Early diagnosis of spinal epidural metastases.

Early signs of spinal cord injury on neurologic examination have been the primary indication to proceed with myelography in patients with possible spinal epidural metastases. With this approach, loss of ambulation occurs in more than one half of the patients. In an attempt to diagnose epidural metastases before the onset of myelopathy, we designed a prospective study based on the development of back pain, a precursor of spinal cord injury in nearly all cancer patients. Eighty-seven patients were studied. A high incidence of epidural metastases was found in patients with myelopathy (78 percent). In addition, patients with radiculopathy alone frequently had epidural tumor (61 percent). In 36 percent of the patients who presented with back pain but who had normal neurologic findings, there was evidence of epidural metastases on myelography; all of those patients had vertebral metastases on plain roentgenogram. Over-all, the plain roentgenogram of the spine correctly predicted the presence or absence of epidural tumor in 83 percent of the patients. Whereas 93 percent of the patients with myelopathy had more than 75 percent myelographic block, this occurred in 53 percent of those with radiculopathy and in only 33 percent of those with back pain and normal neurologic findings. In most cancer patients, spinal epidural metastases are both detectable and significantly less extensive before the onset of spinal cord injury.

Steric stabilization of microspheres with grafted polyethylene oxide reduces phagocytosis by rat Kupffer cells in vitro.

Sterically stabilized polyethylene oxide-polystyrene copolymer microspheres, (PS-PEO) and charge stabilized polystyrene (PS) microspheres of similar size (1 micron) were prepared in order to compare their uptake by cultured rat Kupffer cells isolated by centrifugal elutriation. The uptake of the sterically stabilized particles was found to be much less than that for the charge stabilized control. The uptake of microspheres stabilized with covalently grafted PEO was lower or equivalent to that of control microspheres stabilized by the adsorption of the non-ionic PEO-polypropylene oxide (PPO-PEO) surfactant Poloxamer 238 or Methoxy-PEO. Phagocytic uptake by Kupffer cells at low and body temperature (8 degrees C and 37 degrees C) demonstrated that PS-PEO particles showed both low adherence and low metabolic uptake. The adsorption of PEO, as Poloxamer 238, to particles with covalently attached or grafted PEO resulted in a synergistic reduction in uptake that was greater than the individual effects of grafting and adsorption alone (P less than or equal to 0.001). It is suggested that this combination produces a more effective steric barrier on the particle surface with the Poloxamer adsorbing to the surface between the grafted PEO chains. The relevance to drug targeting/carrier systems is discussed.

Influence of surface coverage with poly(ethylene oxide) on attachment of sterically stabilized microspheres to rat Kupffer cells in vitro.

The attachment to rat Kupffer cells of polymeric microspheres, sterically stabilized with different amounts of pendant poly(ethylene oxide) (PEO), was assessed in vitro. Four types of copolymer polystyrene (PS) microspheres were synthesized by variation of four possible monomer ratios that included styrene, methoxy-PEO-methacrylate (750 and 2000 mol. wt PEO) and allylurea. This produced poly(styrene-(methoxy-PEO)methacrylate) microspheres with hydrophilic side-groups of either urea (PS-U-PEO) and/or mixed molecular weight (750/2000 mol. wt) PEO (PS-U-M-PEO, PS-M-PEO), or single molecular weight (2000) PEO (PS-PEO) at their surfaces. The hypothesis was tested that increasing the total content of PEO comprising the steric barrier reduces attachment to cell surfaces. Attachment of PEO microspheres bearing the urea spacer and/or mixed molecular weight PEO was found to be intermediate between charge stabilized control PS and PEO (2000 mol. wt) bearing particles. Post-adsorption of different Poloxamer (PEO-poly(propylene oxide)-PEO) surfactants to the microspheres further decreased attachment. Significant negative linear correlations between surface PEO content, measured by electron spectroscopy for chemical analysis (ESCA), and attachment to Kupffer cells were demonstrated. Decreases in attachment also resulted with all graft PEO particles bearing adsorbed sodium dodecyl sulphate (SDS), whilst the attachment of SDS-treated PS control particles increased. It is proposed that trains of adsorbed graft PEO are displaced by the SDS to increase the effective fraction of graft PEO within the steric layer. Overall, increasing the amount of hydrophilic PEO in the steric layer, from graft and adsorbed sources, reduces the attachment of these particles to Kupffer cells in vitro.

Concurrent 72-hour continuous infusion of etoposide and cisplatin in metastatic breast cancer.

We conducted a multiinstitutional phase II clinical trial to determine the toxicity, response, and survival rate of concurrent 72-h continuous infusion of etoposide and cisplatin in patients with metastatic breast cancer. A total of 26 women were enrolled, 4 of whom received no prior chemotherapy for metastatic disease. All patients were evaluated for toxicity, response, and survival employing the National Cancer Institute (NCI) Common Toxicity Criteria and the Eastern Cooperative Oncology Group (ECOG) response criteria. A total of 84 cycles of therapy were administered, median 3 (range 1 to 6). Severe grade 3 and grade 4 neutropenia occurred in 22 cycles (26%), and there were only 11 episodes (11%) of similar grade thrombocytopenia. Nausea and vomiting were seen in one third of cycles. A single patient (4%) had a complete remission, and seven patients (27%) had partial remissions for an overall objective response rate of 31% (95% confidence interval, 13 to 49%). Three of four patients (75%) without prior therapy for metastatic disease had objective responses. Median survival was 7 months. This combination regimen is active in extensively treated patients with metastatic breast cancer. It is responsible to further investigate the role of etoposide-cisplatin combination chemotherapy as firstline therapy for patients with metastatic breast cancer.

Development and characterization of nine polymorphic microsatellite markers for Mexican spadefoot toads (Spea multiplicata) with cross-amplification in Plains spadefoot toads (S. bombifrons).

We developed nine polymorphic microsatellite markers for the Mexican spadefoot toad, Spea multiplicata. Allele numbers range from five to 12, with observed heterozygosities from 0.48 to 0.87. Because two loci are in linkage disequilibrium, these nine loci provide eight independent markers. Three loci exhibit departure from Hardy-Weinberg equilibrium, possibly resulting from null alleles or population admixture. These markers will be useful for assessing population structure and relatedness in S. multiplicata. Based on our success at cross-amplification in the Plains spadefoot toad (Spea bombifrons), these loci also may be useful in this species with additional optimization.

Prevention and screening for breast cancer.

Breast cancer is the most common cancer among women in both Europe and the U.S. It is the second leading cause of cancer deaths for women in the U.S., but the first in Poland. Age, family history, reproductive factors, proliferative breast disease, and radiation are established risk factors. Diet may account for differences in international incidence rates; however, the majority of women who get breast cancer do not have identifiable risk factors other than age and being female. Primary prevention of breast cancer is unknown. Control relies on secondary prevention aimed at suppression of clinically occult disease, mammographic screening, and early detection of palpable disease through physical examination and breast self-examination. Dietary and medical prevention strategies are being tested in the U.S. Screening mammography has demonstrated effectiveness in reducing mortality in women over 50. The "Partnerships in Healthcare" program aims to enhance the early detection of breast cancer in Poland by providing mammography units, training for technicians and nurses, and incentives to develop multidisciplinary approaches to diagnosis and treatment.

Intrinsic conduction maximizes cardiopulmonary performance in patients with dual chamber pacemakers.

Dual chamber pacemaker programmability allows the possibility of atrially-tracked ventricular pacing in patients who would otherwise have intrinsic atrioventricular (AV) conduction. Thirteen patients with permanent AV sequential pacemakers (ages 50-79) were evaluated with paired exercise tests to determine the cardiopulmonary effects of pacemaker induced right ventricular activation compared with normal AV and intraventricular conduction. Peak oxygen uptake (VO2), oxygen pulse (O2P), respiratory rate (RR), and respiratory exchange ratio (RER) were determined using breath-by-breath analysis of expired gases. Patients exercised to fatigue and exercise tests were performed in random sequence. For patients with intrinsic AV conduction (group I, n = 8) the AV delay was programmed to preserve intrinsic conduction during one study; the alternate test used AV delay programming to produce ventricular pacing. Five patients with chronic AV block (group II) acted as a control for the effects of a rate adaptive AV delay compared to a fixed AV delay. Paired t-testing showed a significantly lower peak VO2 (P less than 0.015) and O2P (P less than 0.01) in patients with atrially-tracked ventricular pacing compared to intrinsic conduction. In contrast, group II showed a significant improvement in peak VO2 with rate adaptive AV delay compared to fixed AV delay programming (P less than 0.05). In conclusion, intrinsic conduction should be preserved in patients with dual chamber pacemakers whenever possible.

Radiofrequency catheter ablation of an atriofascicular pathway during atrial fibrillation: a case report.

INTRODUCTION: A male patient with an atriofascicular pathway underwent catheter ablation of the atriofascicular pathway during atrial fibrillation. METHODS AND RESULTS: The patient had preexcited atrial fibrillation both clinically and repeatedly during electrophysiologic study. A preexcited tachycardia with a 1:1 AV relationship and regular RR intervals was also induced. Catheter ablation of the atriofascicular pathway could only be performed during persistent atrial fibrillation, based on mapping of the pathway's insertion into the right bundle branch. Following successful ablation and cardioversion to sinus rhythm, a regular QRS tachycardia (atrioventricular [AV] nodal reentry) having the same rate, atrial activation sequence, and His-atrial time as the regular preexcited tachycardia noted preablation was initiated. An AV nodal slow pathway modification eliminated this tachycardia. Neither atrial fibrillation nor AV nodal reentry has recurred on follow-up. CONCLUSION: This is the first report of atriofascicular mapping and ablation performed exclusively during atrial fibrillation and illustrates the utility of mapping the pathway's ventricular insertion. Other unusual features ("bystander" pathway activation during AV nodal reentry, possible role of the pathway in genesis of atrial fibrillation) are discussed.

The effect of age on five ions of the kidney in the Fischer 344 rat.

It was proposed that the diminished renal function observed with advancing age could be due to a lower concentration of essential ions within the organ or an accumulation of ions which could produce cellular toxicity. This investigation reports the effect of age (3, 6, 12, 24 and 28 months) on the concentrations of magnesium, calcium, zinc, copper and iron in renal homogenates of Fischer 344 strain rats. Samples of renal tissues were homogenized in a solution containing 5 p. 100 La + 25 p. 100 HNO3. The samples were digested, centrifuged and assayed by atomic absorption spectrophotometry. With age, the magnesium concentration decreased (P less than 0.05) while the calcium and copper concentrations remained unchanged, and the zinc concentration decreased slightly while the iron concentration markedly increased (P less than 0.05). In summary, these data and other data obtained from similar studies of the brain and heart, suggest that the changes observed with age are unique to the kidney. Our results suggest that changes in ionic concentration in the kidney with respect to age could contribute to the diminished function observed in that organ with senescence.

Early detection and treatment of spinal epidural metastases: the role of myelography.

Spinal epidural metastases were detected in 75 of 140 cancer patients with back pain who were evaluated prospectively by clinical criteria, spine roentgenography, and bone scan. Fifty-five of the 75 patients with epidural metastases had no evidence of myelopathy when diagnosed. Of the patients diagnosed and treated while still ambulatory, more than 90% remained so. Myelograms were performed in 127 patients to diagnose the 75 with epidural disease. To try to reduce the number of myelograms needed, we attempted to design radiotherapy ports based on clinical symptoms and the plain spine films alone. A port could not be designed for 64 of the 127 patients, either because of diffuse vertebral metastases or a normal plain roentgenogram. A port could be designed for 63 patients, and all epidural disease would have been encompassed in 50 of the 54 patients who had spinal epidural metastases (93%). Most patients with cancer and back pain require myelography for accurate treatment planning. There are, however, situations in which treatment can be determined based on symptoms and plain films alone, with a low risk of missing epidural cancer.

Contact activation of the plasma coagulation cascade. I. Procoagulant surface chemistry and energy.

Contact activation of the intrinsic pathway of porcine blood plasma coagulation is shown to be a steep exponential-like function of procoagulant surface energy, with low activation observed for poorly water-wettable surfaces and very high activation for fully water-wettable surfaces. Test procoagulants studied were a system of oxidized polystyrene films with varying wettability (surface energy) and glass discs bearing close-packed self-assembled silane monolayers (SAMs) with well-defined chemistry consisting of 12 different terminating chemical functionalities. A monotonic trend of increasing coagulation activation with increasing water wettability was observed for the oxidized polystyrene system whereas results with SAM procoagulants suggested a level of chemical specificity over and above the surface energy trend. In particular, it was noted that coagulation activation by SAMs terminated with--CO2H was much higher than anticipated based on surface wettability whereas--NH3(+)-terminated SAMs exhibited very low procoagulant activity. SAMs terminated in--(CH2)2(CF2)7CF3 behaved as anticipated based on surface energy with very low procoagulant activity and did not exhibit special properties sometimes attributed to perfluorinated compounds. Quantitative ranking of the inherent coagulation activation properties of procoagulant surfaces was obtained by application of a straightforward phenomenological model expressed in a closed-form mathematical equation relating coagulation time to procoagulant surface area. Fit of the model with a single adjustable parameter to experimental measurements of porcine platelet-poor plasma coagulation time was very good, implying that assertions and simplifications of the model adequately simulated reality. Two important propositions of the model were that (1) the number of putative "activating sites" scaled linearly with procoagulant surface area, and (2) contact activation of the plasma coagulation cascade was catalytic in the sense that these activating sites were not consumed or "poisoned" by irreversible or slowly reversible protein adsorption during coagulation. An extension of the coagulation model proposed that procoagulant activation properties scale exponentially with the surface density of polar (acid-base) sites, which, in turn, was related to procoagulant wettability.

The disposition and metabolism of tiazofurin in rodents, rabbits, and dogs.

The pharmacokinetics and metabolism of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) have been examined in the mouse, rat, rabbit, and dog using tritiated drug as a marker. In all four species, tiazofurin, given as a single bolus iv injection, is removed from the circulation in a triphasic manner, with a generally prolonged terminal half-life. In all cases, the mean concentration of unchanged drug prevailing during this terminal phase was well within the cytotoxic range (IC50 vs. P388 cells is 2 microM in vitro). Urinary excretion accounted for between approximately 40 and 90% of the administered dose in all four species, with only minor quantities (less than 3%) of drug-derived radioactivity detected in the feces. The metabolism of tiazofurin was examined in mice and rats: although no evidence was uncovered for hydroxylation of tiazofurin at carbon atom 5 of the thiazole ring, phosphorylation of the drug at its 5'-hydroxyl was demonstrable in nearly every organ of both species, but, liver, striated muscles, and kidney were the only tissues catalyzing the synthesis of thiazole-4-carboxamide adenine dinucleotide to any prominent degree. This synthesis did not appear to be a saturated process, even at doses as high as 8000 mg/m2. Since rodent skeletal muscle accumulated high concentrations of tiazofurin phosphates in vivo, it is suggested that musculature may serve as a reservoir for the drug, and contribute to its rather protracted terminal half-life in plasma.