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.

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 Recent American Heart Association guidelines highlight the paucity of data on effectiveness and/or mechanisms underlying use of beta-adrenergic receptor (beta AR) antagonists after acute coronary syndromes in patients subsequently undergoing revascularization. It is important to assess whether beta AR antagonists might protect the heart and improve ventricular function in this scenario. The authors therefore used esmolol (an ultra-short-acting beta AR antagonist) to determine whether beta AR antagonist treatment improves left ventricular function in a canine model of acute reversible coronary ischemia followed by coronary reperfusion during cardiopulmonary bypass (CPB). The authors also tested whether the mechanism includes preserved beta AR signaling. Methods Dogs were randomized to either esmolol or saline infusions administered during CPB (n = 29). Pre-CPB and end-CPB transmyocardial left ventricular biopsies were obtained; plasma catecholamine concentrations, myocardial beta AR density, and adenylyl cyclase activity were measured. In addition, left ventricular systolic shortening and postsystolic shortening were determined immediately prior to each biopsy. Results While beta AR density remained unchanged in each group, isoproterenol-stimulated adenylyl cyclase activity decreased 26 +/- 6% in the control group but increased 38 +/- 10% in the esmolol group (pre-CPB to end-CPB, mean +/- SD, P = 0.0001). Left ventricular systolic shortening improved in both groups after release of coronary (LAD) ligature; however, the esmolol group increased to 72 +/- 23% of pre-CPB values compared to 48 +/- 12% for the control group (P = 0.0008). Conclusions These data provide prospective evidence that esmolol administration results in improved myocardial function. Furthermore, the mechanism appears to involve enhanced myocardial beta AR signaling.

Background— β-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Methods and Results— Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol ( r =−0.72, P <0.0001) and was the most significant multivariate predictor of change in LVEF ( P =0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687±333 versus 420±246 pg/mL, P <0.05) and greater decrease in plasma norepinephrine in response to bucindolol (−249±171 versus −35±277 pg/mL, P <0.05). Conclusions— This study suggests a direct relationship between contractile reserve and improvement in LVEF with β-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Abstract Rarely, myelodysplastic syndrome (MDS) is complicated by an acquired form of α-thalassemia (α-thalassemia in myelodysplastic syndrome [ATMDS]) characterized by hypochromic, microcytic, anisopoikilocytic red blood cells with hemoglobin H (HbH) inclusions. Acquired mutations in ATRX, a chromatin remodeling gene, have recently been found in 12 patients with typical features of ATMDS, though they have not been detected in MDS patients with similar red blood cell findings but little HbH. The α-globin genes themselves have appeared normal in all ATMDS patients studied to date. Here we characterize the molecular defect in a unique MDS patient with rare HbH inclusions in which an abnormal clone lost a greater than 1.9-Mb segment of the telomeric region of the short arm of one allele of chromosome 16, including both α-globin genes. Red blood cell changes associated with this acquired somatic genotype (––/αα) are surprisingly severe, demonstrating that a minor globin chain imbalance may be unexpectedly deleterious during the abnormal erythropoiesis that occurs in the context of MDS.

There has been a longstanding debate regarding the role of proteolysis in Huntington's disease. The toxic peptide theory posits that N-terminal cleavage fragments of mutant Huntington's disease protein [mutant huntingtin (mhtt)] enter the nucleus to cause transcriptional dysfunction. However, recent data suggest a second model in which proteolysis of full-length mhtt is inhibited. Importantly, the two competing theories differ with respect to subcellular distribution of mhtt at initiation of toxicity: nuclear if cleaved and cytoplasmic in the absence of cleavage. Using quantitative single-cell analysis and time-lapse imaging, we show here that transcriptional dysfunction is “downstream” of cytoplasmic dysfunction. Primary and reversible toxic events involve destabilization of microtubules mediated by full-length mhtt before cleavage. Restoration of microtubule structure by taxol inhibits nuclear entry and increases cell survival.