Variation between hosts in the developmental success of the free-living stages of trichostrongyle infections of sheep

Variation between hosts of different ages and genotypes in the developmental success of trichostrongylid parasite eggs from sheep was investigated in two trials. The percentage development to infective third-stage larvae of eggs collected from lambs and adult ewes infected with Ostertagia circumcincta was compared in an indoor trial. In addition, sheep previously bred for either high or low faecal egg count and grazed outdoors on parasite contaminated pasture were sampled; egg development, faecal egg count, generic profile and faecal dry matter were measured. In both trials, development to L3 was significantly lower in eggs derived from adult ewes than from lambs and, in the field trial, from animals selected for low faecal egg count. The observed differences could not be accounted for by variations in faecal egg count, faecal dry matter content nor by differences in the generic composition of worm egg output. Although not shown conclusively, the results are consistent with an immune mechanism influencing the development of free-living stages of gastrointestinal nematodes outside the host. These results have significant implications for our understanding of parasite epidemiology, particularly as it relates to sources of pasture contamination.     

Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer

A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.     

Inhibition of IL-1 induced tissue factor (TF) synthesis and procoagulant activity (PCA) in purified human monocytes by IL-4, IL-10 and IL-13

Exposure of monocytes to pro-inflammatory cytokines or lipopolysaccharide (LPS) may induce synthesis and expression of tissue factor (TF). In this paper we have focused on the induction of TF-activity in human monocytes by the pro-inflammatory cytokines recombinant human interleukin 1 (rhIL-1 alpha) (rhIL-1 beta) (rhIL-6) and human tumour necrosis factor alpha (rhTNF-alpha), measured as procoagulant activity (PCA) in a microtitre plate-based clot assay. In addition we have studied the modulation of IL-1 alpha/beta induced TF-mRNA and PCA by rhIL-4, rhIL-10 and rhIL13. IL-1 alpha and IL-1 beta induced a concentration dependent increase in TF-activity. Neither IL-6 nor TNF-alpha gave rise to procoagulant activity at the concentrations tested (0.2-20 ng/ml). IL-4, IL-10 and IL-13, all effectively diminished IL-1 alpha/beta induced PCA, shown at the protein- and at the mRNA-level, while cell viability was unaffected. These results add to the previously demonstrated role of IL-4 and IL-10 as inhibitors of LPS-induced TF-activity, showing that these anti-inflammatory cytokines are not specific for LPS-activation but interfere with other stimulating substances such as IL-1, which may be involved in diseases where LPS is not present.     

Blocking filter vents increases carbon monoxide levels from ultralight, but not light cigarettes

Effect of vent blocking on carbon monoxide (CO) exposure from a best-selling light cigarette was examined in 12 daily cigarette smokers. Mean CO boosts were not different from each other with (a) 0% filter vents blocked (5.0 ppm), (b) vents covered with lips (4.9 ppm), (c) 50% of vents covered with tape (4.8 ppm), and (d) vents covered with a pinch of the fingertips (4.9 ppm). A second study in another 12 smokers was conducted to replicate these findings as well as earlier findings that blocking vents doubles CO intake from 1-mg tar cigarettes. While blocking half the vents with fingers significantly increased CO boost from ultralight cigarettes (2.8 vs. 5.4 ppm, p < 0.001), it did not influence boosts from light cigarettes (6.3 vs. 6.5 ppm, p = 0.8). The lowest yield cigarettes (1 mg tar) may be special. Smoking machine simulations provide poor models of human smoke intake. It is unclear whether tar and nicotine intake from light cigarettes was influenced by vent blocking.     

Doppler grid surface scanning applications for pulmonary subsurface parenchymal perfusion assessment

Subsurface perfusion to lung parenchyma underlying the pleura is difficult to assess in live ventilated animals. The purpose of this study was to assess applicability of a newly developed laser Doppler grid scanning imaging technology that measures perfusion of pleural subsurface lung regions in intact normal and abnormal animal lungs. Eighty-six Doppler grid perfusion measurements were performed in five New Zealand White Rabbits (3-5 kg); four with unilateral bullous lung disease, one normal control. Left upper lobe lung surface was exposed to 10 1-sec spot Nd:YAG exposures (70 W/cm2). One week following laser exposure, all rabbits underwent sequential bilateral open thoracotomy. Unaffected left lower lobes in these animals and all four lobes of a previously untreated rabbit were used as controls. Pleural subsurface perfusion measurements were recorded over a contiguous 900-pixel square surface grid using quantitative noncontact laser Doppler imaging during open thoracotomy procedures. Scans were obtained in a normal volume ventilation mode, at 30 cm of inspiratory hold airway pressure, and postinflation. A perfusion-pressure response curve was obtained in normal lung at 10-, 20-, and 30-cm static airway pressure. Post mortem measurements were used as 0 flow controls. Normal lung tissue was found to have relatively high pleural subsurface perfusion (1362 +/- 328 corrected units on a scale of 0-4095). Areas of atelectasis had decreased perfusion (659 +/- 512 U., 48.4 +/- 12.5% compared to normal lung, p < 0.02), but returned to normal levels after inflation of the lung (1253 +/- 363 U., p = 0.21 compared to normal). Pleural subsurface perfusion decreased uniformly and progressively as lung inflation pressure increased (p < 0.0001). Perfusion increased immediately to supranormal values following release of high inspiratory inflation pressure holds (1603 +/- 626 U., 117 +/- 18% compared to normal lung, p = 0.03). Bullae had markedly decreased perfusion (541 +/- 68 U.) that was not further reduced by increased inflation pressures. Noncontact laser Doppler grid perfusion imaging appears to provide a new tool for measuring pleural subsurface perfusion over a large area of lung surface in clinical experimental settings. Results are rapid, reproducible, and consistent. Sampling errors inherent in current point sampling Doppler flow techniques are reduced by the multiple contiguous measurements. We have used this technique to demonstrate inspiratory pressure-related reduction in pleural subsurface perfusion in normal lung, reversible decreased perfusion in atelectatic regions, and reduced perfusion in bullous and laser-treated lung regions.     

Clinical response of localized recurrent periodontitis treated with scaling, root planing, and tetracycline fiber

The purpose of this study was to compare the clinical efficacy of scaling and root planing alone versus tetracycline fiber therapy used adjunctively with scaling and root planing in the treatment of nonresponsive active periodontitis in patients under supportive periodontal therapy. Thirty patients who were receiving supportive treatment and had at least two nonadjacent periodontitis sites with a probing depth of between 4 and 8 mm and bleeding on probing, or had aspartate aminotransferase (AST) levels above 800 microIU in the gingival crevicular fluid in separate quadrants participated in this study. For each patient, the test sites were treated with scaling and root planing plus tetracycline fibers while the control site was treated with scaling and root planing only. Probing depths, clinical attachment levels, gingival recession, AST levels, and bleeding on probing were recorded and subgingival plaque samples were collected at baseline and 1, 3, and 6 months following treatment. At 3 months after treatment, there was a reduction of bleeding on probing and probing depth, and a gain of clinical attachment in both test and control sites. The mean reduction in probing depth of the test sites was 1.38 mm and the attachment gain was 0.8 mm after 6 months. The clinical response obtained at 3 months following therapy was maintained throughout the 6-month follow-up period. However, there were no statistically significant differences between sites treated with scaling and root planing alone and those treated with combined tetracycline therapy. Most of the reductions of probing depths in the fiber group were attributed to gingival recession. The present study did not confirm the efficacy of adjunctive tetracycline fibers in treating nonresponsive sites in maintenance subjects with regard to probing depth reduction or clinical attachment gain. Reinfection of the pockets from untreated sites and extra-crevicular regions may explain the insignificant response to local tetracycline therapy.     

Kinetic analysis of dynamic 13C NMR spectra: metabolic flux, regulation, and compartmentation in hearts

Control of oxidative metabolism was studied using 13C NMR spectroscopy to detect rate-limiting steps in 13C labeling of glutamate. 13C NMR spectra were acquired every 1 or 2 min from isolated rabbit hearts perfused with either 2.5 mM [2-13C]acetate or 2.5 mM [2-13C]butyrate with or without KCl arrest. Tricarboxylic acid cycle flux (VTCA) and the exchange rate between alpha-ketoglutarate and glutamate (F1) were determined by least-square fitting of a kinetic model to NMR data. Rates were compared to measured kinetics of the cardiac glutamate-oxaloacetate transaminase (GOT). Despite similar oxygen use, hearts oxidizing butyrate instead of acetate showed delayed incorporation of 13C label into glutamate and lower VTCA, because of the influence of beta-oxidation: butyrate = 7.1 +/- 0.2 mumol/min/g dry wt; acetate = 10.1 +/- 0.2; butyrate + KCl = 1.8 +/- 0.1; acetate + KCl = 3.1 +/- 0.1 (mean +/- SD). F1 ranged from a low of 4.4 +/- 1.0 mumol/min/g (butyrate + KCl) to 9.3 +/- 0.6 (acetate), at least 20-fold slower than GOT flux, and proved to be rate limiting for isotope turnover in the glutamate pool. Therefore, dynamic 13C NMR observations were sensitive not only to TCA cycle flux but also to the interconversion between TCA cycle intermediates and glutamate.     

Induced hypothermia in critical respiratory failure after lung transplantation

A practical approach to detect and identify ceftazidime-hydrolyzing extended-spectrum mutants of OXA-10 beta-lactamase is presented. Large numbers of bacteria were screened by colony hybridization, a 720-bp part of blaOXA was amplified by PCR from the hybridization-positive isolates, and the products were digested by PvuII and HaeIII.