 mos, IQR 9-25), 2.5% received targeted therapy then CN (OS 14 mos, IQR 9-26), 18% received CN only (OS 14 mos, IQR5-40), 67% received targeted therapy only (OS 9 mos, IQR 4-19). On multivariable Cox proportional hazards regression upfront CN (regardless of post-CN therapy) was associated with improved OS (HR 0.54,95% CI 0.41,0.72). Using propensity scores, upfront CN patients (N = 161) were matched to upfront targeted therapy patient (N = 111) and the average treatment effect of CN was 8.3 months survival improvement (95% CI 4.0, 13.2). Conclusions: Although utilization of targeted agents in non-clear cell mRCC exceeds 80%, those with greatest OS received CN either upfront or after targeted therapy, though the latter was rare (2.5%). The variety of sequencing strategies observed is evidence of uncertainty regarding the best care for non-clear cell mRCC patients given limited options.

Skeleton weed, centaurea juncea, is a declared weed in Western Australia because it competes with grain crops for nutrients and moisture. When it is found during harvesting, mechanised teams search and eradicate it. In an earlier report of field trials (Hartley et al, 1989) it was reported that search teams' detection rate was poor and since search teams had usually never seen skeleton weeds, visual discrimination learning was to be expected and observed during searches. The present study investigated the nature of this discrimination learning in a laboratory by developing a training programme of colour photographic slides of weeds in stubble. Subjects receiving specific training with feedback on their performance compared with those receiving pseudo-training showed a significant improvement in detections. Subsequently the benefit of the programme was validated in a field trial.

Outside of northern Quebec, there is little evidence to confirm reports of nesting by Canada Geese in Arctic habitats of North America, but they nest regularly in the Arctic tundra of West Greenland, from about 62˚ N to as far north as 76.96˚ N, 71.11˚ W. In 2013, we documented successful nesting by a pair of Canada Geese on northern Baffin Island (71.36˚ N, 79.59˚ W), approximately 1200 km north of the nearest known site of regular nesting by this species in northern Quebec. Photographs, egg measurements, and mitochondrial DNA evidence confirmed that these were Canada Geese. Egg laying began around 17 June, the nest of five eggs hatched on 18 July, and we determined that fledging should have occurred around 20 September. Daily mean temperatures on northern Baffin Island fell below freezing after 5 September 2013, and we suspect that the probability of recruitment for this brood was very low. Climate warming in the Arctic is likely to favor northward range expansion by Canada Geese.

454 Background: Since the 1990s, the therapies for metastatic renal cell carcinoma (mRCC) expanded from immunotherapies to survival-extending targeted therapies. Targeted therapy is most efficacious in clear cell RCC. Trial results likely overestimate population norms. Population-based studies on histologically limited cohorts omit a large proportion of patients, giving an overly optimistic prognosis. To clarify the changing prognosis of mRCC we examine a heterogeneous RCC cohort from the Surveillance Epidemiology and End Results (SEER) registry. Methods: mRCC patients were identified from SEER diagnosed calendar years 1990-2009. Cases were primary renal tumors confirmed by histology/cytology, not diagnosed on autopsy. Survival was analyzed by treatment era (cytokine 1990-2005, targeted 2006-2009) and classified by histology. Multivariate Cox regression identified factors independently associated with overall survival (OS). Results: Of 14,521 mRCC patients identified, clear cell mRCC represented 4,136 (median OS 12 months). Non-clear cell RCC represented 10,385 cases (median OS 4 months) of which 8,860 were designated NOS. For clear cell mRCC unadjusted median OS improved from 11 to 14 months pre/post targeted era (p

Site-specific recognition of duplex DNA by triplex-forming oligonucleotides (TFOs) provides a promising approach to manipulate mammalian genomes. A prerequisite for successful gene targeting using this approach is that the targeted gene must contain specific, high-affinity TFO target sequences (TTS). To date, TTS have been identified and characterized in only approximately 37 human or rodent genes, limiting the application of triplex-directed gene targeting. We searched the complete human and mouse genomes using an algorithm designed to identify high-affinity TTS. The resulting data set contains 1.9 million potential TTS for each species. We found that 97.8% of known human and 95.2% of known mouse genes have at least one potential high-affinity TTS in the promoter and/or transcribed gene regions. Importantly, 86.5% of known human and 83% of the known mouse genes have at least one TTS that is unique to that gene. Thus, it is possible to target the majority of human and mouse genes with specific TFOs. We found substantially more potential TTS in the promoter sequences than in the transcribed gene sequences or intergenic sequences in both genomes. We selected 12 mouse genes and 2 human genes critical for cell signaling, proliferation, and/or carcinogenesis, identified potential TTS in each, and determined TFO binding affinities to these sites in vitro. We identified at least one high-affinity, specific TFO binding site within each of these genes. Using this information, many genes involved in mammalian cell proliferation and carcinogenesis can now be targeted.

REFERENCES 1. Mazzu A, Di Tano G, Cogode R, Lo Presti G. Myocardial bridging involving more than one site of the left anterior descending coronary artery: an uncommon cause of acute ischemic syndrome. Cathet Cardiovasc Diagn 1995;34:329-32. 2. Manakata K, Sate N, Sasaki Y, Yasutake M, Kusama Y, Takayama M, et al. Two cases of variant form angina pectoris associated with myocardial bridge--a possible relationship among coronary vasospasm. Jpn Circ J 1992;56:1248-52. 3. Bestetti RB, Finzi LA, Amaral FT, Secches AL, Oliveira JS. Myocardial bridging of coronary arteries associated with an impending acute myocardial infarction. Clin Cardiol 1987;10:129-31. 4. Bestetti RB, Costa RS, Zucolotto S, Oliveira JS. Fatal outcome associated with autopsy proven myocardial bridging of the left anterior descending coronary artery. Eur Heart J 1989;10:573-6. 5. Chee TP, Jensen DP, Padnick MB, Cornell WP, Desser KB. Myocardial bridging of the left anterior descending coronary artery resultresulting in subendocardial infarction. Arch Intern Med 1981;141: 1703-4. 6. Bestetti RB, Costa RS, Kazava DK, Oliveira JS. Can isolated myocardial bridging of the left anterior descending coronary artery be associated with sudden death during exercise? Acta Cardiol 1991;46:27-30. 7. Feld H, Guadanino V, Hollander G, Greengart A, Lichstein E, Shani J. Exercise-induced ventricular tachycardia in association with a myocardial bridge. Chest 1991;99:1295-6. 8. Laifer LI, Weiner BH. Percutaneous transluminal coronary angioplasty of a coronary artery stenosis at the site of myocardial bridging. Cardiology 1991;79:245-8. 9. Chaimer KS, Bukis E, Hartnell G, Ress JR. Myocardial bridging of the coronary arteries. Clin Radiol 1989;40:355-9. 10. Julliere Y, Berder V, Suty-Selten C, Buffet P, Danchin N, Cherrier F. Isolated myocardial bridges with angiographic milking of the left anterior descending coronary artery: a long-term follow-up study. Am Heart J 1995;129:663-5. 11. Ramos SG, Montenegro AP, Felix PR, Kazawa DK, Rossi MA. Occlusive thrombosis in myocardial bridging. Am Heart J 1993;125:1771~3. 12. Nair CK, Dang B, Heintz MH, Sketch MH. Myocardial bridges: effect of propranolol on systolic Compression. Can J Cardiol 1986;2:218-21. 13. Iversen S, Hake U, Mayer E, Erbel R, Diefenbach C, Oelert H. Surgical treatment of myocardial bridging causing coronary artery obstruction. Scand J Thorac Cardiovasc Surg 1992;26:107-11.

In samango monkeys (Cercopithecus mitis labiatus), males compete for residency in unimale troops where they defend females against other males, although extratroop males may sneak copulations with females opportunistically. Here, we attempt to determine whether these are alternative strategies yielding equivalent lifetime reproductive success, or whether the extratroop male component is simply a tactic followed by males who are unable to follow the resident troop male strategy because of their age or physical condition. Observations of mating success and male-male competition support the latter of these hypotheses. Modeling the expected reproductive success of males following the different strategies suggests that dedicated extratroop males in this population would not be able to live for long enough to compensate for their extremely low rate of mating success compared with males achieving troop residency. However, other studies of Cercopithecus mitis have revealed a much higher proportion of mating by extratroop males, and it is suggested that ecological and demographic factors may affect the costs and benefits of these two male strategies.

This paper is concerned with the techniques required for the acquisition and processing of signals arising in ultrasonic non-destructive testing of steel structures in the underwater environment. The primary aim is to minimize diver participation in the inspection and interpretation of results. The resulting systems, which involve significant use of microprocessor hardware were designed to operate with equal facility with either single or multiple ultrasonic channels, the latter being important with the ancillary requirements of beam steering and beam shaping. The paper describes two approaches to the detection and location of faults, one concerned with the use of large ultrasonic crystals has led to the development of the Strathclyde SHOE, the other employs ultrasonic arrays for area scanning via beam steering. An analysis is included for signal returns on the arrays for estimating the location of a reflection point which leads to enhanced range resolution.

This paper describes the development of a multi-path and multimode propagation model for NDE. The mode content of a multipath is estimated using Maximum Likelihood (ML) estimation based on a receiving array delay vector. The model analysis allows a defect to be located by employing both the mode estimates and a ML estimation of the shear and longitudinal propagation angles. Some aspects of the attendant processing hardware are also discussed.

A new model for piezoelectric ultrasonic transducers is proposed. It is derived from the fundamental piezoelectric equations and it has the following features: i) It is valid over a wide range of frequencies. ii) It is applicable in both transmission and reception modes. iii) It involves realizable elements which are readily simulated. iv) It involves feedback mechanisms which clearly relate pressure and voltage interactions. The model has been widely investigated using computer simulation, water tank measurements and photo -elastic visualisation studies using glass models. Some of the results of such investigations are presented.

Polymerization of soluble fibronectin molecules results in fibres that are visible as networks using fluorescently labelled fibronectin protomers or by antibody labelling. Displacement of fibres composed of modified protomers in living cells provides information regarding matrix structure, organization, and movement. A static analysis of fibronectin structures and patterns of organization provide insight into their reorganization during adhesion and motility. Confocal microscopy and atomic force microscopy (AFM) reveal fibronectin-containing networks aligned in arrays perpendicular to the retracting cell edge and in apparently disordered networks of fibres under the cell. The change in patterns suggests a reorganization of fibronectin from disordered arrays used for adhesion into ordered arrays during movement of the cell. Comparison of confocal images with corresponding AFM images confirms that the fibres left on the surface as the cell moves away do contain fibronectin. The orientation of these fibres relative to the tail (uropod) and the receding edges of the cell leads us to propose that cells generate a force on the fibres that exceeds the adhesion force of the fibres to the surface causing them to pull fibronectin fibres into straight arrays. However, when the fibres are parallel to the direction of pull, the fibres remain attached to the surface. The data supports the hypothesis that disorganized, linear fibres are the product of Fn polymerization induced by the cell beneath it and serve to adhere the cell to the substrate as the cell spreads, whereas arrays of fibres found outside the cell are formed as existing fibrils and reorganize during cell motility.

Z. Bardy GH, Troutman C, Johnson G, Mehra R, Poole JE, Dolack GE, Kudenchuk P J, Gartman DM. Electrode system influence on biphasic waveform defibrillation efficacy in h~urnax~s. Circulation 1991; 84:665-71. 2. Kavanagh KM, Tang ASL, Rollins DL, Smith WM, Ideker RE. Comparison of the internal defibrillation thresholds for monophasic and double and single capacitor biphasic waveforms. J Am Coll Cardiol 1989;14:1343-9. 3. Swartz JF, Fletcher RD, Karasik PE. Optimization of biphasic waveforms for human nonthoracotomy defibrillation. Circulation 1993; 88:2646-54. 4. Neuzner J, Pitschner HF, Huth C, Schlepper M. Effect of biphasic waveform pulse on endocardial defibrillation efficacy in humans. PACE 1994;17:207-12. 5. Block M, HammeI D, Bocker D, Borgreffe M, Budde T, Isbruch F, Wietholt D, Scheld HH, Breithardt G. A prospective randomized crossover comparison of monoand biphasic defibrillation using nonthoracotomy lead configurations in humans. J Cardiovasc Electrophysiol 1994;5:581-90. 6. Natale A, Deshpande S, Budziszewski M. Defibrillation threshoid with three different biphasic shapes incorporated in commercially available devices [Abstract]. Circulation 1994;90(part 2):I-499.

ERp29 is a recently discovered resident of the endoplasmic reticulum (ER) that is abundant in brain and most other mammalian tissues. Investigations of nonneural secretory tissues have implicated ERp29 in a major role producing export proteins, but a molecular activity remains wanting for this functional orphan. Intriguingly, ERp29 appears to be heavily utilized in the cerebellum, a brain region not conventionally regarded as neurosecretory. To elucidate this functional quandary, we used immunochemical approaches to characterize the regional, cellular, and subcellular distributions of ERp29 in rat brain. Immunohistochemistry revealed ubiquitous expression in neuronal and nonneuronal cells, with a distinctive variation in somatic ERp29 levels. Highly expressing cells were found in diverse locations, implying that ERp29 is not biased towards the cerebellum functionally. Using immunolocalization data mined from the literature, a proteomic profile was developed to assess the functional significance of ERp29's characteristic expression pattern. Surprisingly, ERp29 correlated poorly with classical markers of neurosecretion, but strongly with a variety of major membrane proteins. Together with immunogold localization of ERp29 to somatic ER, these observations led to a novel hypothesis that ERp29 is involved primarily in production of endomembrane proteins rather than proteins destined for export. This study establishes ERp29 as a general ER marker for brain cells and provides a stimulating clue about ERp29's enigmatic function. ERp29 appears to have broad significance for neural pathophysiology, given its ubiquitous distribution and prominence in brain over classical ER residents like BiP and protein disulfide isomerase.

A high priority for most parents is to have ready access to paediatric medical services, particularly when their child becomes ill. A difficult balance is therefore sometimes required between the provision of these services in a small local hospital where the throughput of work (and hence opportunities for education and training) will be limited, and the disadvantages of distance and delay where there is geographical isolation from such services. It is also important that doctors have the opportunity to gain experience in the range of environments in which they may work after completion of their training, whether in primary or secondary care. We report an innovative initiative to sustain a local inpatient paediatric service and to enhance the provision of education and training for doctors through development of a training network and rotation. We also highlight issues arising from this, in particular the implications for adequate availability of support from career grade paediatric staff.

In the United Kingdom and Republic of Ireland 10% of all deliveries are vacuum assisted. The vacuum is preferred over forceps because it is easier to perform and associated with less maternal morbidity. It is, however, also associated with subaponeurotic haemorrhage that has an incidence of 6.4 per 1000 vacuum assisted deliveries and a mortality of 23%. Based on a figure of 77,500 births annually in Ireland, North and South, it is possible that as many as 11 neonatal deaths each year may attributable to what is generally considered a safe obstetric intervention. In North America concerns about the safety of vacuum assisted delivery resulted in the issuing of public health advisories in both Canada and the United States. To date such concerns have not been raised in either the United Kingdom or Republic of Ireland. We report a case of fatal subaponeurotic haemorrhage to highlight and bring these concerns to the attention of obstetricians, paediatricians and midwives. We also call for the introduction of a national surveillance in order to assess the true extent of this potentially fatal complication.

Presents an overview of a preliminary study into the issues associated with Kalman filter stability. Future advanced combat aircraft will require further levels of system integration it is believed that Kalman filters will play a key role in this increased integration and consequently their performance and robustness are of interest. The paper applies the /spl mu/-analysis robust stability technique to a two dimensional tracking/navigation system which requires a nonlinear or extended Kalman filter. Results show that the robust stability margins provide an indication of poor robustness, under some circumstances, but further work is required to predict instability or divergence in the extended Kalman filter.

Aims: To determine the number of children on the Child Protection Register (CPR) attending the accident and emergency (A&E) department and the referral source, diagnostic category, and frequency distribution for such attendances. To determine whether lack of knowledge that a child is on the CPR results in failure to suspect non-accidental injury (NAI) if the standard indicators of NAI have been sought. Methods: Access to the CPR was obtained. Records of each child attending the A&E departments of the United Hospitals Trust between June 1994 and May 2000 were reviewed. Results: Over the six years 191 children were on the CPR. Seventy nine (41%) attended A&E departments on 206 occasions. Frequency of attendance ranged to 18 with a mean of 2.6. Self referral was the commonest source of referral (81%) followed by general practitioners (13%), 999 calls (5%), and a small number from schools (1%). Most presentations involved trauma—upper limb (21%), lower limb (14%), and head injury (8%). Almost all cases of trauma were adjudged to be consistent with the history and NAI not suspected. Common childhood illnesses accounted for the remainder of presentations. Only six children were identified as being on the CPR at the time of presentation. Concerns were raised in two other cases and concerns should have been raised in three other children. Social Services were alerted on five occasions directly by the parents themselves. Conclusions: It is concluded that in the absence of knowledge of the status of a child on the CPR attending the A&E department, that screening for the standard indicators of NAI is adequate to detect most cases of NAI.

The fluorescence of mononucleoside adducts derived from the binding of anti-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene (BPDE I) to N6-deoxyadenosine (BPDE-dA adducts) is 10-100 times stronger (depending on the methanol/water solvent composition) than the fluorescence of adducts derived from the binding of this diol epoxide derivative to N2-deoxyguanosine. It is shown here that these fluorescence characteristics can be used to quantitate the relatively low yields of BPDE-dA adducts by fluorescence detection when BPDE-modified DNA is subjected to enzymatic degradation to the mononucleoside levels, followed by HPLC analysis of the digests.

The detection of an asymptomatic murmur in a child usually results in a referral to a consultant paediatrician. In most cases a chest radiograph (CXR) and electrocardiograph (ECG) are performed as an aid to diagnosis, however the evidence for this is contradictory. A retrospective chart review of children referred with asymptomatic cardiac murmurs in a one-year period was conducted. We wished to determine whether CXR and ECG are useful diagnostic aids. 81 patient charts were reviewed. Of those patients with a clinical diagnosis of pathological murmur all had normal CXR and ECG. Never the less 2 cases were referred for echocardiogram and were found to have structural heart disease. Of those with a clinical diagnosis of innocent murmur most (81%) had a CXR and ECG and in most cases (96%) these were normal. Those cases with abnormal investigations subsequently were shown to have structurally normal hearts on echocardiogram. We conclude that routine use of CXR and ECG in evaluating asymptomatic cardiac murmurs in children is not useful.

The aim of this study was to examine the prevalence of exercise limitation due to diastolic heart failure among patients felt to have cardiac breathlessness by their general medical practitioner but not referred to hospital. We found that 18% of patients had a simple investigated profile compatible with isolated diastolic dysfunction as a cause of their symptoms. Symptoms appeared to pre-date major cardiac events (infarction; stroke; arrhythmia) that dominated the subsequent clinical course. The patients in this group have adverse cardiovascular risk profiles. Obesity was a common co-morbidity which may impair detailed 2-D echocardiographic assessment.

Benzo[a]pyrene diol epoxide (BPDE) has been shown to bind specifically to the exocyclic amino group of deoxyguanosine in duplex DNA. Interestingly, this metabolite exhibits stereoselectivity in its tumorigenic and mutagenic effects. It is thought that local DNA conformation is altered at the site of the adduct, resulting in aberrant biological processes, and that in certain sequence contexts BPDE-DNA adducts induce bends in the DNA. In the work presented here, we compared DNA structural alterations of BPDE-modified DNA and unmodified DNA via tapping mode atomic force microscopy (AFM). DNA fragments 366 base pairs (bp) in length were generated by PCR from the duplicated multiple-cloning site of pBEND2 inserted into pGEM-3Zf(-), and either mock-modified or treated with BPDE to give modification levels between 1 and 5% of the nucleotides. Control or BPDE-modified DNA was adsorbed to mica and visualized in air by AFM. The contour lengths and end-to-end lengths of individual molecules were measured. The ratio of end-to-end distance to contour length was significantly smaller for modified DNA molecules than for the unmodified DNA preparation, although the frequency distributions of the contour lengths were similar for the two preparations. This suggests BPDE-DNA adducts cause significant bending of DNA molecules, confirming previous conclusions based on more indirect measurements. The average induced bend angle for BPDE-DNA adducts is estimated to be at least 30 degrees.

Inheritance of a mutant allele of the breast cancer susceptibility gene BRCA1 confers increased risk of developing breast and ovarian cancers. Likewise, inheritance of a mutant allele of the retinoblastoma susceptibility gene (RB1) results in the development of retinoblastoma and/or osteosarcoma, and both alleles are often mutated or inactivated in sporadic forms of these and other cancers. We now demonstrate that the product of the RB1 gene, Rb, regulates the expression of the murine Brca1 and human BRCA1 genes through its ability to modulate E2F transcriptional activity. The Brca1 gene is identified as an in vivo target of E2F1 in a transgenic mouse model. The Brca1 promoter contains E2F DNA-binding sites that mediate transcriptional activation by E2F1 and repression by Rb. Moreover, ectopic expression of cyclin D1 and Cdk4 can stimulate the Brca1 promoter in an E2F-dependent manner, and this is inhibited by coexpression of the p16(INK4a) cyclin-dependent kinase inhibitor. The human BRCA1 promoter also contains a conserved E2F site and is similarly regulated by E2F1 and Rb. This functional link between the BRCA1 and Rb tumor suppressors may provide insight into the mechanism by which BRCA1 inactivation contributes to cancer development.

A search for OH masers associated with 22 B-type star-forming regions has resulted in three new detections. The regions were chosen from the IRAS Point Source Catalog by the infrared colours, and are the coolest objects in the catalogue. Previously undetected OH masers are positionally associated with two of these IRAS sources, 07427−2400 and 18265−1517. A third IRAS source, 16596−4012, is found to have an OH cloud positionally associated with it

To examine prognostic factors, treatment outcomes and design future studies for Osteolymphoma (OL)--also known as primary bone lymphoma.Between 1979 and 1993, 70 patients with OL were treated in nine Australian centres. The effect of patient-, tumour-, and treatment-related factors on local control, distant disease-free survival and overall survival were assessed by multivariate analysis.Most patients (94%) received radiotherapy (RT) (median dose 40 Gy) and 56% received chemotherapy. Multifocal disease was present in 20% of patients. The five year rates of overall survival and local control were 59% and 82%. Although there was a trend towards better results with the addition of chemotherapy, on multivariate analysis, there were no factors identified which appeared to impact upon overall and disease-free survival. Among the distant recurrences, there was a high proportion in bone (33%). Six patients suffered pathological fractures after treatment.High rates of local control were achieved by RT, but the overall survival remains relatively poor, worse than nodal lymphoma. The natural history of the disease suggests that OL may be a distinct entity, different to nodal lymphomas, so the results of clinical trials in nodal lymphoma may not be relevant to OL. Prospective studies could define the outcome of combined modality therapy and set a benchmark for testing further proposals, as well as improving our knowledge of the clinical features of OL.