Citations

AbstractThe Edmonston vaccine strain of measles virus (MV-Edm) propagates efficiently in a broad range of human tumor cells, killing them selectively. However, the oncolytic potency of MV-Edm in different human tumor xenograft therapy models is highly variable and there is no convenient way to map the distribution of virus-infected tissues in vivo. To enhance the oncolytic potency of MV-Edm against radiosensitive malignancies and to facilitate noninvasive imaging of infected tissues, we generated a recombinant MV-Edm encoding the human thyroidal iodide symporter (NIS). MV-NIS replicated almost as efficiently as unmodified MV-Edm, and human tumor cells efficiently concentrated radioiodine when infected with MV-NIS. Intratumoral spread of MV-NIS was noninvasively demonstrated by serial gamma-camera imaging of iodine-123 (123I) uptake both in MV-sensitive KAS-6/1 myeloma xenografts, which regressed completely after a single intravenous dose of MV-NIS, and in MM1 myeloma xenografts, which were unresponsive to MVNIS therapy. However, MV-resistant MM1 tumors regressed completely when 131I was administered 9 days after a single intravenous injection of MV-NIS (radiovirotherapy). 131I alone had no effect on MM1 tumor growth. While the potential hematopoietic toxicity of this new therapy requires further evaluation, image-guided radiovirotherapy is a promising new approach to the treatment of multiple myeloma, an incurable but highly radiosensitive plasma cell malignancy. Testing in other radiosensitive cancers is warranted.

ABSTRACT Canine distemper virus (CDV) infects many carnivores, including ferrets and dogs, and is the member of the Morbillivirus genus most easily amenable to experimentation in a homologous small-animal system. To gain insights into the determinants of CDV pathogenesis, we isolated a strain highly virulent for ferrets by repeated passaging in these animals. Sequence comparison of the genome of this strain with that of its highly attenuated precursor revealed 19 mutations distributed almost evenly in the six genes. We then recovered a virus from a cDNA copy of the virulent CDV strain's consensus sequence by using a modified reverse genetics system based on B cells. We infected ferrets with this virus and showed that it fully retained virulence as measured by the timing of rash appearance, disease onset, and death. Body temperature, leukocyte number, lymphocyte proliferation activity, and cell-associated viremia also had similar kinetics. We then addressed the question of the relative importance of the envelope and other viral constituents for virulence. Viruses in which the envelope genes (matrix, fusion, and hemagglutinin) of the virulent strain were combined with the other genes of the attenuated strain caused severe rash and fever even if the disease onset was delayed. Viruses in which the nucleocapsid, polymerase, and phosphoprotein genes (coding also for the V and C proteins) of the virulent strain were combined with the envelope genes of the attenuated strain caused milder signs of disease. Thus, virulence-inducing mutations have accumulated throughout the genome.

Background Prevention of thromboembolic complications after elective lower extremity arthroplasty has increasingly relied on routine thromboprophylaxis in all patients. Not all patients are at equal risk, however, and prophylaxis is not devoid of complications. The aim of this study was to examine the risk factors for clinically relevant pulmonary embolism and deep venous thrombosis after elective primary hip or knee arthroplasty in a large patient population. Methods During the 10-yr study period, 116 of 9,791 patients undergoing primary hip or knee arthroplasty at the authors' institution who experienced pulmonary embolism or deep venous thrombosis within 30 days of surgery were matched at a 1:1 ratio with patients undergoing the same surgery with the same surgeon who did not experience an adverse event. Medical records were reviewed, with data abstracted using a standardized data collection form. Results Increased body mass index (P = 0.031; odds ratio = 1.5 for each 5-kg/m2 increase) and American Society of Anesthesiologists physical status classification of 3 or greater (P = 0.005; odds ratio = 2.6) were found to independently increase the likelihood of pulmonary embolism or deep venous thrombosis. In addition, use of antithrombotic prophylaxis was found to decrease the likelihood of these thromboembolic events (P = 0.050; odds ratio = 0.2 for aspirin or subcutaneous heparin, and odds ratio = 0.4 for warfarin or low-molecular-weight heparin). Conclusions In patients undergoing primary elective lower extremity arthroplasty, obesity, poor American Society of Anesthesiologists physical status classification, and lack of thromboprophylaxis are independent risk factors for clinically relevant thromboembolic events.

Background Rapid recovery and weaning from ventilatory support and cardiovascular stability are suggested advantages of isoflurane inhalation, in concentrations ranging from 0.1 to 0.6 vol%, for long-term sedation in mechanical ventilated patients. This study was designed to determine whether isoflurane in low concentrations impairs pulmonary gas exchange by increasing ventilation and perfusion (V(A)/Q) mismatch during lung injury. Methods Fourteen anesthetized dogs received in random order 0, 0.25, or 0.5 vol% end-tidal isoflurane before and after induction of lung injury with oleic acid. Gas exchange was assessed by blood gas analysis and by estimating the V(A)/Q distributions using the multiple inert gas elimination technique. Results Administration of oleic acid produced a lung injury with severe V(A)/Q mismatch and 38 +/- 4% intrapulmonary shunting of blood. During lung injury, isoflurane accounted for a dose-related increase in blood flow to shunt units from 38 +/- 4 to 42 +/- 3 (0.25 vol%) and 48 +/- 4% (0.5 vol%) (P < 0.05), dispersion pulmonary blood flow distribution from 0.94 +/- 0.07 to 1.01 +/- 0.09 (0.25 vol%) and 1.11 +/- 0.11% (0.5 vol%) (P < 0.05), and a decrease in perfusion of normal V(A)/Q units from 58 +/- 5 to 55 +/- 4 (0.25 vol%) and 50 +/- 4% (0.5 vol%) (P < 0.05) (mean +/- SE). Isoflurane decreased arterial oxygen partial pressure from 72 +/- 4 to 62 +/- 4 mmHg (0.25 vol%) and 56 +/- 4 mmHg (0.5 vol%) (P < 0.05) and oxygen delivery from 573 +/- 21 to 529 +/- 19 ml. kg. min (0.25 vol%) and 505 +/- 22 ml. kg. min (0.5 vol%) (P < 0.05). Gas exchange, perfusion of shunt and normal V(A)/Q units, and pulmonary blood flow distribution was similar in absence of lung injury with and without isoflurane. Isoflurane 0.5 vol% lowered cardiac output during all conditions (P < 0.05). CONCLUSIONS Inhalation of low concentrations of isoflurane contributed to increased V(A)/Q mismatch and decreased systemic blood flow and oxygen delivery in mechanically ventilated animals with injured lungs.

Background Recently, various studies have questioned the efficacy of intraoperative acute normovolemic hemodilution (ANH) in reducing bleeding and the need for allogeneic transfusions in cardiac surgery. The aim of the present study was to reevaluate the effects of a low-volume ANH in elective, adult open-heart surgery. Methods Two hundred four consecutive adult patients undergoing cardiac surgery were prospectively randomized in a nonblinded manner into two groups: ANH group (103 patients), where 5-8 ml/kg of blood was withdrawn before systemic heparinization and replaced with colloid solutions, and a control group, where no hemodilution was performed (101 patients). Procedures included single and multiple valve surgery, aortic root surgery, coronary surgery combined with valve surgery, or partial left ventriculectomy. The purpose of the study was to evaluate the efficacy of ANH in reducing the need for allogeneic blood components. Routine hematochemical evaluations, perioperative blood loss, major complications, and outcomes were also recorded. Results No differences were found between the groups regarding demographics, baseline hematochemical data, and operative characteristics. There was no difference in the amount of transfusions of packed red cells, fresh frozen plasma, platelet concentrates, total number of patients transfused (control group, 36% vs. ANH group, 34.3%; P = 0.88), and amount of postoperative bleeding (control group, 412 ml [313-552 ml] vs. ANH group, 374 ml [255-704 ml]) (median [25th-75th percentiles]); P = 0.94. Further, perioperative complications, postoperative hematochemical data, and outcomes were not different. Conclusions In patients undergoing elective open-heart surgery, low-volume ANH showed lack of efficacy in reducing the need for allogeneic transfusions and postoperative bleeding.