ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer.
Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) <12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels >150 ng/dL) were eligible. ATN-224 was administered at two dose-levels, 300 mg (n=23) or 30 mg (n=24) daily, by way of randomization. PSA progression was defined as a ≥50% increase (and >5 ng/mL) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the two treatment groups.
At 24 weeks, 59% (95% CI 33–82%) of men in the low-dose arm and 45% (95% CI 17–77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21–40+) and 26 weeks (95% CI 24–39+) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (p=0.006) and a significant mean PSADT increase (p=0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes.
Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.
This cross-sectional study examined associations of occupational tasks with radiographic and symptomatic osteoarthritis (OA) in a community-based sample.
Participants from the Johnston County Osteoarthritis Project (n = 2729) self-reported the frequency of performing 10 specific occupational tasks at the longest job ever held (never/seldom/sometimes vs often/always) and lifetime exposure to jobs that required spending > 50% of their time doing 5 specific tasks or lifting 22, 44, or 110 pounds 10 times weekly. Multivariable logistic regression models examined associations of each occupational task separately with radiographic and symptomatic knee and hip OA, controlling for age, race, gender, body mass index, prior knee or hip injury, and smoking.
Radiographic hip and knee OA were not significantly associated with any occupational tasks, but several occupational tasks were associated with increased odds of both symptomatic knee and hip OA: lifting > 10 pounds, crawling, and doing heavy work while standing (OR 1.4–2.1). More occupational walking and standing and less sitting were also associated with symptomatic knee OA, and more bending/twisting/reaching was associated with symptomatic hip OA. Exposure to a greater number of physically demanding occupational tasks at the longest job was associated with greater odds of both symptomatic knee and hip OA.
Our results confirm an association of physically demanding occupational tasks with both symptomatic knee and hip OA, including several specific activities that increased the odds of OA in both joint groups. These tasks represent possibilities for identifying and targeting at-risk individuals with preventive interventions.
OSTEOARTHRITIS; OCCUPATIONS; HIP; KNEE
The protein Keap1 is central to the regulation of the Nrf2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases involving excessive oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for several small molecule covalent activators of the Nrf2 pathway. However, despite structural information being available for several BTB domains from related proteins, there have been no reported crystal structures of Keap1 BTB, and this has precluded a detailed understanding of its mechanism of action and interaction with antagonists. We report here the first structure of the BTB domain of Keap1, which is thought to contain the key cysteine residue responsible for interaction with electrophiles, as well as structures of the covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively inactive C151W BTB mutant. In addition to providing the first structural confirmation of antagonist binding to Keap1 BTB, we also present biochemical evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2 activation through disruption of the BTB-Cul3 interface.
The unregulated activity of inteins during expression and consequent side reactions during work-up limits their widespread use in biotechnology and chemical biology. Therefore, we exploited a mechanism-based approach to regulate intein autocatalysis for biotechnological application. The system, inspired by our previous structural studies, is based on reversible trapping of the intein’s catalytic cysteine residue through a disulfide bond. Using standard mutagenesis, the disulfide trap can be implemented to impart redox control over different inteins and for a variety of applications both in vitro and in Escherichia coli. Thereby, we first enhanced the output for bioconjugation in intein-mediated protein ligation, also referred to as expressed protein ligation, where precursor recovery and product yield were augmented fourfold to sixfold. Second, in bioseparation experiments, the redox trap boosted precursor recovery and product yield twofold. Finally, the disulfide-trap intein technology stimulated development of a novel bacterial redox sensor. This sensor reliably identified hyperoxic E. coli harboring mutations that disrupt the reductive pathways for thioredoxin and glutathione, against a background of wild-type cells.
redox regulation; expressed protein ligation; bioseparations; redox sensor
To examine cross-sectional baseline data from the Johnston County Osteoarthritis Project for the association between individual and community socioeconomic status (SES) measures with hip osteoarthritis (OA) outcomes.
We analyzed data on 3,087 individuals (68% Caucasian and 32% African American). Educational attainment and occupation were used as individual measures of SES. Census block group household poverty rate was used as a measure of community SES. Hip OA outcomes included radiographic OA (rOA) and symptomatic OA (sxOA) in one or both hip joints. Multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of each hip OA outcome with each SES variable separately, then with all SES measures simultaneously. Associations between hip OA outcomes and SES variables were evaluated for effect modification by race and gender.
Living in a community of high household poverty rate showed independent associations with hip rOA in one or both hips (OR=1.50; 95% CI=1.18–1.92) and bilateral (both hips) rOA (OR=1.87; 95% CI=1.32–2.66). Similar independent associations were found between low educational attainment among those with sxOA in one or both hips (OR=1.44; 95% CI=1.09, 1.91) or bilateral sxOA (OR=1.91; 95% CI=1.08–3.39), after adjusting for all SES measures simultaneously. No significant associations were observed between occupation and hip OA outcomes, nor did race or gender modify the associations.
Our data provide evidence that hip OA outcomes are associated with both education and community SES measures, associations which remained after adjustment for covariates and all SES measures.
The effectiveness of any new technology is typically measured in order to determine whether it successfully achieves equal or superior objectives over what is currently offered. Research in telemental health—in this article mainly referring to telepsychiatry and psychological services—has advanced rapidly since 2003, and a new effectiveness review is needed.
Materials and Methods:
The authors reviewed the published literature to synthesize information on what is and what is not effective related to telemental health. Terms for the search included, but were not limited to, telepsychiatry, effectiveness, mental health, e-health, videoconferencing, telemedicine, cost, access, and international.
Telemental health is effective for diagnosis and assessment across many populations (adult, child, geriatric, and ethnic) and for disorders in many settings (emergency, home health) and appears to be comparable to in-person care. In addition, this review has identified new models of care (i.e., collaborative care, asynchronous, mobile) with equally positive outcomes.
Telemental health is effective and increases access to care. Future directions suggest the need for more research on service models, specific disorders, the issues relevant to culture and language, and cost.
telepsychiatry; effectiveness; telemental health; videoconferencing; telemedicine
The relationship between late-life blood pressure (BP) and cognitive function in the elderly is poorly understood. Inconsistent results have been reported from existing studies. We report the results from a prospective cohort study on the association between BP and cognitive function in elderly African Americans.
Prospective cohort study conducted from 1997 to 2009.
Community-based study in Indianapolis.
3145 African Americans aged 65 years or older.
At each assessment, participants’ cognitive function was measured by the Community Screening Interview for Dementia score. Other measurements included BP, height, weight, education level, antihypertensive medication use, alcohol use, smoking and histories of chronic medical conditions.
5995 longitudinal assessments contributed by 2721 participants with complete independent variables were analyzed using a semiparametric mixed effects model. Systolic BP around 135 mmHg and diastolic BP around 80 mmHg were associated with optimal cognitive function after adjusting for other variables (P = 0.019). Weight loss with body mass index less than 30 kg/m2 was significantly related to poorer cognitive performance (P < 0.001). Older age at first assessment, lower education level, smoking, histories of depression, stroke and diabetes mellitus were related to worse cognitive function, while taking antihypertensive medication and drinking alcohol were associated with higher cognitive scores.
Both high and low BP levels were associated with poorer cognitive performance. A joint optimal region of systolic and diastolic BP for cognitive function has been identified, which may provide useful clinical information on optimal BP control in cognitive health and lead to improved quality of life for the elderly.
blood pressure; cognitive function; elderly
Pulmonary vein isolation (PVI) for atrial fibrillation (AF) is associated with a transient increased risk of thromboembolic and hemorrhagic events. We hypothesized that dabigatran can be safely used as an alternative to continuous warfarin for the peri-procedural anticoagulation in PVI.
Methods and Results
999 consecutive patients undergoing PVI were included; 376 patients were on dabigatran (150 mg) and 623 were on warfarin with therapeutic INR. Dabigatran was held 1 to 2 doses prior to PVI and restarted at the conclusion of the procedure or as soon as patients were transferred to the nursing floor. Propensity score matching was applied to generate a cohort of 344 patients in each group with balanced baseline data. Total hemorrhagic and thromboembolic complications were similar in both groups, before (3.2% vs 3.9%; p = 0.59), and after (3.2% vs 4.1%; p = 0.53) matching. Major hemorrhage occurred in 1.1% vs 1.6% (p = 0.48) before, and 1.2% vs 1.5% (p = 0.74) after matching in the dabigatran vs warfarin group respectively. A single thromboembolic event occurred in each of the dabigatran and warfarin groups. Despite higher doses of intra-procedural heparin, the mean ACT was significantly lower in patients who held dabigatran for 1 or 2 doses than those on warfarin.
Our study found no evidence to suggest a higher risk of thromboembolic or hemorrhagic complications with use of dabigatran for peri-procedural anticoagulation in patients undergoing PVI compared to uninterrupted warfarin therapy.
anticoagulants; fibrillation; ablation; catheter ablation; stroke
Homebound seniors suffer from high levels of functional impairment and are high-cost users of acute medical services. This article describes a 7-year experience in building and sustaining a physician home visit program. The House Calls for Seniors program was established in 1999. The team includes a geriatrician, geriatrics nurse practitioner, and social worker. The program hosts trainees from multiple disciplines. The team provides care to 245 patients annually. In 2006, the healthcare system (62%), provider billing (36%), and philanthropy (2%) financed the annual program budget of $355,390. Over 7 years, the team has enrolled 468 older adults; the mean age was 80, 78% were women, and 64% were African American. One-third lived alone, and 39% were receiving Medicaid. Reflecting the disability of this cohort, 98% had impairment in at least one instrumental activity of daily living (mean 5.2), 71% had impairment in at least one activity of daily living (mean 2.6), 53% had a Mini-Mental State Examination score of 23 or less, 43% were receiving services from a home care agency, and 69% had at least one new geriatric syndrome diagnosed by the program. In the year after intake into the program, patients had an average of nine home visits; 21% were hospitalized, and 59% were seen in the emergency department. Consistent with the program goals, primary care, specialty care, and emergency department visits declined in the year after enrollment, whereas access and quality-of-care targets improved. An academic physician house calls program in partnership with a healthcare system can improve access to care for homebound frail older adults, improve quality of care and patient satisfaction, and provide a positive learning experience for trainees.
home visits; house calls; physicians
We examined whether occupational and household tasks contributed to differences in pain between African Americans and whites with radiographic knee osteoarthritis (OA).
Participants from the Johnston County Osteoarthritis Project self-reported the frequency (often/always vs never/seldom/sometimes) of performing 9 occupational tasks involving lower extremity joint loading at their longest job (N = 868) and current job (N = 273), as well as 8 household tasks ever performed (N = 811) and currently being performed (N = 767). The associations of the numbers of occupational or household tasks with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale were first examined in simple linear regression models. If significantly associated with greater pain, each of these was included in adjusted linear regression models to examine whether the association of race with pain remained statistically significant.
African Americans reported significantly greater WOMAC pain scores than whites. Exposures to more occupational tasks at the longest job and the current job were associated with greater WOMAC pain scores (p < 0.01). The association of race with greater pain scores remained statistically significant when controlling for occupational tasks at the longest job, but was reduced by 26% and no longer significant when controlling for the number of current occupational tasks. Exposures to an increasing number of household tasks were associated with lower pain scores and were not further analyzed.
Current performance of physically demanding occupational tasks contributed to racial differences in pain severity among individuals with knee OA. Better workplace policies to accommodate OA-related limitations may help to reduce racial differences in pain.
OSTEOARTHRITIS; OCCUPATIONS; KNEE
In this work, we developed a sensitive method to quantify cotinine (COT), norcotinine (NCOT), trans-3′-hydroxycotinine (OHCOT) and cotinine-N-oxide (COTNO) in rat plasma and brain tissue, using solid phase extraction (SPE), hydrophilic interaction liquid chromatography (HILIC) and tandem mass spectrometry (MS/MS). The linear range was 1–100 ng/ml for each analyte in rat plasma and brain homogenate (3–300 ng/g brain tissue). The method was validated with precision within 15% relative standard deviation (RSD) and accuracy within 15% relative error (RE). Stable isotope-labeled internal standards (IS) were used for all the analytes to achieve good reproducibility, minimizing the influence of recovery and matrix effects. This method can be used in future studies to simultaneously determine the concentrations of COT and three major metabolites in rat plasma and brain tissue.
cotinine; norcotinine; trans-3′-hydroxycotinine; cotinine-N-oxide; plasma; brain; hydrophilic interaction chromatography; tandem mass spectrometry
Deficiencies of lysosomal β-D-galactosidase can result in GM1 gangliosidosis, a severe neurodegenerative disease characterized by massive neuronal storage of GM1 ganglioside in the brain. Currently there are no available therapies that can even slow the progression of this disease. Enzyme enhancement therapy utilizes small molecules that can often cross the blood brain barrier, but are also often competitive inhibitors of their target enzyme. It is a promising new approach for treating diseases, often caused by missense mutations, associated with dramatically reduced levels of functionally folded enzyme. Despite a number of positive reports based on assays performed with patient cells, skepticism persists that an inhibitor-based treatment can increase mutant enzyme activity in vivo. To date no appropriate animal model, i.e., one that recapitulates a responsive human genotype and clinical phenotype, has been reported that could be used to validate enzyme enhancement therapy. In this report, we identify a novel enzyme enhancement-agent, N-nonyl-deoxygalactonojirimycin, that enhances the mutant β-galactosidase activity in the lysosomes of a number of patient cell lines containing a variety of missense mutations. We then demonstrate that treatment of cells from a previously described, naturally occurring feline model (that biochemically, clinically and molecularly closely mimics GM1 gangliosidosis in humans) with this molecule, results in a robust enhancement of their mutant lysosomal β-galactosidase activity. These data indicate that the feline model could be used to validate this therapeutic approach and determine the relationship between the disease stage at which this therapy is initiated and the maximum clinical benefits obtainable.
PMID: 22784478 CAMSID: cams2306
Lysosomal storage disease; β-D-galactosidase; Morquio disease type B; Endoplasmic reticulum quality control; Large animal model; Small molecule therapy
A major consequence of ICU-acquired weakness (ICUAW) is diaphragm weakness, which prolongs the duration of mechanical ventilation. Hyperglycemia (HG) is a risk factor for ICUAW. However, the mechanisms underlying HG-induced respiratory muscle weakness are not known. Excessive reactive oxygen species (ROS) injure multiple tissues during HG, but only one study suggests that excessive ROS generation may be linked to HG-induced diaphragm weakness. We hypothesized that HG-induced diaphragm dysfunction is mediated by excessive superoxide generation and that administration of a specific superoxide scavenger, polyethylene glycol superoxide dismutase (PEG-SOD), would ameliorate these effects.
HG was induced in rats using streptozotocin (60 mg/kg intravenously) and the following groups assessed at two weeks: controls, HG, HG + PEG-SOD (2,000U/kg/d intraperitoneally for seven days), and HG + denatured (dn)PEG-SOD (2000U/kg/d intraperitoneally for seven days). PEG-SOD and dnPEG-SOD were administered on day 8, we measured diaphragm specific force generation in muscle strips, force-pCa relationships in single permeabilized fibers, contractile protein content and indices of oxidative stress.
HG reduced diaphragm specific force generation, altered single fiber force-pCa relationships, depleted troponin T, and increased oxidative stress. PEG-SOD prevented HG-induced reductions in diaphragm specific force generation (for example 80 Hz force was 26.4 ± 0.9, 15.4 ± 0.9, 24.0 ± 1.5 and 14.9 ± 0.9 N/cm2 for control, HG, HG + PEG-SOD, and HG + dnPEG-SOD groups, respectively, P <0.001). PEG-SOD also restored HG-induced reductions in diaphragm single fiber force generation (for example, Fmax was 182.9 ± 1.8, 85.7 ± 2.0, 148.6 ± 2.4 and 90.9 ± 1.5 kPa in control, HG, HG + PEG-SOD, and HG + dnPEG-SOD groups, respectively, P <0.001). HG-induced troponin T depletion, protein nitrotyrosine formation, and carbonyl modifications were largely prevented by PEG-SOD.
HG-induced reductions in diaphragm force generation occur largely at the level of the contractile proteins, are associated with depletion of troponin T and increased indices of oxidative stress, findings not previously reported. Importantly, administration of PEG-SOD largely ablated these derangements, indicating that superoxide generation plays a major role in hyperglycemia-induced diaphragm dysfunction. This new mechanistic information could explain how HG alters diaphragm function during critical illness.
The association of trauma and PTSD with alcohol and cocaine use is explored to determine if there is additive risk associated with dual dependence. Data were collected from out-of-treatment women enrolled in an HIV-prevention study. Women who experienced a DSM-IV qualifying event (N=791) were stratified into four substance use groups based on lifetime alcohol and cocaine use. Women with lifetime co-morbid alcohol and cocaine dependence experienced significantly more traumatic events, had a higher prevalence of violent events and lifetime diagnosis of PTSD and PTSD-related impairment. There is added risk for associated trauma and subsequent PTSD among women who have dual substance dependence.
The Disease Activity Score based on 28 joints (DAS28) has been increasingly used in clinical practice and research studies of rheumatoid arthritis (RA). Studies have reported discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in RA patients. However such comparison is lacking in African-Americans with RA.
This analysis included participants from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry which enrolls self-declared African-Americans with RA. Using tender and swollen joint counts separate ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) were calculated, as were DAS28-ESR4 and DAS28-CRP4, which included the patient’s assessment of disease activity. The scores were compared using paired t-test, simple agreement and kappa, correlation coefficient and Bland-Altman plots.
Of the 233 included participants, 85% were women, mean age at enrollment was 52.6 years, and median disease duration at enrollment was 21 months. Mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs. 3.9; p<0.001). Similarly, mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs. 3.9; p<0.001). ESR-based DAS28 remained higher than CRP-based DAS28 even when stratified by age, sex, and disease duration. Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4.
There was significant discordance between the ESR-based and CRP-based DAS28 which could impact clinical treatment decisions in African-Americans with RA.
DAS28; Rheumatoid Arthritis; African-Americans
Uveal melanoma exhibits a high incidence of metastases and no systemic therapy clearly improves outcomes. The anti-CTLA-4 antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.
To assess ipilimumab in this setting, we performed a multicenter, retrospective analysis of four hospitals in the United States and Europe. Clinical characteristics, toxicities and radiographic disease burden as determined by central, blinded radiology review were determined.
Thirty-nine patients were identified (34 treated with 3 mg/kg and 5 treated with 10 mg/kg). Using the immune-related response criteria and modified WHO criteria, response rate (RR) and combined response plus stable disease (SD) rate were assessed after 12 weeks, 23 weeks and total (median follow-up 50.4 weeks (12.6 months)). At week 12, the RR and response plus SD rate were 2.6% and 46.0%, at week 23: 2.6% and 28.2%. There was one complete response and one late partial response (at 100 weeks after initial SD) for irRR of 5.1%. Immune-related adverse events (irAE) were observed in 28 (71.8%) patients, with seven (17.9%) grade 3-4 events. irAEs were more frequent in patients receiving 10 mg/kg versus 3 mg/kg. The median overall survival from first dose of ipilimumab was 9.6 months (confidence interval 6.3-13.4 months, range: 1.6-41.6 months). Performance status, LDH and absolute lymphocyte count ≥1000 cells/μL at week 7 were significantly associated with survival.
In uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed.
uveal melanoma; ipilimumab; CTLA-4; immunotherapy; absolute lymphocyte count
Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking.
Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t-test, Wilcoxon’s rank sum test, chi-square test, and logistic regression analyses.
Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio >2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA.
CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care.
The development of novel therapeutic agents for disorders of cognition such as Alzheimer’s disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.
Alzheimer’s Disease; cholinergic; memory; pro-cognitive; Mild Cognitive Impairment; aging
Diffusion-weighted MRI has the potential to provide important new insights into physiological and microstructural properties of the body. The Intra-Voxel Incoherent Motion (IVIM) model relates the observed DW-MRI signal decay to parameters that reflect blood flow in the capillaries (D*), capillaries volume fraction (f), and diffusivity (D). However, the commonly used, independent voxel-wise fitting of the IVIM model leads to imprecise parameter estimates, which has hampered their practical usage.
In this work, we improve the precision of estimates by introducing a spatially-constrained Incoherent Motion (IM) model of DW-MRI signal decay. We also introduce an efficient iterative “fusion bootstrap moves” (FBM) solver that enables precise parameter estimates with this new IM model. This solver updates parameter estimates by applying a binary graph-cut solver to fuse the current estimate of parameter values with a new proposal of the parameter values into a new estimate of parameter values that better fits the observed DW-MRI data. The proposals of parameter values are sampled from the independent voxel-wise distributions of the parameter values with a model-based bootstrap resampling of the residuals.
We assessed both the improvement in the precision of the Incoherent Motion parameter estimates and the characterization of heterogeneous tumor environments by analyzing simulated and in-vivo abdominal DW-MRI data of 30 patients, and in-vivo DW-MRI data of three patients with musculoskeletal lesions. We found our IM-FBM reduces the relative root mean square error of the D* parameter estimates by 80%, and of the f and D parameter estimates by 50% compared to the IVIM model with the simulated data. Similarly, we observed that our IM-FBM method significantly reduces the coefficient of variation of parameter estimates of the D* parameter by 43%, the f parameter by 37%, and the D parameter by 17% compared to the IVIM model (paired Student’s t-test, p<0.0001). In addition, we found our IM-FBM method improved the characterization of heterogeneous musculoskeletal lesions by means of increased contrast-to-noise ratio of 19.3%.
The IM model and FBM solver combined, provide more precise estimate of the physiological model parameter values that describing the DW-MRI signal decay and a better mechanism for characterizing heterogeneous lesions than does the independent voxel-wise IVIM model.
Diffusion-weighted imaging; Intra-voxel incoherent motion; Spatial homogeneity prior; Bayesian estimation; Graph min-cut
Efficient ex vivo methods for expanding primary human chondrocytes while maintaining phenotype is critical to advancing autologous cell sourcing efforts for tissue engineering applications. While there is significant activity in the literature, systematic approaches are necessary to determine and optimize the chemical and mechanical scaffold properties for hyaline cartilage generation using limited cell numbers. Functionalized hydrogels possessing continuous variations in physico-chemical properties are therefore an efficient three-dimensional platform for studying several properties simultaneously. Herein, we describe a polyethylene glycol dimethacrylate (PEGDM) hydrogel system possessing a gradient in modulus (~27,000 Pa to 3,800 Pa) containing a uniform concentration of arginine–glycine–aspartic acid peptide (RGD) to enhance cellular adhesion for the correlation of primary human osteoarthritic chondrocyte proliferation, phenotype maintenance, and ECM production to the hydrogel properties. Cell number and chondrogenic phenotype (CD14:CD90 ratios) were found to decline in regions with higher storage modulus (>13,100 Pa), while regions with lower storage modulus maintained cell number and phenotype. Over three weeks of culture, hydrogel regions possessing lower storage modulus experience an increase in ECM content (~200%) compared to regions with higher storage modulus. Variations in the amount and organization of cytoskeletal markers actin and vinculin were observed within the modulus gradient which are indicative of the differences in chondrogenic phenotype maintenance and ECM expression. Thus scaffold mechanical properties significantly impact on modulating human osteoarthritic chondrocyte behavior and tissue formation.
Cartilage; Tissue Engineering; Hydrogel; combinatorial methods; gradient
Sepsis is a major cause of morbidity and mortality in critically ill patients, and despite advances in management, mortality remains high. In survivors, sepsis increases the risk for the development of persistent acquired weakness syndromes affecting both the respiratory muscles and the limb muscles. This acquired weakness results in prolonged duration of mechanical ventilation, difficulty weaning, functional impairment, exercise limitation, and poor health-related quality of life. Abundant evidence indicates that sepsis induces a myopathy characterized by reductions in muscle force-generating capacity, atrophy (loss of muscle mass), and altered bioenergetics. Sepsis elicits derangements at multiple subcellular sites involved in excitation contraction coupling, such as decreasing membrane excitability, injuring sarcolemmal membranes, altering calcium homeostasis due to effects on the sarcoplasmic reticulum, and disrupting contractile protein interactions. Muscle wasting occurs later and results from increased proteolytic degradation as well as decreased protein synthesis. In addition, sepsis produces marked abnormalities in muscle mitochondrial functional capacity and when severe, these alterations correlate with increased death. The mechanisms leading to sepsis-induced changes in skeletal muscle are linked to excessive localized elaboration of proinflammatory cytokines, marked increases in free-radical generation, and activation of proteolytic pathways that are upstream of the proteasome including caspase and calpain. Emerging data suggest that targeted inhibition of these pathways may alter the evolution and progression of sepsis-induced myopathy and potentially reduce the occurrence of sepsis-mediated acquired weakness syndromes.
sepsis; myopathy; critical illness; diaphragm; peripheral muscles; mitochondria; contractile proteins; ICU-acquired weakness
Hospitalized older adults often lack decisional capacity, but outside of the intensive care unit (ICU) and end-of-life care settings, little is known about the frequency of decision making by family members or other surrogates or its implications for hospital care.
To describe the scope of surrogate decision making, the hospital course and outcomes for older adults.
Prospective, observational study.
Medical and Medical ICU services of two hospitals in one Midwest city.
1083 hospitalized older adults identified by their physicians as requiring major medical decisions.
Clinical characteristics, hospital outcomes, nature of major medical decisions and surrogate involvement.
Based on physician reports at 48 hours of hospitalization, 47.4% (44.4%–50.4%) of older adults required at least some surrogate involvement including 23.0% (20.6% – 25.6%) with all decisions made by a surrogate. Among patients who required a surrogate for at least one decision within 48 hours, 57.2% required decisions about life sustaining care (mostly addressing code status), 48.6% about procedures and surgeries and 46.9% about discharge planning. Patients who required a surrogate experienced a more complex hospital course with greater use of ventilators (2.5% patients who made decisions, 13.2% patients who required any surrogate decisions, p<0.0001), artificial nutrition (1.7% patient, 14.4% surrogate, p<0.0001) and greater length of stay (median 6 days patient, 7 days surrogate, p<0.0001). They were more likely to be discharged to an extended care facility (21.2% patient, 40.9% surrogate, p<0.0001), and had higher hospital mortality (0.0% patient; 5.9% surrogate, p<0.0001). Most surrogates were daughters (58.9%), sons (25.0%) or spouses (20.6%). Overall, only 7.4% had a living will and 25.0% a health care representative document in the medical record.
Surrogate decision making occurs for nearly half of hospitalized older adults and includes both complete decision making by the surrogate and joint decision making by the patient and surrogate. Surrogates commonly face a broad range of decisions in both the ICU and the hospital ward setting. Hospital functions should be redesigned to account for the large and growing role of surrogates and to support surrogates as they make health care decisions.
Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally-defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly over-express BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
Acute myeloid leukemia; AML; leukemia; leukemia stem cells; LSCs; oxidative phosphorylation; glycolysis; BCL-2; ABT-263; reactive oxygen species; ROS; oxidative state; energy metabolism
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