Recovery of the lumbopelvic movement and muscle recruitment patterns using motor control exercise program in people with chronic nonspecific low back pain: A prospective study.

This study aims to investigate the dysfunction and recovery of the lumbopelvic movement and motor control of people with chronic nonspecific low back pain after a structured rehabilitation which emphasizes on re-education and training of movement and motor control. The lumbopelvic movement and motor control pattern of 30 adults (15 with chronic low back pain, 15 healthy controls) were assessed using 3D motion and electromyographic analysis during the repeated forward bending test, in additional to the clinical outcome measures. Regional kinematics and muscle recruitment pattern of the symptomatic group was analysed before and after the 6-week rehabilitation, and compared to healthy controls. Significant improvement in back pain, functional capacity and self-efficacy of the symptomatic group was found after the rehabilitation. Patients with chronic nonspecific low back pain were capable to recover to a comparable level of the healthy controls in terms of their lumbopelvic movement and motor control pattern upon completion of a 6-week rehabilitation program, despite their dysfunction displayed at baseline. Phase specific motor control reorganization in which more profound and positive changes shown during the flexion phase. Our findings indicate that the recovery of the movement and motor control pattern in patients with chronic low back pain achieved to a comparable level of the healthy able-bodies. The improvement of both the physical outcome measures suggest that specific rehabilitation program which emphasizes on optimizing motor control during movements would help promoting the functional recovery of this specific low back pain subgroup.

Estimating Myocardial Infarction Size With a Simple Electrocardiographic Marker Score.

Background Myocardial infarction (MI) size is a key predictor of prognosis in post-MI patients. Cardiovascular magnetic resonance (CMR) is the gold standard test for MI quantification, but the ECG is less expensive and more widely available. We sought to quantify the relationship between ECG markers and cardiovascular magnetic resonance infarct size. Methods and Results Patients with prior MI enrolled in the DETERMINE (Defibrillators to Reduce Risk by Magnetic Resonance Imaging Evaluation) and PRE-DETERMINE Trial and Registry were included. ECG leads were analyzed for markers of MI: Q waves, fragmented QRS, and T wave inversion. DETERMINE Score=number of leads with [Q waves×2]+[fragmented QRS]+[T wave inversion]. Left ventricular ejection fraction (LVEF) and infarct size as a percentage of left ventricular mass (MI%) were quantified by cardiovascular magnetic resonance. The Modified Selvester Score estimates MI size from 37 ECG criteria. In 551 patients (aged 62.1±10.9 years, 79% men, and LVEF=40.3±11.0%), MI% increased as the number of ECG markers increased (P<0.001). By univariable linear regression, the DETERMINE Score (range 0-26) estimated MI% (R2=0.18, P<0.001) with an accuracy approaching that of LVEF (R2=0.22, P<0.001) and higher than the Modified Selvester Score (R2=0.09, P<0.001). By multivariable linear regression, addition of the DETERMINE Score improved estimation of MI% over LVEF alone (P<0.001) and over Modified Selvester Score alone (P<0.001). Conclusions In patients with prior MI, a simple ECG score estimates infarct size and improves infarct size estimation over LVEF alone. Because infarct size is a powerful prognostic indicator, the DETERMINE Score holds promise as a simple and inexpensive risk assessment tool.

Prevalence and Prognosis of Unrecognized Myocardial Infarction in Asymptomatic Patients With Diabetes: A Two-Center Study With Up to 5 Years of Follow-up.

OBJECTIVE: To determine the prevalence and prognostic significance of unrecognized myocardial infarction (MI) by delayed-enhancement MRI (DE-MRI) in asymptomatic patients with diabetes. RESEARCH DESIGN AND METHODS: In this prospective, two-center study of asymptomatic patients without known cardiac disease (n = 120), two prespecified cohorts underwent a research MRI: 1) a high-risk group with type 1 diabetes and chronic renal insufficiency (n = 50) and 2) an average-risk group with type 2 diabetes (n = 70). The primary end point was a composite of all-cause mortality and clinical MI. RESULTS: Overall, the prevalence of unrecognized MI was 19% by DE-MRI (28% high-risk group and 13% average-risk group) and 5% by electrocardiography. During up to 5 years of follow-up with a total of 460 patient-years of follow-up, the rate of death/MI was markedly higher in patients with diabetes with (vs. without) unrecognized MI (all 44% vs. 7%, high-risk group 43% vs. 6%, and average-risk group 44% vs. 8%; all P < 0.01). After adjustment for Framingham risk score, left ventricular ejection fraction, and diabetes type, the presence of unrecognized MI by DE-MRI conferred an eightfold increase in risk of death/MI (95% CI 3.0-21.1, P < 0.0001). Addition of unrecognized MI to clinical indices significantly improved model discrimination for adverse events (integrated discrimination improvement = 0.156, P = 0.001). CONCLUSIONS: Unrecognized MI is prevalent in asymptomatic patients with diabetes without a history of cardiac disease and confers a markedly increased risk of death and clinical MI.

Ubiquitin orchestrates proteasome dynamics between proliferation and quiescence in yeast.

Proteasomes are essential for protein degradation in proliferating cells. Little is known about proteasome functions in quiescent cells. In nondividing yeast, a eukaryotic model of quiescence, proteasomes are depleted from the nucleus and accumulate in motile cytosolic granules termed proteasome storage granules (PSGs). PSGs enhance resistance to genotoxic stress and confer fitness during aging. Upon exit from quiescence PSGs dissolve, and proteasomes are rapidly delivered into the nucleus. To identify key players in PSG organization, we performed high-throughput imaging of green fluorescent protein (GFP)-labeled proteasomes in the yeast null-mutant collection. Mutants with reduced levels of ubiquitin are impaired in PSG formation. Colocalization studies of PSGs with proteins of the yeast GFP collection, mass spectrometry, and direct stochastic optical reconstitution microscopy of cross-linked PSGs revealed that PSGs are densely packed with proteasomes and contain ubiquitin but no polyubiquitin chains. Our results provide insight into proteasome dynamics between proliferating and quiescent yeast in response to cellular requirements for ubiquitin-dependent degradation.

JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis.

Con A-induced hepatitis in mice is an established model of autoimmune hepatitis (AIH). JKB-122, a toll-like receptor 4 (TLR4) antagonist, was tested for hepatotprotectant activity. Within several hours of Con A challenge (15mg/kg iv), increased production of proinflammatory cytokines with inflammatory infiltrate occurred in the liver. The severity of tissue necrosis and the amount of circulating liver enzymes peak at 24h post Con A challenge. JKB-122 was given 24 and 16h before, then concurrently, and 4 and 8h (× 5 doses) after challenge with Con A. Serum and liver were harvested at 3, 9 and 24h post Con A challenge. JKB-122 at 20 and 50mg/kg po prevented the increase of serum liver enzymes by 47% and 95% respectively vs vehicle control 24h post Con A. JKB-122 significantly inhibited Con A-induced pathological lesions in the liver and the amount of IFN-γ IL-1ß, IL-4, IL-5, IL-6, IL-17A and TNF-α starting as early as 3h post Con A. Moreover, JKB-122 given concurrently (× 3 doses) with Con A showed similar effect. Finally, JKB-122 enhanced the therapeutic effects of submaximal dose of prednisolone with improved lesion score. It is concluded that JKB-122 at 20 and 50mg/kg po caused dose-dependent inhibition of elevated liver enzymes in Con A-induced hepatitis in mice, indicating hepatoprotectant activity. The results suggest that JKB-122 as monotherapy or in combination with prednisolone may offer a viable approach to the treatment of AIH.

Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction.

Treatment of acute myocardial infarction (AMI) has improved significantly in recent years, but many patients have adverse left ventricular (LV) remodeling, a maladaptive change associated with progressive heart failure. Although this change is usually associated with large infarcts, some patients with relatively small infarcts have adverse remodeling, whereas other patients with larger infarcts (who survive the first several days after AMI) do not. This paper reviews the relevant data supporting the hypothesis that individual differences in the intensity of the post-AMI inflammatory response, involving 1 or more inflammatory-modulating pathways, may contribute to adverse LV remodeling. It concludes by outlining how individual variations in the inflammatory response could provide important novel therapeutic targets and strategies.

Time elapsed after contrast injection is crucial to determine infarct transmurality and myocardial functional recovery after an acute myocardial infarction.

BACKGROUND: In acute myocardial infarction (MI), late Gadolinium enhancement (LGE) has been proposed to include the infarcted myocardium and area at risk. However, little information is available on the optimal timing after contrast injection to differentiate these 2 areas. Our aim was to determine in acute and chronic MI whether imaging time after contrast injection influences the LGE size that better predicts infarct size and functional recovery. METHODS: Subjects were evaluated by cardiovascular magnetic resonance (CMR) the first week (n = 60) and 3 months (n = 47) after a percutaneously revascularized STEMI. Inversion-recovery single-shot (ss-IR) imaging was acquired at multiple time points following contrast administration and compared to segmented inversion-recovery (seg-IR) sequences. Inversion time was properly adjusted and images were blinded, randomized and measured for LGE volumes. RESULTS: In acute MI, LGE volume decreased over several minutes (p = 0.005) with the greatest volume occurring at 3 minutes and the smallest at 25 minutes post-contrast injection; however, LGE volume remained constant over time in chronic MI (p = 0.886). Depending on the imaging time, in acute phase, a change in the transmurality index was also observed. A transmural infarction (>75%) at 25 minutes better predicted the absence of improvement in the wall motion score index (WMSI), a higher increase in left ventricular volumes and a lower ejection fraction compared to 10 minutes. CONCLUSIONS: A change was observed in LGE volume in the minutes following contrast administration in acute but not in chronic MI. Infarct transmurality 25 minutes post-contrast injection better predicted infarct size and functional recovery at follow-up.

Effect of weight reduction on the severity of lower urinary tract symptoms in obese male patients with benign prostatic hyperplasia: a randomized controlled trial.

PURPOSE: We assessed whether weight reduction is an effective intervention for the management of lower urinary tract symptoms (LUTS) and investigated the relationship between obesity and LUTS. MATERIALS AND METHODS: This was a prospective randomized controlled trial that enrolled obese men older than 50 years with LUTS. The study period was 52 weeks. All patients received standardized alpha-adrenergic blocker therapy for the treatment of benign prostatic hyperplasia (BPH) during the run-in period. Patients were randomized to receive either a standardized prerecorded video program on the general principle of weight reduction or a comprehensive weight reduction program. Patients were assessed at different time points with symptom assessment, uroflowmetry, transrectal ultrasound, and metabolic assessment. RESULTS: Sixty-five patients were allocated to each study arm. After the study period, no significant difference in weight reduction was found between the two arms. When the pre- and postintervention parameters were compared, none were statistically different between the 2 arms, namely nocturia, International Prostate Symptom Score, quality of life assessment, and uroflowmetry parameters. When the whole study population was taken as a single cohort, these parameters were also not significantly different between the group with a body mass index of 25 to <30 kg/m(2) and the group with a BMI of 30 to 35 kg/m(2). CONCLUSIONS: We found no association between obesity and LUTS. This could have been due to the less marked weight difference in our cohort. Whereas weight reduction may be an effective measure to improve LUTS, the implementation of a successful program remains a challenge.

Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients.

The aim of this study was to evaluate the value of microvascular obstruction (MO) and infarct size as a percentage of left ventricular mass (IS%LV), as measured by contrast-enhanced cardiac magnetic resonance, in predicting major cardiovascular adverse events (MACE) at 2 years in patients with ST-segment elevation myocardial infarction reperfused by primary percutaneous coronary intervention. Individual data from 1,025 patients were entered into the pooled analysis. MO was associated with the occurrence of MACE, defined as a composite of cardiac death, congestive heart failure, and myocardial re-infarction (adjusted hazard ratio: 3.74; 95% confidence interval: 2.21 to 6.34). IS%LV ≥25% was not associated with MACE (adjusted hazard ratio: 0.90; 95% confidence interval: 0.59 to 1.37). The authors conclude that MO is an independent predictor of MACE and cardiac death, whereas IS%LV is not independently associated with MACE.

Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction).

OBJECTIVES: This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. BACKGROUND: Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown. METHODS: Autologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients. RESULTS: In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI. CONCLUSIONS: Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360).

A comparison of cardiac magnetic resonance imaging peri-infarct border zone quantification strategies for the prediction of ventricular tachyarrhythmia inducibility.

BACKGROUND: Peri-infarct border zone (BZ) as quantified by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) has been proposed as a risk stratification tool, and is associated with increased mortality. BZ has been measured by various methods in the literature. We assessed which BZ analysis best predicts inducible arrhythmia during electrophysiological study (EPS). METHODS: LGE was performed in 47 patients with coronary artery disease referred for EPS to assess for ventricular tachycardia (VT). LGE data was analyzed for BZ quantification by 3 previously published methods. Method I (BZ-I) used pixels 2-3 standard deviations over the mean of normal tissue, expressed as % of left ventricular mass, Method II (BZ-II, as described by Yan) and Method III (BZ-III, as described by Schmidt). EPS results were classified as negative (non-inducible) or positive (monomorphic VT - MVT). RESULTS: There were 47 subjects-age 61.7 years, 72% male. During EPS, 20 patients were non-inducible and 18 had induced MVT. Ejection fraction was not significantly different between non-inducible patients and those with MVT (34.1% vs. 28.5%, p = 0.13). BZ-I was significantly different (1.4% vs. 2.6%, p = 0.001), but not BZ-II (7.9% vs. 6.9%, p = 0.68) or BZ-III (2.7 g vs. 2.1 g, p = 0.88). Multivariate analysis demonstrated that only BZ-I was an independent predictor of EPS outcome after controling for infarct size (OR 1.97 per % change, 95% CI 1.04-3.73, p = 0.04). CONCLUSIONS: This study demonstrates significant variability between the published methods for measuring BZ. Also, BZ-I is a stronger predictor of inducible MVT during EPS than ejection fraction and infarct size. BZ may be another LGE marker of elevated risk of arrhythmia.

Prevalence of regional myocardial thinning and relationship with myocardial scarring in patients with coronary artery disease.

IMPORTANCE: Regional left ventricular (LV) wall thinning is believed to represent chronic transmural myocardial infarction and scar tissue. However, recent case reports using delayed-enhancement cardiovascular magnetic resonance (CMR) imaging raise the possibility that thinning may occur with little or no scarring. OBJECTIVE: To evaluate patients with regional myocardial wall thinning and to determine scar burden and potential for functional improvement. DESIGN, SETTING, AND PATIENTS: Investigator-initiated, prospective, 3-center study conducted from August 2000 through January 2008 in 3 parts to determine (1) in patients with known coronary artery disease (CAD) undergoing CMR viability assessment, the prevalence of regional wall thinning (end-diastolic wall thickness ≤5.5 mm), (2) in patients with thinning, the presence and extent of scar burden, and (3) in patients with thinning undergoing coronary revascularization, any changes in myocardial morphology and contractility. MAIN OUTCOMES AND MEASURES: Scar burden in thinned regions assessed using delayed-enhancement CMR and changes in myocardial morphology and function assessed using cine-CMR after revascularization. RESULTS: Of 1055 consecutive patients with CAD screened, 201 (19% [95% CI, 17% to 21%]) had regional wall thinning. Wall thinning spanned a mean of 34% (95% CI, 32% to 37% [SD, 15%]) of LV surface area. Within these regions, the extent of scarring was 72% (95% CI, 69% to 76% [SD, 25%]); however, 18% (95% CI, 13% to 24%) of thinned regions had limited scar burden (≤50% of total extent). Among patients with thinning undergoing revascularization and follow-up cine-CMR (n = 42), scar extent within the thinned region was inversely related to regional (r = -0.72, P < .001) and global (r = -0.53, P < .001) contractile improvement. End-diastolic wall thickness in thinned regions with limited scar burden increased from 4.4 mm (95% CI, 4.1 to 4.7) to 7.5 mm (95% CI, 6.9 to 8.1) after revascularization (P < .001), resulting in resolution of wall thinning. On multivariable analysis, scar extent had the strongest association with contractile improvement (slope coefficient, -0.03 [95% CI, -0.04 to -0.02]; P < .001) and reversal of thinning (slope coefficient, -0.05 [95% CI, -0.06 to -0.04]; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CAD referred for CMR and found to have regional wall thinning, limited scar burden was present in 18% and was associated with improved contractility and resolution of wall thinning after revascularization. These findings, which are not consistent with common assumptions, warrant further investigation.

Infarct healing is a dynamic process following acute myocardial infarction.

BACKGROUND: The role of infarct size on left ventricular (LV) remodeling in heart failure after an acute ST-segment elevation myocardial infarction (STEMI) is well recognized. Infarct size, as determined by cardiovascular magnetic resonance (CMR), decreases over time. The amount, rate, and duration of infarct healing are unknown. METHODS: A total of 66 patients were prospectively enrolled after reperfusion for an acute STEMI. Patients underwent a CMR evaluation within 1 week, 4 months, and 14 months after STEMI. RESULTS: Mean infarct sizes for the 66 patients at baseline (acute necrosis), early follow-up (early scar), and late follow-up (late scar) were 25 ± 17 g, 17 ± 12 g, and 15 ± 11 g, respectively. Patients were stratified in tertiles, based on infarct size, with the largest infarcts having the greatest absolute decrease in mass at early and late scar. The percent reduction of infarct mass was independent of initial infarct size. There was an 8 g or 32% decrease in infarct mass between acute necrosis and early scar (p < 0.01) with a 2 g or 12% additional decrease in infarct mass between early and late scar (p < 0.01). CONCLUSIONS: Infarct healing is a continuous process after reperfusion for STEMI, with greatest reduction in infarct size in the first few months. The dynamic nature of infarct healing through the first year after STEMI indicates that decisions based on infarct size, and interventions to reduce infarct size, must take into consideration the time frame of measurement.

Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation.

Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti-inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease.

Angiographic and magnetic resonance imaging evaluation of in-hospital delay in primary percutaneous intervention delivery on myocardial salvage.

Shortening symptom-to-reperfusion time improves prognosis in patients with ST-segment elevation myocardial infarction. Accordingly, current guidelines target a door-to-balloon time <90 minutes, irrespective of symptom-to-door time; nevertheless, the relation between door-to-balloon and symptom-to-door time and its potential impact on myocardial salvage remains largely unknown. We investigated the influence of door-to-balloon guideline fulfillment on myocardial salvage in patients presenting with different symptom-to-door times. Contrast-enhanced magnetic resonance study was performed acutely to measure infarct size in 172 patients admitted for primary percutaneous coronary intervention of their first ST-segment elevation myocardial infarction to 2 tertiary hospitals. The Bari score was adapted to quantify the angiographic area at risk, and the myocardial salvage index (MSI) was computed as percent area at risk that spared necrosis. Increased symptom-to-balloon time was associated with a significant decrease in MSI only within the first 5 hours (p <0.001). Accomplishment of a target door-to-balloon <90 minutes was associated with a significant increase in MSI only in patients presenting within the first hour of symptom onset (48.5 ± 30.9 vs 29.6 ± 22.3%, p <0.05). Achieving a door-to-balloon time <60 minutes further increased MSI in patients presenting within the second hour of symptoms (43.5 ± 8.6 vs 26.3 ± 20.5%, p <0.01). In conclusion, myocardial salvage progressively decreases up to 5 hours after symptom onset. However, the benefit of the recommended door-to-balloon time appears to be confined to patients presenting within 1 hour of symptom onset.