A promising technique for transplantation of bone marrow-derived endothelial progenitor cells into rat heart.

OBJECTIVE: To investigate the feasibility of intracoronary application of endothelial progenitor cells and the subsequent distribution within the heart. METHODS: Endothelial progenitors cells (EPCs) cultured from rat bone marrow were identified by double-positive staining with Dil-Ac-LDL and BS1-lectin. Twenty-four hours before cell transplantation, EPCs were labeled with 5-bromo-2'-deoxyuridine (BrdU). Cells (5 x 10(5) in 250-microl medium) were injected into healthy rats, either as intracoronary application (n=11) or as intramyocardial injection (n = 6). At 15 min or 3 days posttransplantation, hearts as well as other organs (lung, liver, kidney, and spleen) were collected and processed for subsequent BrdU immunohistochemistry. The number of BrdU-positive cells per tissue area was counted. RESULTS: Compared to intramyocardial injection, intracoronary administration resulted in more than twice as much positive cells in the heart (P < .05), with no local differences within the heart. Whereas after 15 min, EPCs were equally distributed in all examined organs (except for the spleen), cells that were still present after 3 days, approximately 10%, were selectively restricted to the heart. CONCLUSIONS: Our data indicate that the intracoronary application provides a promising technique for EPC transplantation in the rat heart.     

Dietary sodium restriction specifically potentiates left ventricular ACE inhibition by zofenopril, and is associated with attenuated hypertrophic response in rats with myocardial infarction.

INTRODUCTION: In patients with myocardial infarction (MI)-induced heart failure, angiotensin-converting enzyme (ACE) inhibitors are proven effective therapy in inhibiting the progression towards overt heart failure. However, the prognosis in these patients is still very poor, and optimisation of therapy is warranted. The antihypertensive and renoprotective effects of ACE inhibitors (ACE-Is) can be substantially enhanced by dietary sodium restriction. In line with the latter, the aim of the present study was to explore whether dietary sodium restriction enhances the efficacy of ACE-I after MI. METHODS: Rats with MI-induced left ventricular (LV) dysfunction received ACE-I therapy with zofenopril (5.5 mg/kg/day orally), with or without dietary sodium restriction. ACE activity was measured in non-infarcted LV tissue, kidneys and plasma. Effects on cardiac hypertrophy were examined by means of organ weight/body weight ratios. After blood pressure (BP) measurements, functional consequences of therapy were evaluated as LV pressure development in isolated perfused hearts. RESULTS: Dietary sodium restriction alone had no effect on any of the measured parameters, whereas zofenopril alone significantly reduced plasma and kidney ACE activity, but not LV ACE activity, nor LV weight/body weight ratio. However, only when ACE-I therapy was combined with dietary sodium restriction was LV ACE activity significantly reduced. This effect was paralleled by inhibition of LV hypertrophy. BP was reduced after infarction, and further reduced by zofenopril, but not affected by dietary sodium. Neither treatment was associated with effects on the MI-induced reduction of LV function in vitro. CONCLUSIONS: Effects of ACE inhibition with zofenopril can be potentiated by additional dietary sodium restriction. However, these effects were tissue-specific, since LV, but not kidney or plasma, ACE activity was affected by the additional dietary sodium restriction. Effects on LV ACE activity were paralleled by reduced LV hypertrophy. Since the measured parameters did not indicate any adverse side-effects, dietary sodium restriction may provide a safe strategy to improve ACE-I efficacy in patients with infarction-induced LV dysfunction.     

Joint distraction results in clinical and structural improvement of haemophilic ankle arthropathy: a series of three cases

Summary. The incidence of haemophilic arthropathy in multiple joints decreased due to treatment with clotting factor. Nowadays patients are enabled to live a rather normal life, resulting in more (sports) trauma-induced arthropathy in isolated joints like the ankle. As surgical treatment options, fusion of the tibiotalar joint and total ankle replacement are available. Both standard treatments have complications and therefore an alternative treatment is desired. In this study, treatment of haemophilic ankle arthropathy with joint distraction was explored. Three patients with haemophilic ankle arthropathy were treated with joint distraction using an Ilizarov external fixator. Clinical outcomes like function, participation and pain were evaluated in retrospect with three different questionnaires: haemophilia activities list, impact on participation and autonomy and the Van Valburg questionnaire. Structural changes were assessed blinded on X-ray by the Pettersson score and ankle images digital analysis (AIDA) and by an MRI score. All three patients were very satisfied with the clinical outcome of the procedure. They reported a clear improvement for self-perceived functional health, participation in society and autonomy and pain. Partial ankle joint mobility was preserved in the three patients. The Pettersson score remained the same in one patient and slightly improved in the two other patients, while joint space width measured by AIDA and the MRI score demonstrated improvement for all three patients after ankle distraction. This study suggests that joint distraction is a promising treatment for individual cases of haemophilic ankle arthropathy, without additional risk of bleedings during treatment.     

Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats

Evidence is increasing that therapeutic modulation of neurohormonal activation with vasopressin receptor antagonists via V(1A) and V(2) receptors may favourably affect prognosis of heart failure. This study was designed to compare in vivo hemodynamic effects of early treatment (1-21 days after infarction) with a V(1A) (SR-49059 or ((2S)1-[(2R3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide); 0.3 mg/kg/day) and a V(2) (SR-121463B or (1-[4-(N-tert-Butylcarbamoyl)-2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethyoxy)-cyclo-hexane]indol-2one,furmate; 0.5 mg/kg/day) receptor antagonist in myocardial infarcted rats, chronically instrumented for hemodynamic measurements. Left ventricular dysfunction in conscious myocardial infarcted rats, which was evidenced by a significantly decreased cardiac output (myocardial infarction: 70+/-3 vs. sham: 81 +/- 3 ml/min) and stroke volume (myocardial infarction: 190 +/- 10 vs. sham: 221 +/- 7 microl), was restored by the vasopressin V(1A) (81+/-2 ml and 224 +/- 5 microl, respectively) but not V(2) receptor antagonist. Improved cardiac output with the vasopressin V(1A) receptor antagonist resulted from an increased stroke volume at a reduced myocardial infarction induced tachycardia. In addition to the hemodynamic measurements, left ventricular hypertrophy and capillary density were determined, histologically measured as the cross-sectional area of Gomori-stained myocytes and Lectin-stained capillaries per tissue area, respectively. The observed left ventricular concentric hypertrophy (myocardial infarction: 525 +/- 38 vs. sham: 347 +/- 28 microm(2); P < 0.05) and reduced capillary density (myocardial infarction: 2068 +/- 162 vs. sham: 2800 +/- 250 number/mm(2); P<0.05) in the spared myocardium of myocardial infarcted rats, remained unaffected by the vasopressin V(1A) or V(2) receptor antagonist. Thus, chronic vasopressin V(1A) but not V(2) receptor blockade prevents heart failure in 3-week-old infarcted rats. Moreover, the improved cardiac function could not attributed to changes in left ventricular hypertrophy and/or capillary density.     

Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923.

PURPOSE: To assess the impact on survival of increasing dose-intensity (DI) of cyclophosphamide, doxorubicin, and etoposide (CDE) in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Previously untreated SCLC patients were randomized to standard CDE (cyclophosphamide 1,000 mg/m(2) and doxorubicin 45 mg/m(2) on day 1, and etoposide 100 mg/m(2) on days 1 to 3 every 3 weeks, for five cycles) or intensified CDE (cyclophosphamide 1,250 mg/m(2) and doxorubicin 55 mg/m(2) on day 1, and etoposide 125 mg/m(2) on days 1 to 3 with granulocyte colony-stimulating factor [G-CSF] 5 micro g/kg/d on days 4 to 13 every 2 weeks, for four cycles). Projected cumulative dose was almost identical on the two arms, whereas projected DI was nearly 90% higher on the intensified arm. Two hundred forty-four patients were enrolled. The first 163 patients were also randomized (2 x 2 factorial design) to prophylactic antibiotics or placebo to assess their impact on preventing febrile leukopenia (FL). This report focuses on chemotherapy DI results. RESULTS: With a median follow-up of 54 months, 216 deaths have occurred. Actually delivered DI on the intensified arm was 70% higher than on the standard arm. Intensified CDE was associated with more grade 4 leukopenia (79% v 50%), grade 4 thrombocytopenia (44% v 11%), anorexia, nausea, and mucositis. FL and number of toxic deaths were similar on the two arms. The objective response rate was 79% for the standard arm and 84% for the intensified arm (P =.315). Median survival was 54 weeks and 52 weeks, and the 2-year survival rates were 15% and 18%, respectively (P =.885). CONCLUSION: A 70% increase of CDE actual DI does not translate into an improved outcome in SCLC patients.     

Beneficial effects of add-on hydrochlorothiazide in rats with myocardial infarction optimally treated with quinapril

BACKGROUND: The antihypertensive and renoprotective effects of ACE inhibitor (ACEi) therapy are enhanced by inducing a negative sodium balance. Whether this strategy also improves outcome of chronic ACEi treatment after myocardial infarction (MI) is unknown. Therefore, we investigated whether hydrochlorothiazide (HCTZ) or dietary sodium restriction further improves survival in ACEi-treated rats with MI. METHODS: MI was induced by coronary ligation. After 2 weeks rats were randomised to quinapril (QUI), HCTZ added to quinapril (QUI+HCTZ), or low sodium diet added to quinapril (QUI+LS). Survival was monitored for 62 weeks, after which left ventricular (LV) pressures were measured and blood for neurohumoral characterisation was collected. A separate group of rats, subjected to the same procedure, was evaluated after 35 weeks. RESULTS: After 62 weeks, mortality was comparable in all groups. However, survival was improved by HCTZ until 35 weeks. This effect on survival was paralleled by decreased proteinuria and LV end-diastolic pressures in QUI+HCTZ rats at 35, but not 62 weeks. Plasma renin activity was significantly decreased in QUI+HCTZ rats at 35 weeks. Contrary to HCTZ, LS added to QUI caused no benefit. CONCLUSIONS: Adding HCTZ, but not LS, to quinapril improved survival, neurohumoral status, and proteinuria during the early chronic phase of experimental post-MI LV dysfunction. Since no adverse effects were observed, HCTZ may safely be used to improve ACEi therapy.     

Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction

OBJECTIVES: We assessed the effects of erythropoietin (EPO) treatment in a rat model of post-myocardial infarction (MI) heart failure. BACKGROUND: Erythropoietin, traditionally known as a hematopoietic hormone, has been linked to neovascularization. Whereas administration of EPO acutely after MI reduces infarct size and improves cardiac function, its role in the failing heart is unknown. METHODS: Rats underwent coronary ligation or sham surgery. Rats with MI were randomly assigned to: untreated (MI), a single bolus of EPO immediately after MI induction (MI-EPO-early), EPO treatment immediately after MI and once every three weeks (MI-EPO-early+late), and EPO treatment starting three weeks after induction of MI, once every three weeks (MI-EPO-late). After nine weeks, hemodynamics, infarct size, myosin heavy chain (MHC) isoforms, myocyte hypertrophy, and capillary density were measured. RESULTS: Erythropoietin treatment started immediately after MI (MI-EPO-early and MI-EPO-early+late) resulted in a 23% to 30% reduction in infarct size (p < 0.01) and, accordingly, hemodynamic improvement. Erythropoietin treatment, started three weeks after MI (MI-EPO-late), did not affect infarct size, but resulted in an improved cardiac performance, reflected by a 34% reduction in left ventricular end-diastolic pressure (p < 0.01), and 46% decrease in atrial natriuretic peptide levels (p < 0.05). The improved cardiac function was accompanied by an increased capillary density (p < 0.01), an increased capillary-to-myocyte ratio (p < 0.05), and a partial reversal of beta-MHC (p < 0.05) in all treated groups. CONCLUSIONS: In addition to its effect on infarct size reduction, EPO treatment improves cardiac function in a rat model of post-MI heart failure. This observation may be explained by neovascularization, associated with an increased alpha-MHC expression.     

The value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography in the selection of patients with stage IIIA-N2 non-small cell lung cancer for combined modality treatment

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.     

Hodgkin's disease presenting as a parasternal chest wall mass.

A 53 year-old Moroccan woman presented with a tender parasternal mass. Computerized tomography showed a mediastinal mass protruding through the sternum. Cytologic examination of fluid collected from the mass repeatedly showed acute inflammation. Tuberculostatics were started. Since patient did not improve on tuberculostatics, a small supraclavicular lymph node was removed. Histologic examination showed Morbus Hodgkin of the nodular sclerosing type. Ultimately, cytologic examination of fluid from the parasternal mass showed atypical cells. Response on chemotherapy was excellent with complete disappearance of the parasternal mass. This is a very unusual extranodal presentation of Hodgkin's disease.