Bone marrow cell therapy prevents infarct expansion and improves border zone remodeling after coronary occlusion in rats

Background: Since the cell therapy benefits for myocardial infarction are mainly related to infarct reduction by regenerating lost myocardium or increasing survival of tissues at risk, we evaluated the effects of bone marrow-derived mononuclear cells (MNC), implanted after the completion of necrosis, on infarct progression and cardiac remodeling. Methods: After 48 h of induction of myocardial infarction (MI), Lewis-inbred rats were injected with 6 x 10(6) cells (MI + MNC) or saline (MI). After six weeks, scar dimension, ventricular morphology and function were analyzed by echocardiography followed by histomorphology of the infarcted and border zones. Results: After therapy, the relative size of the infarct was smaller in MI + MNC (37 +/- 1% of the left ventricle) than in MI (43 +/- 1%). While the MI group exhibited parallel elongation of the infarcted (31.6 +/- 3.8% increase) and reminiscent ventricular portions (33.5 +/- 3.7%), MNC therapy preserved the initial infarct length. Infarcted walls were thicker (979 +/- 31 mm) in the MNC group than in the untreated group (709 +/- 41 mm), also demonstrating an absence of infarct expansion. In the border zones, MNC led to increased capillary densities and capillary/myocyte ratios. The cardiac systolic function remained depressed in MI, but improved by 19 +/- 5% in MI + MNC which reduced the incidence of pulmonary arterial hypertension (37.5% in MI and 6.25% in MI + MNC). Conclusion: MNC therapy prevented the infarct expansion and thinning related to cardiac remodeling and was associated with an improvement of border zone microcirculation: as a result, MNC therapy reduced typical MI dysfunctional repercussions. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Clinical profile of patients enroled in a cell therapy trial for severe coronary artery disease

Aims and objectives. To compare the clinical profile of patients included in a clinical trial of autologous bone marrow cells as an adjunctive therapy to coronary artery bypass grafting with that of patients undergoing routine coronary artery bypass grafting. Background. The therapeutic potential of autologous bone marrow cells has been explored in the treatment of severe coronary artery disease. There are few data regarding the clinical and socio-economic profile of patients included in clinical trials using bone marrow cell. Design. Case-control study. Method. Sixty-seven patients (61 SD 9) years, 82% men) with multivessel coronary artery disease were divided into two groups: patients in the bone marrow cell group (n = 34) underwent incomplete coronary artery bypass grafting + intramyocardial injection of autologous bone marrow cells (lymphomonocytic fraction -2.0 (SD 0.2 x 108) cells/patient) in the ischaemic, non-revascularised myocardium, whereas patients in the coronary artery bypass grafting group (n = 33) underwent routine bypass surgery. Demographics, socio-economic status, clinical and echocardiographic data were collected. Statistical analysis included the Fisher`s exact test (categorical variables) and the Student`s t-test (continuous variables). Results. There were no significant differences between groups regarding age, gender, BMI, heart rate, blood pressure and echo data. There was a greater prevalence of obesity (65 vs. 33%; OR = 3.7 [1.3-10.1]), of previous myocardial infarction (68 vs. 39%; OR = 3.2 [1.2-8.8]) and prior revascularisation procedures (59 vs. 24%; OR = 4.5 [1.6-12.7]) in the autologous bone marrow cells group and of smokers in the coronary artery bypass grafting group (51 vs. 23%; OR = 3.5 [1.2-10.4]). Conclusions. Patients included in this clinical trial of autologous bone marrow cells for severe coronary artery disease presented a greater prevalence of myocardial revascularisation procedures, indicating a more severe clinical presentation of the disease. Fewer smokers in this group could be attributable to life style changes after previous cardiovascular events and/or interventions. Relevance to clinical practice. The knowledge of the clinical profile of patients included in cell therapy trials may help researchers in the identification of patients that may be enroled in future clinical trials of this new therapeutic strategy.

beta-Blocker Therapy and Mortality of Patients With Chagas Cardiomyopathy A Subanalysis of the REMADHE Prospective Trial

Background-Peculiar aspects of Chagas cardiomyopathy raise concerns about efficacy and safety of sympathetic blockade. We studied the influence of beta-blockers in patients with Chagas cardiomyopathy. Methods and Results-We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and beta-blocker therapy. Primary end point was all-cause mortality or heart transplantation. Altogether 456 patients were studied; 27 (5.9%) were submitted to heart transplantation and 202 (44.3%) died. Chagas etiology was present in 68 (14.9%) patients; they had lower body mass index (24.1+/-4.1 versus 26.3+/-5.1, P=0.001), smaller end-diastolic left ventricle diameter (6.7+/-1.0 mm versus 7.0+/-0.9 mm, P=0.001), smaller proportion of beta-blocker therapy (35.8% versus 68%, P<0.001), and higher proportion of spironolactone therapy (74.6% versus 57.8%, P=0.003). Twenty-four (35.8%) patients with Chagas disease were under beta-blocker therapy and had lower serum sodium (136.6+/-3.1 versus 138.4+/-3.1 mEqs, P=0.05) and lower body mass index (22.5+/-3.3 versus 24.9+/-4.3, P=0.03) compared with those who received beta-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under beta-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with beta-blockers was higher than that of patients without beta-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P=0.009) and beta-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P=0.044) were associated with better survival. Conclusions-Our study suggests that beta-blockers may have beneficial effects on survival of patients with heart failure and Chagas heart disease and warrants further investigation in a prospective, randomized trial.

Refractory Angina Cell Therapy (ReACT) Involving Autologous Bone Marrow Cells in Patients Without Left Ventricular Dysfunction: A Possible Role for Monocytes

Autologous bone marrow mononuclear cell (BMMC) transplantation has emerged as a potential therapeutic option for refractory angina patients. Previous studies have shown conflicting myocardium reperfusion results. The present study evaluated safety and efficacy of CellPraxis Refractory Angina Cell Therapy Protocol (ReACT). in which a specific BMMC formulation was administered as the sole therapy for these patients. The phase I/IIa noncontrolled, open label. clinical trial, involved eight patients with refractory angina and viable ischemic myocardium, without left ventricular dysfunction and who were not suitable for conventional myocardial revascularization. ReACT is a surgical procedure involving a single series of multiple injections (40-90 injections, 0.2 ml each) into ischemic areas of the left ventricle. Primary endpoints were Canadian Cardiovascular Society Angina Classification (CCSAC) improvement at 18 months follow-up and myocardium ischemic area reduction (assessed by scintigraphic analysis) at 12 months follow-up, in correlation with a specific BMMC formulation. Almost all patients presented progressive improvement in angina classification beginning 3 months (p = 0.008) postprocedure which was sustained at 18 months follow-up (p = 0.004), as well as objective myocardium ischemic area reduction at 12 months (decrease of 84.4%, p < 0.004). A positive correlation was found between monocyte concentration and CCSAC improvement (r = -0.759, p < 0.05). Improvement in CCSAC, followed by correlated reduction in scintigraphic myocardium ischemic area, strongly suggests neoangiogenesis as the main stem cell action mechanism. The significant correlation between number of monocytes and improvement strongly supports a cell-related effect of ReACT. ReACT appeared safe and effective.

Outpatient Radioiodine Therapy for Thyroid Cancer A Safe Nuclear Medicine Procedure

Purposes: To evaluate the dosimetric effect of outpatient radioiodine therapy for thyroid cancer in members of a patient`s family and their living environment, when using iodine-131 doses reaching 7.4 GBq. The following parameters were thus defined: (a) whole-body radiation doses to caregivers, (b) the production of contaminated solid waste, and (c) radiation potential and surface contamination within patients` living quarters. Methods: In total, 100 patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation safety guidelines. Both the caregivers and the radiation dose potentiality inside patients` residences were monitored by using thermoluminescent dosimeters. Surface contamination and contaminated solid wastes were identified and measured with a Geiger-Muller detector. Results: A total of 90 monitored individuals received a mean dose of 0.27 (+/- 0.28) mSv, and the maximum dose registered was 1.6 mSv. The mean value for the potential dose within all living quarters was 0.31(+/- 0.34) mSv, and the mean value per monitored surface was 5.58 Bq/cm(2) for all the 1659 points measured. The overall production of contaminated solid wastes was at a low level, being about 3 times less than the exemption level indicated by the International Atomic Energy Agency. Conclusions: This study indicates that the treatment of thyroid cancer by applying radioiodine activities up to 7.4 GBq, on an outpatient basis, is a safe procedure, especially when supervised by qualified professionals. This alternative therapy should be a topic for careful discussion considering the high potential for reducing costs in healthcare and improving patient acceptance.

Double-blind, Randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: Results from EFECT

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR +) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR + advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane ( n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups ( hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate ( 7.4% v 6.7%; P = .736) and clinical benefit rate ( 32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Endostatin- and interleukin-2-expressing retroviral bicistronic vector for gene therapy of metastatic renal cell carcinoma

Background Metastatic renal cell carcinoma (mRCC) is one of the most treatment-resistant malignancies. Despite all new therapeutic advances, almost all patients develop resistance to treatment and cure is rarely seen. In the present study, we evaluated the antitumor effect of a bicistronic retrovirus vector encoding both endostatin (ES) and interleukin (IL)-2 using an orthotopic metastatic RCC mouse model. Methods Balb/C-bearing Renca cells were treated with NIH/3T3-LendIRES-IL-2-SN cells. In the survival studies, mice were monitored daily until they died. At the end of the in vivo experiment, serum levels of IL-2 and ES were measured, the lung was weighed, and the number of metastatic nodules, nodule area, tumor vessels and proliferation of tumor-infiltrating Renca cells were determined. Results Inoculation of NIH/3T3-LendIRES-IL-2-SN cells resulted in an increase in ES and IL-2 levels in the treated group (p < 0.05). There was a significant decrease in lung wet weight, lung nodule area and tumor vessels in the treated group compared to the control group (p < 0.001). The proliferation of Renca cells in the bicistronic-treated group was significantly reduced compared to the control group (p < 0.05). Kaplan-Meier survival curves showed that the probability of survival was significantly higher for mice submitted to bicistronic therapy (log-rank test, p = 0.0016). Bicistronic therapy caused an increase in the infiltration of CD4, CD4 interferon (IFN)gamma-producing, CD8, CD8 IFN gamma-producing and natural killer (CD49b) cells. Conclusions Retroviral bicistronic gene transfer led to the secretion of functional ES and IL-2 that was sufficiently active to: (i) inhibit tumor angiogenesis and tumor cell proliferation and (ii) increase the infiltration of immune cells (C) Copyright. 2011 John Wiley & Sons, Ltd.

IMAGE QUANTIFICATION FOR RADIATION DOSE CALCULATIONS-LIMITATIONS AND UNCERTAINTIES

Radiation dose calculations in nuclear medicine depend on quantification of activity via planar and/or tomographic imaging methods. However, both methods have inherent limitations, and the accuracy of activity estimates varies with object size, background levels, and other variables. The goal of this study was to evaluate the limitations of quantitative imaging with planar and single photon emission computed tomography (SPECT) approaches, with a focus on activity quantification for use in calculating absorbed dose estimates for normal organs and tumors. To do this we studied a series of phantoms of varying complexity of geometry, with three radionuclides whose decay schemes varied from simple to complex. Four aqueous concentrations of (99m)Tc, (131)I, and (111)In (74, 185, 370, and 740 kBq mL(-1)) were placed in spheres of four different sizes in a water-filled phantom, with three different levels of activity in the surrounding water. Planar and SPECT images of the phantoms were obtained on a modern SPECT/computed tomography (CT) system. These radionuclides and concentration/background studies were repeated using a cardiac phantom and a modified torso phantom with liver and ""tumor"" regions containing the radionuclide concentrations and with the same varying background levels. Planar quantification was performed using the geometric mean approach, with attenuation correction (AC), and with and without scatter corrections (SC and NSC). SPECT images were reconstructed using attenuation maps (AM) for AC; scatter windows were used to perform SC during image reconstruction. For spherical sources with corrected data, good accuracy was observed (generally within +/- 10% of known values) for the largest sphere (11.5 mL) and for both planar and SPECT methods with (99m)Tc and (131)I, but were poorest and deviated from known values for smaller objects, most notably for (111)In. SPECT quantification was affected by the partial volume effect in smaller objects and generally showed larger errors than the planar results in these cases for all radionuclides. For the cardiac phantom, results were the most accurate of all of the experiments for all radionuclides. Background subtraction was an important factor influencing these results. The contribution of scattered photons was important in quantification with (131)I; if scatter was not accounted for, activity tended to be overestimated using planar quantification methods. For the torso phantom experiments, results show a clear underestimation of activity when compared to previous experiment with spherical sources for all radionuclides. Despite some variations that were observed as the level of background increased, the SPECT results were more consistent across different activity concentrations. Planar or SPECT quantification on state-of-the-art gamma cameras with appropriate quantitative processing can provide accuracies of better than 10% for large objects and modest target-to-background concentrations; however when smaller objects are used, in the presence of higher background, and for nuclides with more complex decay schemes, SPECT quantification methods generally produce better results. Health Phys. 99(5):688-701; 2010

Endostatin gene therapy enhances the efficacy of IL-2 in suppressing metastatic renal cell carcinoma in mice

We investigated whether the administration of IL-2 combined with endostatin gene therapy was able to produce additive or even synergistic immunomodulatory activity in a mouse model of metastatic renal carcinoma. Renca cells were injected into the tail vein of BALB/c mice. After 24 h, the animals were randomly divided into four groups (5 mice/group). One group of mice was the control, the second group received treatment with 100,000 UI of Recombinant IL-2 (Proleukin, Chiron) twice a day, 1 day per week during 2 weeks (IL-2), the third group received treatment with a subcutaneous inoculation of 3.6 x 10(6) endostatin-producing cells, and the fourth group received both therapies (IL-2 + ES). Mice were treated for 2 weeks. In the survival studies, 10 mice/group daily, mice were monitored daily until they died. The presence of metastases led to a twofold increase in endostatin levels. Subcutaneous inoculation of NIH/3T3-LendSN cells resulted in a 2.75 and 2.78-fold increase in endostatin levels in the ES and IL-2 + ES group, respectively. At the end of the study, there was a significant decrease in lung wet weight, lung nodules area, and microvascular area (MVA) in all treated groups compared with the control group (P < 0.001). The significant difference in lung wet weight and lung nodules area between groups IL-2 and IL-2 + ES revealed a synergistic antitumor effect of the combined treatment (P < 0.05). The IL-2 + ES therapy Kaplan-Meier survival curves showed that the probability of survival was significantly higher for mice treated with the combined therapy (log-rank test, P = 0.0028). Conjugated therapy caused an increase in the infiltration of CD4, CD8 and CD49b lymphocytes. An increase in the amount of CD8 cells (P < 0.01) was observed when animals received both ES and IL-2, suggesting an additive effect of ES over IL-2 treatment. A synergistic effect of ES on the infiltration of CD4 (P < 0.001) and CD49b cells (P < 0.01) was also observed over the effect of IL-2. Here, we show that ES led to an increase in CD4 T helper cells as well as cytotoxic lymphocytes, such as NK cells and CD8 cells, within tumors of IL-2 treated mice. This means that ES plays a role in supporting the actions of T cells.

Low-Level Laser Therapy in Chronic Autoimmune Thyroiditis: A Pilot Study

Background and Objectives: Chronic autoimmune thyroiditis (CAT) remains the most common cause of acquired hypothyroidism There is currently no therapy that is capable of regenerating CAT-damaged thyroid tissue The objective of this study was to gauge the value of applying low-level laser therapy (LLLT) in CAT patients based on both ultrasound studies (USs) and evaluations of thyroid function and thyroid autoantibodies. Study Design/Materials and Methods: Fifteen patients who had hypothyroidism caused by CAT and were undergoing levothyroxine (LT4) treatment were selected to participate in the study Patients received 10 applications of LLLT (830 nm, output power 50 mW) in continuous mode, twice a week, using either the punctual technique (8 patients) or the sweep technique (7 patients), with fluence in the range of 38-108 J/cm(2) USs were performed prior to and 30 days after LLLT USs included a quantitative analysis of echogenicity through a gray-scale computerized histogram index (El). Following the second ultrasound (30 days after LLLT), LT4 was discontinued in all patients and, if required, reintroduced Truodothyronine, thyroxine (T4), free T4, thyrotropin, thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) antibodies levels were assessed before LLLT and then 1, 2, 3, 6, and 9 months after LT4 withdrawal. Results: We noted all patients` reduced LT4 dosage needs, including 7 (47%) who did not require any LT4 through the 9-month follow-up The LT4 dosage used pre-LLLT (96 +/- 22 mu g/day) decreased in the 9th month of follow-up (38 23 mu g/day; P<0.0001) TPOAb levels also decreased (pre-LLLT = 982 +/- 530 U/ml, post-LLLT = 579 454 U/ml, P = 0 016) TgAb levels were not reduced, though we did observe a post-LLLT increase in the EI (pre-LLLT = 0 99 +/- 0.09, post-LLLT= 1.21 +/- 0.19, P=0.001) Conclusion: The preliminary results indicate that LLLT promotes the improvement of thyroid function, as patients experienced a decreased need for LT4, a reduction in TPOAb levels, and an increase in parenchymal echogenicity Lasers Surg. Med. 42:589-596, 2010. (C) 2010 Wiley-Liss, Inc

A mathematical model for Escherichia coli debris size reduction during high pressure homogenisation based on grinding theory

Experimental data for E. coli debris size reduction during high-pressure homogenisation at 55 MPa are presented. A mathematical model based on grinding theory is developed to describe the data. The model is based on first-order breakage and compensation conditions. It does not require any assumption of a specified distribution for debris size and can be used given information on the initial size distribution of whole cells and the disruption efficiency during homogenisation. The number of homogeniser passes is incorporated into the model and used to describe the size reduction of non-induced stationary and induced E. coil cells during homogenisation. Regressing the results to the model equations gave an excellent fit to experimental data ( > 98.7% of variance explained for both fermentations), confirming the model's potential for predicting size reduction during high-pressure homogenisation. This study provides a means to optimise both homogenisation and disc-stack centrifugation conditions for recombinant product recovery. (C) 1997 Elsevier Science Ltd.

Extensive long-standing chromomycosis due to Fonsecaea pedrosoi: Three cases with relevant improvement under voriconazole therapy

Objective: To evaluate voriconazole in the treatment of extensive cases of chromomycosis. Chromomycosis is a chronic infection, which is extremely difficult to eradicate, and is caused by dematiaceous (dark-colored) fungi which affect the skin and subcutaneous tissues, with Fonsecaea pedrosoi being the major etiologic agent. Drugs such as itraconazole, terbinafine, posaconazole and amphotericin B have been employed with variable results. Methods: We treated three Caucasian male patients (ages 44, 57 and 77 years), two were farmers and one a trash collector, with long-standing (20, 10 and 21 years of disease, respectively) and extensive chromomycosis (one lower limb affected, at least) due to Fonsecaea pedrosoi. All patients had received previous therapy with the formerly indicated drugs itraconazole and terbinafine for several months either without or with incomplete response. After that, we started treatment with voriconazole per os 200 mg twice a day. Results: The patients were treated with voriconazole for 12 months until there was clinical and mycological improvement. Clinical response was evident after 30-50 days. One patient developed visual abnormalities and tremors, and the voriconazole was reduced to 200 mg/day without impairment of the clinical and mycological response. The same patient presented photosensitive dermatitis after 12 months of therapy and the voriconazole was stopped. All patients showed elevations of serum gamma-glutamyl transpeptidase (GGT) during the treatment without clinical relevance. Moreover, our three patients obtained partial response with this therapy. Conclusions: This is the first report with a case series of chromomycosis treated with voriconazole. Despite its high cost, voriconazole is a safe and possibly promising drug for use on extensive chromomycosis refractory to conventional treatment.

Cue exposure in moderation drinking: A comparison with cognitive-behavior therapy

To date, the published controlled trials on exposure to alcohol cues have had an abstinence treatment goal. A modification of cue exposure (CE) for moderation drinking, which incorporated priming doses of alcohol, could train participants to stop drinking after 2 to 3 drinks. This study examined the effects of modified CE within sessions, combined with directed homework practice. Nondependent problem drinkers who requested a moderation drinking goal were randomly allocated to modified CE or standard cognitive-behavior therapy (CBT) for alcohol abuse. Both interventions were delivered in 6 90-min group sessions. Eighty-one percent of eligible participants completed treatment and follow-up assessment. Over 6 months, CE produced significantly greater reductions than CBT in participants' reports of drinking frequency and consumption on each occasion. No pretreatment variables significantly predicted outcome, The modified CE procedure appears viable for nondependent drinkers who want to adopt a moderate drinking goal.