Improvement In Global Function Research Articles

A 3-Year, Open-Label, Flexible-Dosing Study of Milnacipran for the Treatment of Fibromyalgia

To evaluate the effects of long-term milnacipran treatment in fibromyalgia patients. Patients completing a previous milnacipran study were eligible to participate in this long-term (up to 3.25 y), open-label study. After washout, dose escalation, and 8 weeks of stable-dose treatment (100 mg/d), patients received flexible doses of milnacipran (50 to 200 mg/d) for the remainder of the study. Safety evaluations included adverse events and vital signs. Clinical measures included weekly recall pain (visual analog scale [VAS]), Patient Global Disease Status (PGDS), and the Short Form-36 Health Survey (SF-36, including the Physical Component Summary [PCS] and Mental Component Summary scores). Cohort analyses were conducted to assess the effects of milnacipran over varying periods of time. Of 1227 patients entering the study, 585 (47.7%) were classified as completers, including 379 (30.9%) patients who were currently enrolled when the study was administratively terminated. Mean duration of treatment was 19 months, with 206 patients reaching the final visit and receiving 36 to 38 months of study treatment. The percentage of patients with ≥1 treatment-emergent adverse event was 88.3%, with nausea (25.9%) and headache (13.4%) being the most common events. Discontinuations due to adverse events occurred in 20.9% of patients. Potentially clinically significant increases in blood pressure or heart rate occurred in ≤1.1% of patients. Mean improvement from baseline in weekly recall VAS pain was 17.6; improvements in global status (PGDS) and physical functioning (SF-36 PCS) were also observed. In all patient cohorts, these improvements were observed by month 3 and remained relatively constant over time. At final study visit in the 3-year cohort, 70.3% of patients rated their overall fibromyalgia as "much improved" or "very much improved." No new safety concerns were identified in this long-term study. Sustained symptom improvements were found in fibromyalgia patients who received up to 3.25 years of milnacipran treatment.

TRANSPLANTATION OF GENETIC MODIFIED STEM CELLS OVEREXPRESSING THERAPEUTIC GROWTH FACTORSFOR THE TREATMENT OF EXPERIMENTAL RAT MYOCARDIAL INFARCTION

We tested the hypothesis that simultaneous transgenic overexpression of a select quartet of growth factors activates diverse signaling pathways for mobilization and participation of various stem/progenitor cells for cardiogenesis in the infarcted heart. IGF-1, VEGF, SDF-1α, and HGF plasmids were synthesized and transfected into rat skeletal myoblasts (SM). Overexpression of growth factors in transfected SM (TransSM) was confirmed by reverse transcription PCR, western blotting, and fluorescence immunostaining. The conditioned medium (CM) from TransSM was cytoprotective for cardiomyocytes following H 2O 2 treatment, promoted a higher transwell migration of HUVEC cells and in vitro tube formation. Intramyocardial transplantation of 1.5×10 6 TransSM in a rat model of acute myocardial infarction induced extensive mobilization of stem/progenitor cells into the infarcted heart on day 7 and improved integration of TransSM in the heart compared to NatSM. Extensive neomyogenesis and angiogenesis with resultant attenuation of infarct size and improvement in global heart function was observed at 8 weeks. In conclusion, simultaneous activation of diverse signaling pathways by overexpression of multiple growth factors caused massive mobilization and homing of stem/progenitor cells from peripheral circulation, the bone marrow, and the heart for accelerated repair of the infarcted myocardium.

Recovery of left ventricular and left atrial mechanics in various entities of aortic stenosis 12 months after TAVI

Transcatheter aortic valve implantation (TAVI) has been shown to improve prognosis of high-risk patients. Data, however, concerning the impact of TAVI on regional and global left atrial (LA) and left ventricular (LV) mechanics in varying entities of severe aortic stenosis (AS) are sparse, particularly in patients with paradoxical low-flow (PLF) AS or with reduced LV ejection fraction (LVEF). This study evaluated the effects of TAVI on LA and LV mechanics in varying entities of AS 12 months after implantation. A total of 54 consecutive patients with severe AS (24 with a normal LVEF and normal flow, 16 with PLF, and 14 with a reduced LVEF) were included. Speckle tracking echocardiography was performed before and 12 months after TAVI to determine LV global and regional longitudinal deformation as well as LA function (reservoir function, conduit phase, and active contraction). In all the three entities of AS, there was a significant improvement in global and regional LV longitudinal function (average global longitudinal strain: -14.1 ± 3.9% at baseline vs. -16.5 ± 4.0% after TAVI, P < 0.001). Interestingly, the beneficial effects were most pronounced in patients with PLF (-14.0 ± 2.9 vs. -17.0 ± 4.4%, P < 0.031). Moreover, the atrial reservoir and conduit function recovered significantly after TAVI in all patients. In conclusion, regardless of the underlying AS entity, TAVI improves global and regional LV and LA mechanics within 12 months.

Quality-of-life impairment after endoluminal locoregional resection and laparoscopic total mesorectal excision

For selected patients with rectal cancer, endoluminal locoregional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to laparoscopic total mesorectal excision (LTME). Few data are available on quality of life (QoL) after LTME and TEM. This study aimed to compare short- and medium-term QoL for T1 rectal cancer patients undergoing LTME or ELRR by TEM. This study investigated 35 patients with T1N0 rectal cancer who underwent TEM (n = 17) or LTME (n = 18). Quality of life was evaluated by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-C38 questionnaires preoperatively and then 1, 6, and 12 months after surgery. Observation 1 month after LTME showed worsening in all items of both questionnaires. After ELRR, the QLQ-CR38 showed worsening of gastrointestinal (p = 0.005) and defecation problems (p = 0.001), and the QLQ-C30 showed worsening of global health status (p = 0.014), physical functioning (p = 0.02) role functioning (p = 0.003), fatigue (p = 0.002), and pain (p = 0.001). The QLQ-CR38 6 months after LTME showed worsening of body image (p = 0.009), micturition (p = 0.035), and gastrointestinal problems (p = 0.011), and the QLQ-C30 showed worsening of physical functioning (p = 0.003), role functioning (p = 0.002), fatigue (p = 0.004), and nausea/vomiting (p = 0.030). After ELRR, neither the QLQ-CR38 nor the QLQ-C30 questionnaire showed any worsening but demonstrated improvement in global health status and physical functioning. The QLQ-CR38 12 months after LTME showed significant improvement in defecation problems (p = 0.004) and weight loss (p = 0.003), and the QLQ-C30 showed significant improvement in global health status (p = 0.001), nausea and vomiting (p = 0.003), and pain (p = 0.005). After ELRR, the QLQ-C30 showed improvement in emotional functioning (p = 0.012), whereas no significant difference was observed by the QLQ-C38. Functional sequelae are present up to 1 month only after ELRR by TEM and up to 6 months after LTME. At 12 months, neither procedure showed a significant difference in QoL compared with preoperative status.

Recovery of left ventricular systolic function in different entities of aortic stenosis 12 months after TAVI

Background: TAVI improves prognosis of high-risk patients. However, data concerning the impact of TAVI on regional and global LV mechanics in varying entities of severe AS are sparse, particularly in patients with paradoxical low flow aortic stenosis (PLF) or with reduced Left Ventricular Ejection Fraction (LVEF). This study evaluated the effects of Transcatheter Aortic Valve Implantation (TAVI) on Left Ventricular (LV) mechanics in varying entities of aortic stenosis (AS) 12 months after implantation. Methods: A total of 54 consecutive patients with severe AS (24 with normal LVEF and normal flow, 16 with PLF, and 14 with reduced LVEF) were included. Normal LVEF and normal flow were defined as LVEF ≥ 50% and SVI ≥ 35 ml/m2. Paradoxical low flow was defined as LVEF ≥ 50% and SVI < 35 ml/m2 and patients with reduced LVEF, as LVEF < 50%. Speckle tracking echocardiography was performed before and 12 months after TAVI to determine LV global and regional longitudinal deformation. Results: In three entities of AS, there was significant improvement of global and regional LV longitudinal function (global longitudinal strain: -14.1±3.9% at baseline vs. -16.5±4.0% after TAVI, P < 0.001). Interestingly, the beneficial effects were most pronounced in patients with PLF (-14.0±2.9% vs. -17.0±4.4%, P < 0.031) but was significant in all subgroups: normal EF (-16.1±3.4% vs. -18.1±3.3%, P = 0.012) and reduced EF (-10.5±3.1% vs. -13.5±3.2%, P = 0.026). ![Figure][1] Bull's-eye diagram Conclusion: Regardless of the underlying AS entity, TAVI improves global and regional left ventricular mechanics within 12 months. This improvement is more pronounced in patients with PLF. [1]: pending:yes

Prediction of global and segmental functional changes after acute myocardial infarction by 2D speckle-tracking echocardiography and cardiac magnetic resonance imaging

Purpose: Myocardial deformation analysis by 2-dimensional (2D) speckle-tracking echocardiography (STE) has been shown to accurately predict viability in patients with chronic ischemic LV dysfunction. This study evaluated STE for prediction of global and segmental left ventricular (LV) functional changes after acute myocardial infarction (AMI) in comparison with late gadolinium enhancement cardiac magnetic resonance (LGE). Methods: In 93 patients (60±11 years) with first AMI (55 with ST-segment elevation myocardial infarction (STEMI) and 38 with Non-ST-segment elevation myocardial infarction (NSTEMI)), all treated by acute percutaneous coronary intervention peak global longitudinal strain was determined to describe global function by STE and peak systolic circumferential strain was determined for segmental function analysis. LGE was performed to define the amount of global and segmental myocardial scar. STE and LGE were performed within 48 hours after AMI. At 6 months follow-up transthoracic echocardiography was repeated to determine global (increase of ejection fraction ≥5%) and segmental (improvement of wall motion score at least one grade) LV recovery as well as global LV remodeling (increase of end-systolic volume >15%). Results: Accuracy to predict global functional improvement and LV remodeling at 6 months follow-up after AMI was similar for STE vs. LGE (AUC=0.715 vs. AUC=0.729, p=0.8830 and AUC=0.806 vs. AUC=0.824; p=0.7141, respectively). In patients with STEMI accuracy of circumferential strain analysis by STE to predict segmental functional improvement was non-inferior compared to analysis of LGE (AUC=0.679 vs. AUC=0.755; p=0.0512), while in patients with NSTEMI accuracy of strain analysis by STE for prediction of segmental functional improvement was lower compared to LGE (AUC=0.666 vs. AUC=0.838; p=0.0004). Conclusions: In patients with AMI, accuracy to predict global functional recovery as well as LV remodeling by 2D STE is comparable to LGE. In patients with STEMI, myocardial deformation analysis by 2D STE allows prediction of segmental functional recovery with non-inferior accuracy compared to LGE, while accuracy to predict segmental functional improvement is less in patients with NSTEMI.

Efficacy of Functional Remediation in Bipolar Disorder: A Multicenter Randomized Controlled Study

OBJECTIVE The authors sought to assess the efficacy of functional remediation, a novel intervention program, on functional improvement in a sample of euthymic patients with bipolar disorder. METHOD In a multicenter, randomized, rater-blind clinical trial involving 239 outpatients with DSM-IV bipolar disorder, functional remediation (N=77) was compared with psychoeducation (N=82) and treatment as usual (N=80) over 21 weeks. Pharmacological treatment was kept stable in all three groups. The primary outcome measure was improvement in global psychosocial functioning, measured blindly as the mean change in score on the Functioning Assessment Short Test from baseline to endpoint. RESULTS At the end of the study, 183 patients completed the treatment phase. Repeated-measures analysis revealed significant functional improvement from baseline to endpoint over the 21 weeks of treatment (last observation carried forward), suggesting an interaction between treatment assignment and time. Tukey's post hoc tests revealed that functional remediation differed significantly from treatment as usual, but not from psychoeducation. CONCLUSIONS Functional remediation, a novel group intervention, showed efficacy in improving the functional outcome of a sample of euthymic bipolar patients as compared with treatment as usual.

The Mental Activity and eXercise (MAX) Trial

The prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years, and strategies for maintaining cognitive function with age are critically needed. Physical or mental activity alone result in relatively small, domain-specific improvements in cognitive function in older adults; combined interventions may have more global effects. To examine the combined effects of physical plus mental activity on cognitive function in older adults. Randomized controlled trial with a factorial design. San Francisco, California. A total of 126 inactive, community-residing older adults with cognitive complaints. All participants engaged in home-based mental activity (1 h/d, 3 d/wk) plus class-based physical activity (1 h/d, 3 d/wk) for 12 weeks and were randomized to either mental activity intervention (MA-I; intensive computer) or mental activity control (MA-C; educational DVDs) plus exercise intervention (EX-I; aerobic) or exercise control (EX-C; stretching and toning); a 2 × 2 factorial design was used so that there were 4 groups: MA-I/EX-I, MA-I/EX-C, MA-C/EX-1, and MA-C/EX-C. Global cognitive change based on a comprehensive neuropsychological test battery. Participants had a mean age of 73.4 years; 62.7% were women, and 34.9% were Hispanic or nonwhite. There were no significant differences between the groups at baseline. Global cognitive scores improved significantly over time (mean, 0.16 SD; P < .001) but did not differ between groups in the comparison between MA-I and MA-C (ignoring exercise, P = .17), the comparison between EX-I and EX-C (ignoring mental activity, P = .74), or across all 4 randomization groups (P = .26). In inactive older adults with cognitive complaints, 12 weeks of physical plus mental activity was associated with significant improvements in global cognitive function with no evidence of difference between intervention and active control groups. These findings may reflect practice effects or may suggest that the amount of activity is more important than the type in this subject population. clinicaltrials.gov Identifier: NCT00522899.

Six-Month Open-Label Follow-Up of Risperidone Long-Acting Injection Use in Pediatric Bipolar Disorder

Recent studies suggest that risperidone long-acting injection (RLAI) may be considered for controlling mood episodes in bipolar disorder patients who have relapsed due to medication nonadherence or failure to respond to standard therapies. Currently, no study has reported the usefulness of RLAI in youths with bipolar disorder. The aim of this study was to evaluate short-term effects of RLAI in the naturalistic treatment of early-onset bipolar disorder and its role in symptomatic remission and adherence to treatment. Nineteen early-onset bipolar disorder outpatients receiving RLAI were observed in a 6-month naturalistic study at the outpatient clinic of the Child and Adolescent Affective Disorders Program at the Institute of Psychiatry of the University of São Paulo, São Paulo, Brazil. All patients met DSM-IV criteria for bipolar disorder. Clinical response to RLAI was evaluated using the Children's Global Assessment Scale (CGAS) and Clinical Global Impressions scale (CGI) across 3 time periods: index time (T0), 8 weeks after (T1), and 24 weeks after (T2). These subjects were recruited from May 2008 to December 2009. Patients receiving RLAI presented considerable improvement in global functioning (CGAS: T0 = 20.6; T1 = 42.9; and T2 = 49.2) and clinical severity (CGI: T0 = 5.9; T1 = 3.9; and T2 = 3.4). Global CGI mean scores of clinical improvement were 2.2 at T1 and 2.4 at T2. There were no significant changes in laboratory measurements and weight throughout follow-up. RLAI was shown to be an alternative treatment for youths with bipolar disorder failing to respond to prior medication trials or with adherence problems. Further blind, randomized controlled studies are necessary to confirm these initial findings. Sistema Nacional de Informaçōes Sobre Ética em Pesquisa Envolvendo Seres Humanos-Commisão Nacional de Ética em Pesquisa identifier: CAAE 0709.0.015.000-06.

Flexor Origin Slide for Contracture of Spastic Finger Flexor Muscles

Contracture of the wrist and extrinsic finger flexor and pronator muscles is a common consequence of central nervous system disorders. The proximal release of the extrinsic flexor and pronator muscles was first described by Page and Scaglietti for a Volkmann contracture. The aim of the present study was to assess the amount of increase in extension and the improvements in global hand function that can be expected following this lengthening procedure in patients with central nervous system disorders. A single-center retrospective review of patients with central nervous system lesions and contractures of the wrist and extrinsic finger flexor and forearm pronator muscles, causing aesthetic, hygienic, or functional impairment, was carried out. The Page-Scaglietti technique was used for all interventions. Before the operation, motor nerve blocks were used to distinguish between spasticity and contractures with surgical intervention only for contractures. The Zancolli and House classifications were used to evaluate improvements. Data from fifty-four hands and fifty patients (thirty-five men and fifteen women) were evaluated. The mean duration of follow-up (and standard deviation) was 26 ± 21 months (range, three to 124 months). The mean gain (and standard deviation) in wrist extension with fingers extended was 67° ± 25° (range, -10° to 110°). Preoperatively, no hands were classified as Zancolli Group 1, whereas twenty-five hands were classified as Zancolli Group 1 at the latest follow-up review. Ten nonfunctional hands (rated as House Group 0 or Group 1) became functional as a supporting hand postoperatively. Zancolli and House classifications increased significantly (p < 0.01) postoperatively. In twelve cases, a partial recurrence of the deformity occurred. In seven of these cases, surgery unmasked spasticity or contracture of the intrinsic muscles, which required further intervention. The Page-Scaglietti technique appears to improve range of motion and function in people with wrist and finger contractures due to central nervous system disorders.

Effect of Septal Ablation on Regional Diastolic Dysfunction and Diastolic Asynchrony in Patients with Hypertrophic Obstructive Cardiomyopathy: A Follow‐Up Study Using Speckle Tracking Echocardiography

Percutaneous transluminal septal myocardial ablation (PTSMA) is an alternative therapy for patients with hypertrophic obstructive cardiomyopathy (HOCM) that results in sustained improvement in the global diastolic dysfunction. Regional diastolic abnormalities and diastolic asynchrony are very common and closely related to global diastolic dysfunction. The aim of this study was to examine the effect of PTSMA on regional diastolic dysfunction and diastolic asynchrony in HOCM patients using speckle tracking echocardiography. Strain rate curves were obtained for 18 different segments of the left ventricular (LV) myocardium in 30 HOCM patients 24 hours before and 1 year after PTSMA. The peak strain rate during the isovolumic relaxation period (SRIVR ), the peak early diastolic strain rate (SRE ), and the time from the onset of the QRS-wave to SRE (TSRE ) were measured for each segment. The left atrial volume indexed to the body surface area (LAVI) was measured as a global diastolic index. At 1 year after PTSMA, there was significant improvement of the global SRIVR (0.14 ± 0.06-0.22 ± 0.07%/sec, P < 0.001) and SRE (0.67 ± 0.24-0.82 ± 0.23%/sec, P = 0.001). The coefficient of variation in TSRE (CVTSRE ) decreased significantly. The changes in the regional myocardial diastolic deformation and CVTSRE correlated well with the reduction in the LAVI. Percutaneous transluminal septal myocardial ablation has a favorable effect on regional diastolic abnormalities and diastolic asynchrony, which may partly account for the persistent improvement in global LV diastolic function in HOCM patients after PTSMA.

Intérêt de l’électroconvulsivothérapie de maintenance dans les troubles de l’humeur

Maintenance electroconvulsive therapy (M-ECT) is a treatment indicated for the treatment and prevention of recurrent depression in patients who either do not respond or do not tolerate psychotropic medication. We evaluated, retrospectively, clinical response to a 6-month minimum course of M-ECT in 25 patients with a diagnosis of bipolar disorder or schizoaffective disorder according to DSM IV-TR criterion. Our study demonstrated a significant improvement of Global Assessment of functioning (GAF) scores after a six month minimum course of M-ECT (34.8 ± 12.6 vs 65.6 ± 10.8; P<0.05) as well as Brief Psychiatric Rating Scale scores (BPRS): 79.3 ± 12.4 vs 43.4 ± 10.2; P<0.05). We observed a slight increase of Mini Mental State Examination (MMSE) scores after M-ECT; nonetheless, it was not statistically significant (24.2 ± 2.4 vs 26.2 ± 2.4; P=0.2). Regarding the mean duration of hospitalizations, we showed a statistically significant decrease in the median number of days of hospitalization (72 [59-93.50] days before M-ECT vs 43 [25-76] days since the first M-ECT; P=0.017). Maintenance ECT allowed a significant improvement in psychiatric symptoms and global functioning of the patients included in this study, as well as a decrease in the number of days of hospitalization. However, our pattern is limited because of its small size; so, further prospective studies in this field, including larger population is highly recommended.

Early Cardiac Retention of Administered Stem Cells Determines Clinical Efficacy of Cell Therapy in Patients With Dilated Cardiomyopathy

The diagnosis of nonischemic dilated cardiomypathy (DCM) comprises a primary myocardial disease of various causes, which is characterized by left ventricular (LV) dilation and impaired myocardial contractility. Although a broad range of pharmacological and device therapies are available, morbidity and mortality remain high in patients with advanced DCM. Thus, there is an urgent need for novel therapies aiming at functional regeneration of myocardial contractility in DCM. Although regenerative therapies using administration of a variety of different cell types have emerged as a promising approach to improve heart function in patients with ischemic disease,1 only a few pilot studies have investigated intracoronary application of autologous bone marrow–derived cells (BMC) in patients with DCM. Seth et al2 performed intracoronary infusion of BMC in 24 patients with DCM and reported a modest 5% increase in LV ejection fraction in parallel with an increased ratio of capillaries to myocytes as evidenced by endomyocardial biopsies at 6 months. In the TOPCARE-DCM pilot study including 33 patients, the improvement in global and regional LV contractile function was rather heterogeneous but was also paralleled by improved microvascular function as assessed by measuring coronary flow reserve at 3 months after intracoronary infusion of BMC.3 Article, see p 165 In this issue of Circulation Research , Vrtovec et al4 now considerably extend these previous observations. The authors randomized 110 patients with DCM to either intracoronary …

Longitudinal health-related quality of life assessment: implications for prognosis in ovarian cancer

BackgroundThere is no information in the literature on the impact of changes in quality of life (QoL) scores on prognosis in ovarian cancer. We investigated whether changes in QoL during treatment could predict survival in ovarian cancer patients.MethodsWe evaluated 137 ovarian cancer patients treated at our institution between Jan 2001 and Dec 2009 who were available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment using EORTC-QLQ-C30. Cox regression evaluated the prognostic significance of baseline and changes in QoL scores after adjusting for clinical and demographic variables.ResultsAssociations between changes in QoL and survival were observed for global function, appetite loss and constipation. Every 10-point increase (improvement) in global function from baseline to 3 months was associated with a 10% decreased risk of death (HR=0.90; 95% CI: 0.81 to 0.99, p=0.03). The corresponding HRs for 10-point increase (deterioration) in appetite loss and constipation scales were 1.20 (95% CI: 1.06 to 1.35; p=0.005) and 1.13 (95% CI: 1.02 to 1.24; p=0.02) respectively.ConclusionsThis exploratory study provides evidence that an improvement in appetite, constipation and global health scores during the first 3 months of treatment is significantly associated with improved survival time in ovarian cancer. These findings justify serial, systematic assessment of global health, appetite and constipation in ovarian cancer patients being treated, and suggest that modalities designed to improve these functions may be beneficial clinically.

Mixed Results for Bone Marrow–Derived Cell Therapy for Ischemic Heart Disease

TWO EARLY-PHASE STUDIES REPORTED IN JAMA 1,2 ADdress the same general question: what is the effect of bone marrow–derived cell therapy on safety and surrogate end points in patients after myocardial infarction (MI)? Other than this thematic similarity, the Timing In Myocardial infarction Evaluation (TIME) trial and the POSEIDON trial have little in common. The TIME trial examined 120 patients with a recent (3-7 days) acute MI (AMI) and autologous mononuclear cells (MNCs) delivered via the intracoronary route with the intervention on day 3 (n=67) or on day 7 (n=53). This was a placebocontrolled, multicenter trial with a fixed dose of MNCs. The major motivation was to test the concept that timing of MNC therapy within the first week after MI influences outcome. The POSEIDON trial involved patients with ischemic cardiomyopathy after distant MIs (years earlier) and used autologous or allogeneic mesenchymal cells (MSCs) administered transendocardially via injection catheters. Two centers recruited 30 patients and randomly assigned them into 1 of 6 permutations of cell origin (self or donor) and dosage (n=5 patients each), with no controls. The goal of the trial was to compare the safety and efficacy of self-derived MSCs with donor MSCs in chronic ischemic cardiomyopathy. TIME is the latest in a series of studies from the Cardiovascular Cell Therapy Research Network (CCTRN), a consortium funded by the National Institutes of Health, which was mandated to conduct and complete trials of cell therapy within its initial 5-year funding period. Three trials (LateTIME, FOCUS-CCTRN, and now TIME) of autologous MNCs have been conducted. The goal of these trials has been to follow up on earlier positive phase 1 and 2 studies of MNCs; however, the CCTRN studies (including TIME) have all had negative results. The CCTRN used a convenient automated system for extracting MNCs from bone marrow aspirates. The older motivating studies, including the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) multicenter trial of MNC therapy, relied instead on laborious manual Ficoll gradient centrifugation of bone marrow aspirates. TIME followed up on the subgroup analysis of REPAIR-AMI, hinting at superior functional outcomes in patients who had received MNCs more than 4 days after MI vs those who received therapy earlier. However, in TIME no significant incremental treatment effects on function, volumes, or infarct size were observed in patients treated with MNCs either 3 or 7 days after MI. The lack of benefit of MNC therapy in TIME and in the other CCTRN studies raises 2 possibilities: MNCs do not work, in which case the previous positive clinical studies were red herrings, or the CCTRN trials used an inactive cell product. The latter possibility cannot be discounted because MNCs isolated by the automated system used in this study have not been tested in an animal model of MI, and cell bioactivity has not been verified in any human studies of heart disease. In addition, the cell product used in TIME contained heparin at a dose that has been shown to impair the migratory capacity of MNCs. Such details of cell manufacturing are known to influence MNC potency substantially. Given these uncertainties, TIME (and the other 2 CCTRN studies) are well-intentioned, nicely designed, and impeccably executed, but difficult to interpret. POSEIDON, on the other hand, follows a more conventional development pathway, with ample preclinical validation and early proof-of-concept data in patients. The patients with chronic ischemic cardiomyopathy included in POSEIDON have a compelling clinical need. Their functional status is depressed and their ventricles have undergone extensive deleterious structural remodeling. The major finding of POSEIDON is that therapy with allogeneic (ie, donor-derived) MSCs appears to be safe and at least as active as therapy with autologous (ie, selfderived) MSCs. Allogeneic (but not autologous) MSCs reduced end-diastolic volume, whereas both allogeneic and autologous MSCs reduced early enhancement defect (a controversial measure of infarct size derived from computed tomography). The apparent changes in myocardial structure were not matched by improvements in global ventricular function; neither allogeneic nor autologous MSCs showed any significant increase in ejection fraction when analyzed individually or pooled together.

Abstract 9534: Expression of Heme Oxygenase-1 in Cardiac Stem Cells Enhances the Efficacy of Cell Therapy for Attenuating Left Ventricular Dysfunction and Remodeling After Myocardial Infarction

Although transplantation of cardiac stem cells (CSCs) improves LV function and structure after myocardial infarction (MI), this salubrious effect is limited by early massive CSC loss due to apoptosis. Heme oxygenase-1 (HO-1) is known to exert potent antiapoptotic and cytoprotective effects. Thus, we hypothesized that expression of HO-1 in CSCs will enhance their survival and reparative ability. To test this hypothesis, lin - /c-kit + CSCs were isolated and expanded from wild-type (WT), HO-1 transgenic (TG) or knockout (KO) mice. HO-1 protein overexpression in HO-1 TG CSCs (confirmed by FACS and immunoblotting) was mild (3-fold greater than WT CSCs). Mice underwent a 60-minute coronary occlusion followed by reperfusion; 48 h later, they received intramyocardial injection of vehicle or WT, HO-1 TG or HO-1 KO CSCs (10 5 CSCs/heart). Sham mice underwent 1-hour open-chest state with no intervention. At 35 days post-MI, both WT and HO-1 TG CSC transplantation resulted in alleviation of LV dysfunction and remodeling compared with vehicle group; however, the magnitude of the beneficial effects of HO-1 TG CSCs was significantly greater than that of WT CSCs. Compared with WT CSCs, transplantation of HO-1 TG CSCs resulted in a greater improvement in global and regional LV function (assessed by two independent methods - echocardiography and conductance catheter) and a greater increase in viable myocardial tissue in the risk region, suggesting increased formation of new cardiomyocytes (Fig). In contrast, transplantation of HO-1 KO CSCs failed to produce any LV structural or functional benefits. These results indicate, for the first time, that even a mild increase in HO-1 promotes CSC competence and that expression of HO-1 is a powerful strategy to enhance the cardiac reparative actions of CSCs in limiting LV dysfunction and remodeling post-MI. The data provide a potential therapeutic approach for promoting myocardial regeneration via modification of CSCs with cytoprotective genes.

Early prediction of clinical and functional outcome in schizophrenia

The objective of this paper was to investigate the prognostic and predictive value of a small panel of independent and clinically important factors based on symptom improvement, baseline cognitive impairment, and weight change during the early treatment phase. MethodsThe study sample was based on a double-blind, 6-month continuation study of ziprasidone and olanzapine (N=94). We developed a parsimonious 6-month GAF prediction function using a logistic regression model, and evaluated its predictive accuracy and performance using bootstrap estimates of c-statistics and error in predicted probability. ResultsAt up to 6 months of follow-up, 52 (55%) of all subjects treated with ziprasidone or olanzapine met the responder criterion of ≥50% improvement in GAF. At Week 2 (acute phase), the majority of ziprasidone (75%) and olanzapine (70%) patients showed greater than 25% improvement in the BPRS psychotic symptom subscale score. These early psychotic symptom responders (Week 2) showed significantly greater improvement in global functioning than early non-responders at all time points (Week 6 and Month 6) (all p's<0.05), confirming early response as an indicator of continued responsiveness to treatment over at least 6 months. A multivariate prediction function based on baseline neurocognitive scores and GAF, early reduction of psychotic symptoms at 2 weeks, and percentage of weight change observed at 6 weeks (All p's <0.05), showed statistically acceptable predictive performance (boostrap c-statistics=0.8598). ConclusionsOur findings suggest that a parsimonious model incorporating a psychotic symptom assessment score, baseline neurocognitive performance, and risk of weight gain can be developed for predicting patients' likelihood of achieving favorable, long-term treatment outcomes.

Activation of Diverse Signaling Pathways by Ex-Vivo Delivery of Multiple Cytokines for Myocardial Repair

We tested the hypothesis that simultaneous transgenic overexpression of a select quartet of growth factors activates diverse signaling pathways for mobilization and participation of various stem/progenitor cells for cardiogenesis in the infarcted heart. Human insulin growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1a), and hepatocyte growth factor (HGF) plasmids were synthesized and transfected into skeletal myoblasts (SM) from young male wild-type or transgenic rats expressing green fluorescent protein (GFP). Overexpression of growth factors in transfected SM ((Trans)SM) was confirmed by reverse transcription polymerase chain reaction, western blotting, and fluorescence immunostaining. Using our custom-made growth factor array and western blotting, multiple angiogenic and prosurvival factors were detected in (Trans)SM, including secreted frizzled related protein-1,2,4,5, matrix metalloproteinases-3 and 9, connexin-43, netrin-1, Nos-2, Wnt-3, Akt, MAPK42/44, Stat3, nuclear factor kappa B (NFκB), hypoxia-inducible factor 1 (HIF-1α), and protein kinase C (PKC). The conditioned medium (CM) from (Trans)SM was cytoprotective for cardiomyocytes following H(2)O(2) treatment [P<0.01 vs. CM from native SM ((Nat)SM)], promoted a higher transwell migration of human umbilical cord vein endothelial cells (223.3±1.8, P<0.01) and in vitro tube formation (47.8±1.9, P<0.01). Intramyocardial transplantation of 1.5×10(6) (Trans)SM (group-3) in a rat model of acute myocardial infarction induced extensive mobilization of cMet(+), ckit(+), ckit(+)/GATA(4+), CXCR4(+), CD44(+), CD31(+), and CD59(+) cells into the infarcted heart on day 7 and improved integration of (Trans)SM in the heart compared to (Nat)SM (group 2) (P<0.05). Extensive neomyogenesis and angiogenesis in group-3 (P<0.01 vs. group-2), with resultant attenuation of infarct size (P<0.01 vs. group-2) and improvement in global heart function (P<0.01 vs. group-2) was observed at 8 weeks. In conclusion, simultaneous activation of diverse signaling pathways by overexpression of multiple growth factors caused massive mobilization and homing of stem/progenitor cells from peripheral circulation, the bone marrow, and the heart for accelerated repair of the infarcted myocardium.

Early Improvement of the Regional and Global Ventricle Function Estimated by Two‐Dimensional Speckle Tracking Echocardiography after Percutaneous Aortic Valve Implantation Speckle Tracking after CoreValve Implantation

To assess changes in myocardial deformation and ejection fraction (EF) by two-dimensional speckle tracking echocardiography (2DSTE) after transcatheter aortic valve implantation (TAVI). A total of 24 patients (50% males, age 78 ± 4 years) were selected for TAVI because of severe aortic stenosis. A comprehensive echocardiographic study was performed before TAVI, at discharge, and after 1-month follow-up. EF was assessed by 2D conventional echocardiography with Simpson method and by 2DSTE. Radial and circumferential strains were evaluated in six segments in the short-axis view at the level of the papillary muscles, and longitudinal strain in six segments in the four-chamber apical view, by means of 2DSTE. All studies were performed with an iE-33 echocardiography device (Philips). At discharge, the mean EF estimated by 2DSTE improved significantly when compared with the basal one (56 ± 7% vs. 51 ± 8%, P < 0.01), while EF by Simpson method did not change (67 ± 9% vs. 64 ± 16%, P = 0.2). At that time, global radial (21.4 ± 9% vs. 11.5 ± 7.6%, P = 0.000), circumferential (-20.7 ± 8% vs. -15.2 ± 7%, P = 0.02), and longitudinal strains (-14.8 ± 6.2% vs. -12 ± 6%, P = 0.02) improved significantly when compared with the basal one. At 1-month follow-up, global radial (20.1 ± 5.6% vs. 21.4 ± 9%, P = 0.88) and circumferential (-20 ± 8% vs. -20.7 ± 8%, P = 0.35) strains did not vary and a new significant improvement was observed in longitudinal global strain (-19.2 ± 6.5% vs. -14.8 ± 6.2%, P = 0.002). A new echocardiographic technique, such as 2DSTE, shows a significant early improvement in global and segmental left ventricular systolic function after TAVI, which could not be detected by conventional methods.

Administration of Cardiac Stem Cells in Patients With Ischemic Cardiomyopathy: The SCIPIO Trial

SCIPIO is a first-in-human, phase 1, randomized, open-label trial of autologous c-kit(+) cardiac stem cells (CSCs) in patients with heart failure of ischemic etiology undergoing coronary artery bypass grafting (CABG). In the present study, we report the surgical aspects and interim cardiac magnetic resonance (CMR) results. A total of 33 patients (20 CSC-treated and 13 control subjects) met final eligibility criteria and were enrolled in SCIPIO. CSCs were isolated from the right atrial appendage harvested and processed during surgery. Harvesting did not affect cardiopulmonary bypass, cross-clamp, or surgical times. In CSC-treated patients, CMR showed a marked increase in both LVEF (from 27.5 ± 1.6% to 35.1 ± 2.4% [P=0.004, n=8] and 41.2 ± 4.5% [P=0.013, n=5] at 4 and 12 months after CSC infusion, respectively) and regional EF in the CSC-infused territory. Infarct size (late gadolinium enhancement) decreased after CSC infusion (by manual delineation: -6.9 ± 1.5 g [-22.7%] at 4 months [P=0.002, n=9] and -9.8 ± 3.5 g [-30.2%] at 12 months [P=0.039, n=6]). LV nonviable mass decreased even more (-11.9 ± 2.5 g [-49.7%] at 4 months [P=0.001] and -14.7 ± 3.9 g [-58.6%] at 12 months [P=0.013]), whereas LV viable mass increased (+11.6 ± 5.1 g at 4 months after CSC infusion [P=0.055] and +31.5 ± 11.0 g at 12 months [P=0.035]). Isolation of CSCs from cardiac tissue obtained in the operating room is feasible and does not alter practices during CABG surgery. CMR shows that CSC infusion produces a striking improvement in both global and regional LV function, a reduction in infarct size, and an increase in viable tissue that persist at least 1 year and are consistent with cardiac regeneration. This study is registered with clinicaltrials.gov, trial number NCT00474461.