Biomedical subjects
P Stevens
Publications and source records attributed to P Stevens.
Clinical experience with a new antithrombotic (dermatan sulfate) in chronic hemodialysis patients.
Dose finding studies with a new antithrombotic (dermatan sulfate) for the prevention of clot formation in the extracorporeal circuit were performed in chronic hemodialysis patients in comparison with standard heparin treatment. Dermatan sulfate (DS), which inhibits the coagulation via the heparin cofactor II pathway, was given in single predialysis injections, immediately before commencement of the dialysis procedures, in dosages ranging from 2 mg/kg to 6 mg/kg body weight. In our pilot study, an open non comparative study in patients using plate type dialyzers, we observed moderate clot formation in the extracorporeal circuit. In our second study, with a randomized heparin-controlled design in patients with plate type dialyzers, still significant clot formation occurred in the extracorporeal circuit. In the third study, in chronic hemodialysis patients using a cuprophane hollow fiber dialyzer, we also investigated the addition of a small bolus of standard heparin (20 I.U./kg body weight) to the injection of DS. A single bolus injection of 6 mg/kg, with or without the addition of a bolus of standard heparin, had a comparable efficacy as standard heparin treatment. No major bleeding events were encountered in the studies and DS had a reduced effect on the activated partial thromboplastin time as compared to standard heparin. In conclusion, these results suggest that DS in a dose of 6 mg/kg, with or without a small dose of standard heparin, given as single predialysis bolus injections, appears to be an effective alternative to standard heparin and, in addition, it may simplify the anticoagulant administration protocol.
Dermatan sulphate in haemodialysis.
Experimental work suggests that dermatan sulphate has potential as an antithrombotic agent: it can inhibit venous thrombi yet has less effect upon bleeding than heparin. While heparin functions as an anticoagulant primarily by its ability to accelerate the action of the plasma protein inhibitor antithrombin III, dermatan sulphate acts selectively through a structurally related inhibitor, heparin co-factor II, to inhibit thrombin. We have done a series of dose-finding studies of the use of dermatan sulphate as an anticoagulant/antithrombotic agent in patients on maintenance haemodialysis. Dermatan sulphate proved to be an effective anticoagulant in this setting.
Mosquitoes and malaria transmission in irrigated rice-fields in the Benoue valley of northern Cameroon.
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Human monoclonal antibodies to glycolipid A that exhibit complement species-specific effector functions.
Two human IgM monoclonal anti-glycolipid A antibodies (MAbs) were evaluated for their abilities to bind to various endotoxins and pathogenic gram-negative bacteria and to activate complement pathways, thereby accomplishing bactericidal and opsonic effector functions. Both MAbs cross-reacted with glycolipid A mutant lipopolysaccharides from rough colony-forming gram-negative bacteria and with selected endotoxins from smooth colony-forming bacteria. However, MAb 10235 bound to all clinical isolates of Escherichia coli and Klebsiella pneumoniae tested but only very weakly to Pseudomonas aeruginosa, whereas MAb 10058 bound to all three genera. Several strains of serum-insensitive organisms were selected for evaluation of antigen-specific, complement-mediated effector functions for the two MAbs. Assessment of bactericidal and opsonic activities showed that neither MAb was able to activate complement from nonprimate species (mouse, rat, rabbit, guinea pig, or sheep). However, both MAbs were highly effective in using primate sources of serum complement to mediate these effector functions.
Effects of granulocyte colony-stimulating factor in modifying mortality from Pseudomonas aeruginosa pneumonia after hemorrhage.
BACKGROUND AND METHODS: Alterations in immune function occurring after hemorrhage and trauma may contribute to the high occurrence rates of nosocomial pneumonia, multiorgan system failure, morbidity, and mortality in this setting. Therapy with granulocyte colony-stimulating factor (G-CSF) can increase neutrophil numbers and function, and enhance resistance to infection in experimental and clinical settings associated with abnormal immune function. To investigate whether treatment with G-CSF could increase resistance to pneumonia after hemorrhage, we bled mice 30% of the blood volume and treated them with various doses of G-CSF, starting either immediately or 2 days after hemorrhage. Pseudomonas aeruginosa pneumonia was induced by the intratracheal instillation of 2 x 10(7) colony-forming units of P. aeruginosa 4 days after blood loss, and mortality was assessed over the next 7 days. RESULTS: Treatment of mice with 100 or 500 micrograms/kg/day G-CSF, but not with 50 micrograms/kg/day, resulted in significant increases in the numbers of circulating polymorphonuclear cells. Platelet counts significantly decreased in mice given 500 micrograms/kg/day G-CSF. Mice given 100 micrograms/kg/day G-CSF starting 2 days after blood loss had improved outcome compared with vehicle-treated controls (38% survival rate in the G-CSF treated group vs. 8% in controls, p less than .05). There also was a trend toward an improved survival rate in mice treated with 50 micrograms/kg/day G-CSF for 4 days after hemorrhage (46% survival rate in G-CSF treated vs. 17% in controls). CONCLUSIONS: G-CSF prophylactically administered after hemorrhage can improve survival from pneumonia due to P. aeruginosa. However, the protection afforded by G-CSF was highly dependent on the dosing schedule used.
Computer-assisted planning for orthopedic surgery.
Faced with challenging deformities and crippling arthritis, orthopedic surgeons frequently are called upon to perform increasingly complex reconstructive surgery. The desired goals of treatment include correction of deformities, relief of pain, and preservation or restoration of function.
Synergism of basic fibroblast growth factor and interleukin-1 beta to induce articular cartilage-degradation in the rabbit.
Interleukin-1 beta (IL-1) and basic fibroblast growth factor (bFGF) synergistically induce proteases in vitro. To investigate this synergy in vivo, we injected IL-1 and bFGF alone and in combination into the lapine knee. Three days later, we compared the glycosaminoglcan (GAG) content of tibial cartilage of cytokine-treated and contralateral control-knees. IL-1 caused significant increases of granulocytes and GAG in the synovial fluid but minor cartilage-GAG losses of 11, 11 & 16% at 5kU, 10 kU and 100 kU IL-1/knee, respectively. bFGF at 2 and 10 micrograms/knee caused no changes. 10 micrograms bFGF in combination with 10 kU IL-1 induced a 33% GAG loss (p less than 0.01) that lasted 21 days. IL-1/bFGF induced cartilage degradation may be useful to 1) evaluate agents which modulated proteoglycan catabolism and 2) assess factors that accelerate cartilage-repair.
Interleukin-2 enhances the translocation of Escherichia coli from the intestines to other organs.
To determine if interleukin-2 (IL-2) would inhibit gastrointestinal bacterial translocation, mice were gut-decontaminated and recolonized with Escherichia coli C25; some groups were pretreated with 200 mg/kg cyclophosphamide. IL-2 (1.68 mg/kg) or sterile diluent was injected twice daily for 3 or 5 days, and mice were sacrificed the next day. High cecal levels of E. coli C25 were present in all mice. The overall incidence of E. coli C25 translocation to mesenteric lymph nodes was not reduced by IL-2. The median numbers of translocated E. coli C25/g of mesenteric lymph node were significantly (P less than .005) higher after both 3 days (659 vs. 117) and 5 days (550 vs. 50) of treatment with IL-2 with cyclophosphamide and after 5 days (1784 vs. 225) of IL-2 without cyclophosphamide. IL-2 prevented neutropenia and exacerbated lymphopenia caused by cyclophosphamide. The in vitro growth of E. coli C25 was not affected by up to 10(5) units/ml IL-2. Ileal and cecal structures assessed by light and electron microscopy were not altered by IL-2. Thus, IL-2 unexpectedly enhanced the translocation of E. coli C25 from the gastrointestinal tracts of both cyclophosphamide-pretreated and normal mice.
Solitary pulmonary nodules: comparison of classification with standard, thin-section, and reference phantom CT.
Standard, thin-section, and reference phantom computed tomography (CT) were performed to evaluate 75 consecutive patients with solitary pulmonary nodules. Follow-up was available for 62 nodules in 59 patients; 53 of the nodules were benign and nine were malignant. Twenty-one of the 62 nodules were assessed as benign with thin-section CT, while 33 of the 62 nodules were assessed as benign with reference phantom CT. Two of the nodules classified as benign with both thin-section and reference phantom CT proved to be malignant (a peripheral, ossified carcinoid and a 3.5-cm-diameter calcified carcinoma). The sensitivity of reference phantom CT (58%) for classification of benign nodules was higher than the sensitivity of thin-section CT (36%). The sensitivity of standard CT was lowest (12%). The presence of fat at thin-section CT was a reliable criterion for benignancy in six hamartomas. While both thin-section and reference phantom CT were useful in the identification of benign pulmonary nodules, reference phantom CT increased sensitivity by 22% compared with thin-section CT.
Surfactant substitution in ventilated very low birth weight infants: factors related to response types.
We investigated factors than may influence the response to surfactant substitution. Thirty-five very low birth weight infants with respiratory distress syndrome were treated with Curosurf at 3-12 h of age. From the changes in oxygenation, the therapeutic response was categorized as rapid and sustained, rapid with relapse, or poor. Phospholipids and surfactant protein A were quantified in gastric aspirate samples obtained immediately after birth. They showed that 16 infants had accelerated lung maturity, despite clinical and radiologic signs of respiratory distress syndrome. Ten of them had suffered from birth asphyxia or connatal infection. Nevertheless, 12 of these 16 infants responded rapidly to surfactant substitution. Poor response was seen in four infants with connatal infection. Of 19 infants with immature lung profile, 18 showed a rapid initial response to surfactant substitution. Dynamic compliance of the respiratory system or arterial blood pressure before substitution, the ultrastructure of the surfactant preparation, or persistence of the ductus arteriosus did not influence the response type, but fraction of inspired oxygen was higher before surfactant substitution in infants with poor response. Prognosis was related to short-term response: Of 17 infants who showed a rapid and sustained response, none died, whereas eight of 18 infants with relapse after rapid initial response or poor response died (p less than 0.05). We conclude that surfactant substitution may be beneficial not only in babies with primary surfactant deficiency but also in other pulmonary disorders that are common in very low birth weight infants. The type of response may be of prognostic value.
Endotoxin and cytokine profile in plasma of baboons challenged with lethal and sublethal Escherichia coli.
This descriptive study compares the inflammatory, coagulant, and hemodynamic responses of the baboon to a 2-hr infusion of lethal and sublethal concentrations of Escherichia coli (40 and 4.0 billion organisms per kilogram, respectively). The response to lethal E. coli challenge occurred in three stages: an inflammatory stage marked by a fall in white blood cell count (0-2 hr), a coagulant stage marked by a fall in fibrinogen concentration (2-6 hr), and a hypoxic cell injury stage marked by a rise in SGPT/BUN and by a gradual cardiovascular collapse, and death (6-24 hr). The inflammatory, or first stage coincided with the appearance in plasma of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1 beta), which peaked at 120 and 240-300 min, respectively; a slow but continuous appearance and rise of interleukin-6 (IL-6); and the appearance of endotoxin reaching a maximum at 120 min. This contrasted markedly with the response to sublethal E. coli, in which only one of the three stages was observed (inflammatory) and only minor amounts of the cytokines or endotoxin appeared in the plasma. This study describes the cytokine and endotoxin profiles and the bacteremia in the primate under experimental conditions. It shows for the first time the extreme qualitative differences in their response to lethal and sublethal concentrations of E. coli. It raises the possibility that lethality is associated with an override of the tissue threshold for processing these mediators, as marked by their appearance in plasma in response to lethal E. coli infusion.
Lecithin/sphingomyelin ratio from tracheal aspirates and compliance of the respiratory system in infants with bronchopulmonary dysplasia.
In 55 infants with respiratory distress syndrome the dynamic compliance of the respiratory system (CRS) was measured by pneumotachography during the course of the disease. Lecithin/sphingomyelin ratio (L/S) was evaluated at birth and every 10th day. Thirteen infants who developed bronchopulmonary dysplasia (BPD) had lower L/S ratios at birth than those infants without BPD (mean = 1.0 versus 3.5, p less than 0.01). During the course of disease, L/S ratios were variable and increased in all infants independently of outcome. In the first days of life CRS was low (0.30 ml/cm H2O/kg) in all infants independently of outcome. In infants with BPD who survived, CRS was significantly higher from the 30th day on than in infants who died from the disease (0.35 versus 0.23 ml/cm H2O/kg). Together with an decrease in oxygen supply at this time (less than 70%) the CRS is a reliable predictor of survival in cases of BPD.
Interleukin-2 increases the oxidative activity and induces migration of murine polymorphonuclear leukocytes in vivo.
Since recombinant human interleukin-2 (IL-2) can protect mice from a lethal bacterial challenge and can induce a vascular leak, we investigated the effects of IL-2 on the oxidative metabolism and migration of murine polymorphonuclear leukocytes (PMN) in vivo. To assess oxidative activity of PMN, we used luminol-dependent chemiluminescence (CL) to measure oxygen radical formation after stimulation of the PMN with phorbol myristate acetate (PMA). We demonstrated that single IP doses of IL-2, from 0.2-3 mg/kg, could significantly increase CL from peripheral blood PMN obtained after IL-2 treatment. The increase of PMN-CL induced by IL-2 in vivo reached a maximum 4.5 fold increase at 3 and 6 h after IL-2 treatment. At 1, 12, and 24 h after rIL-2 treatment, there were no changes in CL and PMN activity remained within normal limits. Intraperitoneally administered IL-2 also caused a significant influx of PMN into the peritoneal cavity. IL-2 increased the percentage of PMN among the peritoneal exudate cells from a control baseline level of less than 1% to 18% PMN after IL-2 treatment. These data that demonstrate the capacity of IL-2 to augment the function and metabolism of PMN in vivo and illustrates the broad range of effects of IL-2 on the immune system in vivo and may explain in part the protective effects of IL-2 in experimental bacterial infections and the possible role of PMN in the systemic toxicities induced by IL-2.
The first chapter of children's rights.
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Treatment of experimental disseminated Mycobacterium avium complex infection in mice with recombinant IL-2 and tumor necrosis factor.
Mycobacterium avium complex (MAC) is the most common bloodstream pathogen isolated from patients with AIDS. We have previously shown that TNF alone or in combination with IL-2 can activate human and murine macrophages in vitro to kill MAC strains isolated from disseminated infections. To determine whether treatment with TNF and IL-2 could effect the course of disseminated MAC infections in a murine model of disseminated MAC infection, we infected C57BL mice with 3 x 10(8) bacteria i.v. and 1 wk later administered: 1) IL-2, 100 micrograms/kg; 2) TNF, 25 micrograms/kg; 3) IL-2, 50 micrograms/kg, and TNF, 12.5 micrograms/kg; and 4) saline. IL-2 was injected i.p. daily with TNF being administered in cycles of 3 out of 4 consecutive days. Fourteen days after starting therapy, blood was cultured and mice were sacrificed for quantitative cultures of liver and spleen homogenates. IL-2, TNF, and IL-2/TNF treated groups showed an 87 +/- 5%, 57 +/- 9%, 88 +/- 6% decrease in bacteremia (p = 0.05 for TNF-treated animals and less than 0.04 for the other two groups, compared with control). The combination IL-2/TNF was the only treatment that showed a trend toward an absolute decrease in the number of bacteria in the blood. Reduction in colony counts of liver and spleen were 77 +/- 4% and 87 +/- 6%, respectively, for treatment with IL-2, 58 +/- 7% and 87 +/- 5% for TNF, and 60 +/- 10% and 82 +/- 6% for IL-2/TNF, respectively. These results suggest that both cytokines may play a role in the control of Mycobacterium avium infection and that the combination of a half-dose of IL-2 and TNF, despite not showing any greater efficacy, can be less toxic than TNF or IL-2 alone and might be useful for the therapy of disseminated infection.
Treatment of radiation side effects with oral pilocarpine.
Radiation therapy is commonly utilized either alone or in combination with surgery in the treatment of malignancies arising in the upper aerodigestive tract. Frequent post-treatment sequelae include xerostomia, dysgeusia, and dysphagia. Numerous commercial products designed to decrease these symptoms have not been uniformly successful. This pilot study was designed to evaluate prospectively oral pilocarpine as a means of stimulating minor and major salivary gland flow to eradicate these radiation-induced symptoms. The results of this pilot study support the hypothesis that the salivary glands are capable of responding to oral pilocarpine, and this therapeutic approach warrants further study.
Effect of lung collapse on alveolar surfactant in rabbits subjected to unilateral pneumothorax.
To determine whether atelectasis might modify lung surfactant, we injected N2 into the right pleural space of adult rabbits. Daily, under sedation, pleural gas volume and pressure were measured and adjusted to 20 ml/kg and 0 to +2 cm H2O with N2. On the sixth day, pHa, PaCO2, PaO2, and FRC were measured. Pressure-volume diagrams or bronchoalveolar lavages (BAL) were performed separately on right and left lungs. Surfactant subfractions were obtained from BAL fluid, and total protein, LDH, and cell counts were determined. Phospholipid (PL) was assayed in lung homogenate, BAL fluid, and subfractions, and PL composition was determined on the largest BAL subfraction (P4). On the sixth day the pleural gas volume was 19.7 +/- 2.7 (SD) ml/kg, and PaO2 and FRC were significantly decreased. Air volume in excised right lungs at 30 cm H2O was 13.1 +/- 2.8 (SE) ml/kg with pneumothorax (PN) and 22.8 +/- 1.9 (SE) ml/kg in controls. Total PL was decreased 43% in BAL and 59% in P4 of collapsed lungs. Phosphatidylglycerol to phosphatidylinositol (PI) plus phosphatidylserine (PS) ratio of P4 was substantially decreased in both lungs of PN animals. Cell counts, LDH, and protein in BAL did not suggest inflammation or epithelial damage. We conclude that pneumothorax decreases the quantity of alveolar surfactant in the collapsed lung and alters its phospholipid composition toward the fetal pattern in both lungs, possibly due in part to the proliferative response of the lungs to pneumothorax.