Background Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. ...Methods In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. Results Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly ( P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months ( P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control ( P = .02) but not in treated patients ( P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). Conclusions ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.
With prevalent global air pollution, individuals with certain genetic predispositions and sensitivities are at of higher risk of developing respiratory symptoms including chronic cough. Studies to ...date have relied on patient-filled questionnaires in epidemiological studies to evaluate the gene-by-environment interactions. In a controlled human exposure study, we evaluated whether genetic risk score (GRS) based on cough-related single-nucleotide polymorphisms (SNPs) are associated with a cough count over 24 h post-exposure to diesel exhaust (DE), a model for traffic-related air pollution. DE is a mixture of several known air pollutants including PM
, CO, NO, NO
, and volatile organic compounds. Under closely observed circumstances, we determined that GRS constructed from 7 SNPs related to TRPA1, TRPV1, and NK-2R were correlated with cough count. Selection of channels were based on prior knowledge that SNPs in these channels lead to acute airway inflammation as a result of their increased sensitivity to particulate matter. We performed a linear regression analysis and found a significant, positive correlation between GRS and cough count following DE exposure (p = 0.002, R
= 0.61) and filtered air (FA) exposure (p = 0.028, R
= 0.37). Although that correlation was stronger for DE than for FA, we found no significant exposure-by-GRS interaction. In summary, cough-relevant GRS was associated with a higher 24 h cough count in a controlled setting, suggesting that individuals with a high GRS may be more susceptible to developing cough regardless of their exposure. The trend towards this susceptibility being more prominent in the context of traffic-related air pollution remains to be confirmed.Trial registration: ClinicalTrial.gov NCT02236039; NCT0223603. Registered on August 11, 2014, https://clinicaltrials.gov/ct2/show/NCT02236039 .
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding ...publication (DOI: 10.1021/jm100059d) we describe Astex’s approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
Peer providers with lived experiences of mental health and substance use are a growing component of the workforce responsible for the prevention and treatment of behavioral health disorders. This ...systematic literature review aims to better define the roles of peers and their unique contributions to behavioral health care.
Researchers searched MEDLINE, CINAHL Complete, PsycINFO, Cochrane Central, and Scopus databases for studies published between January 1, 2013 and April 3, 2020. Studies were included if they (1) were experimental or observational studies, (2) included an adult population of people with a behavioral health disorder, and (3) used paid peer providers in addition to traditional behavioral health services. Researchers extracted sample demographics, intervention characteristics, outcome data, and significant associations from studies that met inclusion criteria and assessed the trends in these data in May 2020.
A total of 23 articles assessing peer-provided services were included. Peers were employed most frequently in mental healthcare roles in the Department of Veterans Affairs, hospital, and community health facilities. A total of 14 studies observed significant clinical improvements in participants’ social functioning, quality of life, patient activation, and behavioral health. A majority of studies involved the supervision of peers and required peers to have completed training in service delivery.
Peers are effective providers of behavioral health treatment and relapse prevention services who encourage recovery through resilience building, empowerment, and self-advocacy. There remains a need for more evidence-based interventions on the efficacy of peers in substance use disorder treatment and the impact of formalized certification and training opportunities.
Although climate change has been implicated in population declines of tropical forest birds, there is a critical lack of data on the mechanisms underlying these declines. Attempts to link climatic ...factors to variation in adult survival, fecundity or nest success have been largely inconclusive. Recent community‐scale analyses have suggested that tropical birds may be less likely to breed under adverse conditions, but long‐term data on individual reproduction are needed to test this hypothesis. Here we leverage 12 years of data on a lowland forest bird, the greater ani Crotophaga major, to investigate how demographic parameters vary with phase of the El Niño – Southern Oscillation (ENSO), a major driver of climatic conditions in tropical wet forest. The likelihood of breeding and annual reproductive rate both decreased dramatically in El Niño‐like years, with only 37.5% of adults attempting breeding in 2015 (a strong El Niño year). For birds that did breed, however, clutch size and daily nest predation rate were unaffected by climate. Of the local climate variables investigated, dry season length and the frequency of high temperatures were most closely associated with reproductive failure. These results indicate that El Niño conditions alter the demography of greater anis by reducing the likelihood of reproduction, a response that may be more widespread than currently recognized. We suggest that reduced reproduction under adverse conditions represents an important and understudied aspect of the life histories of tropical forest birds.
Abstract
The corpus callosum is the largest white matter pathway in the brain connecting the two hemispheres. In the context of developmental absence (agenesis) of the corpus callosum (AgCC), a ...proposed candidate for neuroplastic response is strengthening of intrahemispheric pathways. To test this hypothesis, we assessed structural and functional connectivity in a uniquely large cohort of children with AgCC (n = 20) compared with typically developing controls (TDC, n = 29), and then examined associations with neurobehavioral outcomes using a multivariate data-driven approach (partial least squares correlation, PLSC). For structural connectivity, children with AgCC showed a significant increase in intrahemispheric connectivity in addition to a significant decrease in interhemispheric connectivity compared with TDC, in line with the aforementioned hypothesis. In contrast, for functional connectivity, children with AgCC and TDC showed a similar pattern of intrahemispheric and interhemispheric connectivity. In conclusion, we observed structural strengthening of intrahemispheric pathways in children born without corpus callosum, which seems to allow for functional connectivity comparable to a typically developing brain, and were relevant to explain neurobehavioral outcomes in this population. This neuroplasticity might be relevant to other disorders of axonal guidance, and developmental disorders in which corpus callosum alteration is observed.
Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal ...afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets.
To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms.
Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model.
Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure.
CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).
Summary
Autosomal dominant mutations in the sodium‐gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and ...malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype–phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.
This study examined the efficacy of Collaborative & Proactive Solutions (CPS) in treating oppositional defiant disorder (ODD) in youth by comparing this novel treatment to Parent Management Training ...(PMT), a well-established treatment, and a waitlist control (WLC) group. One hundred thirty-four youth (ages 7-14, 61.9% male, 83.6% White) who fulfilled Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria for ODD were randomized to CPS, PMT, or WLC groups. ODD was assessed with semistructured diagnostic interviews, clinical global severity and improvement ratings, and parent report measures. Assessments were completed pretreatment, posttreatment, and at 6 months following treatment. Responder and remitter analyses were undertaken using intent-to-treat mixed-models analyses. Chronological age, gender, and socioeconomic status as well as the presence of comorbid attention deficit/hyperactivity and anxiety disorders were examined as predictors of treatment outcome. Both treatment conditions were superior to the WLC condition but did not differ from one another in either our responder or remitter analyses. Approximately 50% of youth in both active treatments were diagnosis free and were judged to be much or very much improved at posttreatment, compared to 0% in the waitlist condition. Younger age and presence of an anxiety disorder predicted better treatment outcomes for both PMT and CPS. Treatment gains were maintained at 6-month follow-up. CPS proved to be equivalent to PMT and can be considered an evidence-based, alternative treatment for youth with ODD and their families.
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