Relationships between dairy slurry total solids, gas emissions, and surface crusts.

Livestock slurry storages are sources of methane (CH4), nitrous oxide (NO2), and ammonia (NH3) emissions. Total solids (TS) content is an indicator of substrate availability for CH4 and N2O production and NH3 emissions and is related to crust formation, which can affect these gas emissions. The effect of TS on these emissions from pilot-scale slurry storages was quantified from 20 May through 16 Nov. 2010 in Nova Scotia, Canada. Emissions from six dairy slurries with TS ranging from 0.3 to 9.5% were continuously measured using flow-through steady-state chambers. Methane emissions modeled using the USEPA methodology were compared with measured data focusing on emissions when empty storages were filled, and retention times were >30 d with undegraded volatile solids (VS) remaining in the system considered available for CH4 production (VS carry-over). Surface crusts formed on all the slurries. Only the slurries with TS of 3.2 and 5.8% were covered completely for ∼3 mo. Nitrous oxide contributed <5% of total greenhouse gas emissions for all TS levels. Ammonia and CH4 emissions increased linearly with TS despite variable crusting, suggesting substrate availability for gas production was more important than crust formation in regulating emissions over long-term storage. Modeled CH4 emissions were substantially higher than measured data in the first month, and accounting for this could improve overall model performance. Carried-over VS were a CH4 source in months 2 through 6. The results of this study suggest that substrate availability regulates emissions over long-term storage and that modifying the USEPA model to better describe carbon cycling is warranted.

Greenhouse gas emissions from surface flow and subsurface flow constructed wetlands treating dairy wastewater.

Agricultural wastewater treatment is important for protecting water quality in rural ecosystems, and constructed wetlands are an effective treatment option. During treatment, however, some C and N are converted to CH(4), N(2)O, respectively, which are potent greenhouse gases (GHGs). The objective of this study was to assess CH(4), N(2)O, and CO(2) emissions from surface flow (SF) and subsurface flow (SSF) constructed wetlands. Six constructed wetlands (three SF and three SSF; 6.6 m(2) each) were loaded with dairy wastewater in Truro, Nova Scotia, Canada. From August 2005 through September 2006, GHG fluxes were measured continuously using transparent steady-state chambers that encompassed the entire wetlands. Flux densities of all gases were significantly (p < 0.01) different between SF and SSF wetlands changed significantly with time. Overall, SF wetlands had significantly (p < 0.01) higher emissions of CH(4) N(2)O than SSF wetlands and therefore had 180% higher total GHG emissions. The ratio of N(2)O to CH(4) emissions (CO(2)-equivalent) was nearly 1:1 in both wetland types. Emissions of CH(4)-C as a percentage of C removal varied seasonally from 0.2 to 27% were 2 to 3x higher in SF than SSF wetlands. The ratio of N(2)O-N emitted to N removed was between 0.1 and 1.6%, and the difference between wetland types was inconsistent. Thus, N(2)O emissions had a similar contribution to N removal in both wetland types, but SSF wetlands emitted less CH(4) while removing more C from the wastewater than SF wetlands.

[A comparative randomized phase-II study of Xeloda (capecitabine) and paclitaxel in patients with breast cancer progressing after anthracycline antibiotics]. / Sravnitel'noe randomizirovannoe issledovanie po II faze kselody (kapetsitabina) i paklitaksela u bol'nykh rakom molochnoi zhelezy, progressiruiushchikh posle antratsiklinovykh antibiotikov.

A randomized study of the effectiveness of treatment with capecitabine (Xeloda) (22) and paclitaxel (taxol) (19) was carried out in breast cancer patients resistant to anthracycline antibiotic drugs. Capecitabine and paclitaxel showed comparable effectiveness, although the former appeared less toxic, particularly, in hematologic complication situations. Therefore, it may be administered to out-patients who previously received several courses of chemotherapy.

Clinical pharmacokinetics of 2'-deoxy-2'-methylidenecytidine (DMDC), a deoxycytidine analogue antineoplastic agent.

This article reviews the clinical pharmacokinetics of a deoxycytidine analogue of cytarabine, 2'-deoxy-2'-methylidenecytidine (DMDC). DMDC belongs to the antimetabolite class of anticancer drugs and is phosphorylated into its active, triphosphate, form within the tumour cell. Cancer cell death appears to be a result of the impairment of DNA synthesis by the triphosphate form. DMDC undergoes deamination to the inactive 2'-deoxy-2'-methylideneuridine (DMDU), its main plasma metabolite. Following intravenous administration at 30 to 450 mg/m2, DMDC has low systemic clearance (10 to 15 L/h/m2), moderate volume of distribution (nominally similar to total body water) and a short elimination half-life of between 2 and 6 hours. Renal clearance of DMDC accounts for approximately 30 to 50% of total clearance. Following oral administration of DMDC at 12 to 50 mg/m2, mean maximum DMDC plasma concentrations are within the 100 to 400 microg/L range and are generally reached within 2 hours. Oral bioavailability of DMDC is in the order of 40%, largely as a result of first-pass metabolism in the gut and liver. This first-pass effect results in considerable interpatient variability in systemic exposure to DMDC after oral administration. The systemic availability of DMDC is proportional to the administered dose and, although there was evidence that systemic exposure to DMDC decreased on repeated administration, there are no excessive time-dependent changes in systemic exposure to DMDC. Following oral administration, DMDC is metabolised in the gut wall and liver by deamination to DMDU. The kidneys eliminate DMDC and DMDU, with up to 50% of the administered dose recovered in urine, on average, as parent drug and metabolite. Dose escalation to the maximum tolerated dose was facilitated by a pharmacokinetically guided dose escalation strategy. DMDC has shown activity in non-small-cell lung cancer and colorectal cancers following oral administration. Several tumour responses are observed at the highest doses of DMDC, indicating a possible dose-response relationship with this drug. The main clinical adverse event of DMDC therapy is myelotoxicity. The haematological toxicity of DMDC was schedule dependent; twice daily administration was associated with greater toxic effects than a once daily regimen. A pharmacokinetic-pharmacodynamic model characterised the relationship between plasma DMDC concentrations and the time-dissociated toxicity. This model-dependent approach may be used to predict the consequences of as-yet-untested therapy as well as relating acceptable risks of haematological toxicity to target drug exposure.

A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours.

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1-14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m(-2) twice a day and of docetaxel from 75 to 100 mg m(-2). The dose-limiting toxicity (DLT) was asthenia grade 2-3 at a dose of 1000 mg m(-2) bid of capecitabine combined with docetaxel 100 mg m(-2). Neutropenia grade 3-4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m(-2) twice a day plus docetaxel 100 mg m(-2) was tolerable, as was capecitabine 1250 mg m(-2) twice a day plus docetaxel 75 mg m(-2).

Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide.

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.

Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions.

Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB+/- mice. When TrkB-mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.

Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector.

Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.

Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

PURPOSE: To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose. PATIENTS AND METHODS: Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled. Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of a minimum of 3 patients starting at 110 mg/m2 and escalating by means of a modified Fibonacci scheme to 1,657 mg/m2/d. Pharmacologic samples were obtained on days 1 and 15. Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy. RESULTS: Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m2/d. The MTD was 1,657 mg/m2/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient. Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (Cmax) 1 hour after ingestion. Linear increases in the area under the concentration-time curve (AUC) and Cmax were seen with linear increases in administered dose. CONCLUSION: The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m2/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated.

In utero cardiac gene transfer via intraplacental delivery of recombinant adenovirus.

BACKGROUND: The relationship among the maternal, placental, and uniquely shunted embryonic circulation was explored to provide access to the embryonic cardiovascular system in utero. Manipulation of gene expression in the developing heart would be particularly useful for studying the effects of altered gene expression on cardiac development and in the etiology of congenital cardiac anomalies. METHODS AND RESULTS: Dye studies demonstrated that intraplacental injection allows direct access to the embryonic cardiac and systemic circulation. To evaluate the efficacy of cardiac gene transfer using this approach, replication-deficient recombinant adenoviral vectors encoding luciferase or beta-galactosidase as reporter genes were injected intraplacentally into embryonic day (E)12.5 murine embryos, an age at which the mass of the heart was observed to be large compared with other organs. Embryos were assayed for transgene expression at E15.5 and at birth. Survival rates at these times were similar among vector-injected and control groups. At E15.5 and at birth, luciferase activity within the heart was 9- and 23-fold higher, respectively, than in the remainder of the embryo, although levels of expression were generally lower at birth than during embryonic life. Beta-galactosidase expression was observed within all regions of the embryonic heart and was localized to approximately 15% of atrial and ventricular cells. CONCLUSIONS: Intraplacental delivery of adenovirus at embryonic day 12.5 results in somatic gene transfer to the murine embryonic heart, which persists at least until birth. The combination of intraplacental injection to directly access the fetal coronary circulation and injection at E12.5 when the mass of the heart is large compared with other organs results in transgene expression in cardiac cells. Intraplacental injections early in embryonic life may thus be useful to study the effects of temporal manipulation of gene expression on cardiac development and disease.

In vivo expression of full-length human dystrophin from adenoviral vectors deleted of all viral genes.

Adenoviral vectors have been shown to effect efficient somatic gene transfer in skeletal muscle and thus offer potential for the development of therapy for Duchenne muscular dystrophy (DMD). Efficient transfer of recombinant genes has been demonstrated in skeletal muscle using recombinant adenoviruses deleted of E1. Application of this vector system to the treatment of DMD is limited by the vector immunogenicity, as well as by size constraints for insertion of recombinant genes, precluding the incorporation of a full-length dystrophin minigene construct. We describe in this study the use of helper adenovirus to generate a recombinant vector deleted of all viral open reading frames and containing a full-length dystrophin minigene. We show that this deleted vector (delta vector) is capable of efficiently transducing dystrophin in mdx mice, in myotubes in vitro and muscle fibers in vivo. Our modification of adenoviral vector technology may be useful for the development of gene therapies for DMD and other diseases.

Valvulitis involving a bioprosthetic valve in a patient with systemic lupus erythematosus.

A 37-year-old man with systemic lupus erythematosus, who underwent an aortic valve replacement with a Carpentier-Edwards porcine valve for severe aortic insufficiency, was admitted to the hospital with pulmonary edema. Transesophageal echocardiography revealed severe aortic insufficiency arising from partial dehiscence of the valve sewing ring, as well as centrally from the valve cusp. In addition, marked thickening of the mitral valve was observed with severe eccentric regurgitation. At surgery, valvulitis of the native mitral and bioprosthetic aortic valves was demonstrated, with a perforation of the porcine valve cusp. After replacement of both valves, the patient had a stormy postoperative course with recurrent communications between the left ventricle and atrium requiring multiple surgeries and eventually died. This case illustrates the severity of valvulopathy and ensuing complications that can affect patients with systemic lupus erythematosus and demonstrates that the valvulopathy can affect bioprosthetic valves, a finding that has significant implications as to the type of valve replacement in these patients.

Polyethylene glycol-conjugated superoxide dismutase protects rats against oxygen toxicity.

Superoxide dismutase (SOD) has an important role in the protection against O2 toxicity. Conjugation of Cu,Zn-SOD to polyethylene glycol (PEG-SOD) prolongs its plasma half-life and facilitates its cellular uptake. However, prior studies have shown that intravenous injection of PEG-SOD does not protect animals against O2 toxicity. In this study, we demonstrated that tracheal insufflation of PEG-SOD resulted in a dose-dependent protection against O2 toxicity. Nine of 15 rats (60%) insufflated with 25,000 U PEG-SOD survived continuous 100% O2 exposure for more than 7 days compared with control rats (n = 45), all of which died within 3 days of O2 exposure (P < 0.025). In contrast, insufflation of 25,000 U SOD, 9.7 mg methoxy-PEG (equivalent to the amount of methoxy-PEG present in 25,000 U PEG-SOD), or a combination of SOD and methoxy-PEG had no protective effect. Furthermore, intravenous or intraperitoneal injection of PEG-SOD did not afford significant protection. Protection against O2 toxicity by PEG-SOD insufflation was associated with attenuated O2-induced pulmonary injury as evidenced by a reduced volume of pleural effusion. Insufflation of PEG-SOD markedly increased pulmonary SOD activity (to 300 and 370% of controls at 24 and 50 h, respectively) without affecting pulmonary catalase activity. We conclude that insufflation of PEG-SOD protects rats against O2 toxicity, possibly by enhancing pulmonary SOD activity.

Rheology and anesthesiology.

We present a review of blood rheology with special emphasis on its application in anesthesiology. The rheological behavior of blood is determined by 2 variables, non-Newtonian viscosity and yield stress. The physical significance of these quantities is discussed. Blood viscosity directly affects total peripheral resistance, and changes in the state of peripheral vessels cannot be accurately evaluated unless simultaneous measurements of blood viscosity are made. Blood viscosity also influences cardiac output, and elevations in hematocrit may reduce total O2 transport by increasing viscosity to the point that cardiac output decreases. The role of blood viscosity and blood yield stress in the pathogenesis of deep-vein thrombosis is mentioned, and the role of anesthesia in affecting viscosity by decreasing venous flow is discussed. Clinical examples of the role of blood rheology in neonatal respiratory distress and during open heart surgery are also given.

Lung cancer and air pollution in southcentral Los Angeles County.

An increased rate of lung cancer has been consistently observed from 1968-1972 among males in southcentral Los Angeles. This excess risk occurs across several social classes and occupational categories. No differential excess of oral cavity, pancreatic, laryngeal and bladder cancer was observed in the same area, lessening the possibility that regional variations in smoking habits accounted for the excess lung cancer. Air sampling has indicated an excess of certain polynuclear aromatic hydrocarbons (PAH) in southcentral Los Angeles. There was a correlation between the geographic distribution of lung cancer cases and the general location of industries which have emitted these PAH. A case-controlled study of smoking, occupational and residential history in the southcentral area is underway.

Changes in arterial pressure, viscosity and resistance during cardiopulmonary bypass.

Large changes in arterial pressure and systemic vascular resistance are frequently observed at the onset of and during cardiopulmonary bypass, particularly when hemodilution is employed. In order to assess the extent to which these changes are induced by changes in blood viscosity, we measured viscosity, pressure, and flow in a series of 17 patients. Hemodilution was used in Group A (12 patients) but not in Group B (5 patients). At the beginning of cardiopulmonary bypass, the arteriovenous pressure difference decreased an average of 53.8 per cent in the Group A patients, concomitant with a 41.7 per cent decrease in blood viscosity. The arteriovenous pressure difference in the Group B patients increased an average of 6.4 per cent, while the blood viscosity increased by 8 per cent. A nomogram was theoretically derived for the Group A patients, which allows rapid estimation of the extent of viscosity-induced hypotension for a given volume of priming fluid, initial patient hematocrit, and patient weight. After correction for viscosity changes due to hemodilution, the Group A patients were found to exhibit essentially normal values of systemic vascular resistance at the start of bypass, with a mean of 1,155 dynes-sec./cm.5. On the other hand, the Group B patients had elevated resistance values, with a mean of 1,611 dynes-sec./cm.5. During perfusion, the resistance of both groups tended to increase, sometimes by 100 per cent or more. In some cases, however, the resistance values changed in an erratic fashion. These effects were not due to changes in blood viscosity.