S-Nitrosoglutathione Reductase Is Essential for Protecting the Female Heart From Ischemia-Reperfusion Injury.

RATIONALE: Protein S-nitros(yl)ation (SNO) has been implicated as an essential mediator of nitric oxide-dependent cardioprotection. Compared with males, female hearts exhibit higher baseline levels of protein SNO and associated with this, reduced susceptibility to myocardial ischemia-reperfusion injury. Female hearts also exhibit enhanced S-nitrosoglutathione reductase (GSNO-R) activity, which would typically favor decreased SNO levels as GSNO-R mediates SNO catabolism. OBJECTIVE: Because female hearts exhibit higher SNO levels, we hypothesized that GSNO-R is an essential component of sex-dependent cardioprotection in females. METHODS AND RESULTS: Male and female wild-type mouse hearts were subjected to ex vivo ischemia-reperfusion injury with or without GSNO-R inhibition (N6022). Control female hearts exhibited enhanced functional recovery and decreased infarct size versus control males. Interestingly, GSNO-R inhibition reversed this sex disparity, significantly reducing injury in male hearts, and exacerbating injury in females. Similar results were obtained with male and female GSNO-R-/- hearts using ex vivo and in vivo models of ischemia-reperfusion injury. Assessment of SNO levels using SNO-resin assisted capture revealed an increase in total SNO levels with GSNO-R inhibition in males, whereas total SNO levels remained unchanged in females. However, we found that although GSNO-R inhibition significantly increased SNO at the cardioprotective Cys39 residue of nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 3 in males, SNO-NADH dehydrogenase subunit 3 levels were surprisingly reduced in N6022-treated female hearts. Because GSNO-R also acts as a formaldehyde dehydrogenase, we examined postischemic formaldehyde levels and found that they were nearly 2-fold higher in N6022-treated female hearts compared with nontreated hearts. Importantly, the mitochondrial aldehyde dehydrogenase 2 activator, Alda-1, rescued the phenotype in GSNO-R-/- female hearts, significantly reducing infarct size. CONCLUSIONS: These striking findings point to GSNO-R as a critical sex-dependent mediator of myocardial protein SNO and formaldehyde levels and further suggest that different therapeutic strategies may be required to combat ischemic heart disease in males and females.

Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.

IMPORTANCE: Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE: To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS: A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES: Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES: Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS: Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95% CI, 1.93%-3.48%] vs human controls, 7.17% [95% CI, 5.91%-8.44%] vs elephants, 14.64% [95% CI, 10.91%-18.37%]; P < .001; doxorubicin exposure: human controls, 8.10% [95% CI, 6.55%-9.66%] vs elephants, 24.77% [95% CI, 23.0%-26.53%]; P < .001). CONCLUSIONS AND RELEVANCE: Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.

Protocolized abuse screening to decrease provider bias and increase capture of potential events.

BACKGROUND: Early identification of child abuse is critical to prevent death and disability. Studies suggest implicit bias of providers may lead to overrepresentation of minority and impoverished children in child abuse reporting. At our institution, universal screening for sexual and physical abuse for all children under 18 years of age was implemented in 2016. A rigorous, objective evaluation protocol focusing on the mechanism of injury and exam findings to improve recognition and eliminate bias was implemented in 2019. FINDINGS: Demographics and clinical characteristics of patients less than 18 years of age were abstracted by chart review (2014-2015) and from a forensic database (2016-2022). International Classification of Diseases codes 995.5 (version 9) and T76.12XA (version 10) were used to identify patients before the establishment of forensic database. Relative frequency and patient characteristics of the three time periods (pre universal screening: 2014-2015, post universal screening: 2016-2019, post protocol implementation: 2020-2022) were compared using Chi-square tests and modified Poisson regression. Universal screening significantly increased the number of cases identified. The demographic profile of potential victims by race significantly changed over the reporting periods with an increased number of white children identified, consistent with state demographics. The proportion of publicly insured patients trended down with universal screening and protocol implementation, despite a significant increase in the number of children publicly insured in the state during this time. CONCLUSION: These single institutional results lend support to objective, evidence-based protocols to help eliminate bias surrounding race and poverty.

Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors.

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.

Psychometric properties and correlates of Chinese version of Perceived Stress Scale (CPSS-10) in people with common mental disorders with different employment Statuses.

BACKGROUND/OBJECTIVES: Several studies have indicated that stress is associated with common mental disorders, and work stress trebles the risk of developing them. However, a validated assessment tool for measuring and establishing psychological stress correlates in this group of clients remains unavailable. The objectives of the present study were to examine the psychometric properties of the Chinese version of the Perceived Stress Scale-10 (CPSS-10) on people with common mental disorders with different employment statuses and explore its correlates. METHODS: Two hundred and fifty-two participants with common mental disorders were recruited. The data were analysed through exploratory factor and confirmatory analyses to investigate construct validity. The convergent and discriminant validities were examined based on their correlation with other measures, while the internal consistency was estimated using Cronbach's α coefficient. A t-test was used to detect differences between groups. The CPSS-10 correlates were explored using multiple linear regression analysis. RESULTS: Principal component analysis with varimax rotation yielded two factors, which accounted for 63.82% of the total variance, while confirmatory factor analysis confirmed its factor structure. The CPSS-10 had a positively moderate to strong correlation with other measures, thereby indicating its acceptable convergent and discriminant validities. The internal consistency ranged from acceptable to good for the two subscales and ten overall items, while the item-total correlation was adequate except for the seventh item. There were no group differences in gender nor employment status. Finally, the CPSS-10 predictors were studied. CONCLUSION: The CPSS-10 is a reliable and valid instrument for people with common mental disorders with different employment statuses.

Conditioning Electrical Stimulation Is Superior to Postoperative Electrical Stimulation in Enhanced Regeneration and Functional Recovery Following Nerve Graft Repair.

Background. Autologous nerve graft is the most common clinical intervention for repairing a nerve gap. However, its regenerative capacity is decreased in part because, unlike a primary repair, the regenerating axons must traverse 2 repair sites. Means to promote nerve regeneration across a graft are needed. Postoperative electrical stimulation (PES) improves nerve growth by reducing staggered regeneration at the coaptation site whereas conditioning electrical stimulation (CES) accelerates axon extension. In this study, we directly compared these electrical stimulation paradigms in a model of nerve autograft repair. Methods. To lay the foundation for clinical translation, regeneration and reinnervation outcomes of CES and PES in a 5-mm nerve autograft model were compared. Sprague-Dawley rats were divided into: (a) CES, (b) PES, and (c) no stimulation cohorts. CES was delivered 1 week prior to nerve cut/coaptation, and PES was delivered immediately following coaptation. Length of nerve regeneration (n = 6/cohort), and behavioral testing (n = 16/cohort) were performed at 14 days and 6 to 14 weeks post-coaptation, respectively. Results. CES treated axons extended 5.9 ± 0.2 mm, significantly longer than PES (3.8 ± 0.2 mm), or no stimulation (2.5 ± 0.2 mm) (P < .01). Compared with PES animals, the CES animals had significantly improved sensory recovery (von Frey filament testing, intraepidermal nerve fiber reinnervation) (P < .001) and motor reinnervation (horizontal ladder, gait analysis, nerve conduction studies, neuromuscular junction analysis) (P < .01). Conclusion. CES resulted in faster regeneration through the nerve graft and improved sensorimotor recovery compared to all other cohorts. It is a promising treatment to improve outcomes in patients undergoing nerve autograft repair.

Case report of integrated supported employment for a person with severe mental illness.

OBJECTIVE: We illustrate the implementation of an integrated supported employment (ISE) program that augments the individual placement and support model with social skills training in helping people with severe mental illness (SMI) achieve and maintain employment. METHOD: A case illustration demonstrates how ISE helped a 41-year-old woman with SMI to get and keep a job with support from an employment specialist. An independent, blinded assessor conducted data collection of employment information, including self-efficacy and quality of life, at pretreatment and at 3-month, 7-month, 11-month, and 15-month follow-up assessments. RESULTS: The participant eventually stayed in a job for 8 months and reported improved self-efficacy and quality of life. CONCLUSION: The case report suggests that ISE could improve the employment outcomes of people with SMI. Moreover, changes in the participant's self-efficacy and quality of life were shown to be driven by the successful employment experience.

Conditioning electrical stimulation promotes functional nerve regeneration.

Peripheral nerve regeneration following injury is often incomplete, resulting in significant personal and socioeconomic costs. Although a conditioning crush lesion prior to surgical nerve transection and repair greatly promotes nerve regeneration and functional recovery, feasibility and ethical considerations have hindered its clinical applicability. In a recent proof of principle study, we demonstrated that conditioning electrical stimulation (CES) had effects on early nerve regeneration, similar to that seen in conditioning crush lesions (CCL). To convincingly determine its clinical utility, establishing the effects of CES on target reinnervation and functional outcomes is of utmost importance. In this study, we found that CES improved nerve regeneration and reinnervation well beyond that of CCL. Specifically, compared to CCL, CES resulted in greater intraepidermal skin and NMJ reinnervation, and greater physiological and functional recovery including mechanosensation, compound muscle action potential on nerve conduction studies, normalization of gait pattern, and motor performance on the horizontal ladder test. These findings have direct clinical relevance as CES could be delivered at the bedside before scheduled nerve surgery.

Reliability of the Chinese version of the perceived family burden scale.

The study examined reliability of the 24-item Chinese version of the perceived family burden scale (CPFBS), which is a measure of behaviors associated with Chinese people with schizophrenia and the impacts of these behaviors on caregivers and relatives. Many patients with mental illness are returning to the community and living with families. Unfortunately, family members who have to live with the patients experience a sense of burden. The CPFBS is able to measure the perceived burden of the family, which enables therapists to formulate the most appropriate family intervention for them. The CPFBS was translated and culturally adapted from the English version. Some 21 main caregivers of individuals with schizophrenia were asked to rate the items on the scale by a competent administrator through a telephone interview (this was carried out twice, with 1 day between each interview). The results showed that CPFBS had high internal consistency (alpha=0.85) and acceptable test-retest reliability (r=0.86). We suggest that the CPFBS is ready to be used by clinicians and researchers in the study on family burden of individuals with schizophrenia in Hong Kong and in Chinese communities in other countries.

Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors.

Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 µM concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.

A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas.

The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.

Vocational outcomes of an integrated supported employment program for individuals with persistent and severe mental illness.

We examined the effectiveness of an integrated supported employment (ISE) program, which augments Individual Placement & Support (IPS) with social skills training (SST) in helping individuals with SMI achieve and maintain employment. A total of 163 participants were randomly assigned to three vocational rehabilitation programs: ISE, IPS, and traditional vocational rehabilitation (TVR). After fifteen months of services, ISE participants had significantly higher employment rates (78.8%) and longer job tenures (23.84 weeks) when compared with IPS and TVR participants. IPS participants demonstrated better vocational outcomes than TVR participants. The findings suggested that ISE enhances the outcomes of supported employment, endorsing the value of SST in vocational rehabilitation.

Effect of a qigong exercise programme on elderly with depression.

OBJECTIVES: This report released findings of a randomized controlled trial conducted in Hong Kong to further our understanding of the psychosocial effects of qigong on elderly persons with depression. DESIGN: Eighty-two participants with a diagnosis of depression or obvious features of depression were recruited and randomly assigned into the intervention and comparison group. The intervention group was given a 16-week period of Qigong practice while the comparison group participated in a newspaper reading group with same duration and frequency. RESULTS: After eight weeks of qigong practice, the intervention group participants outstripped themselves in improvement in mood, self-efficacy and personal well being, and physical and social domains of self-concept when compared with comparison subjects. After 16 weeks of practice, the improvement generalized to the daily task domain of the self-concept. CONCLUSIONS: This report shows that regular qigong practice could relieve depression, improve self-efficacy and personal well being among elderly persons with chronic physical illness and depression.