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Background: Conservative management of atypical endometrial hyperplasia (AEH) or endometrial cancer (EMCA) often relies on the treatment of synthetic progestins, which show varied success and response rates. We evaluate the correlation between steroid receptor expression and response to progestin therapy in patients with AEH and EMCA., Methods: Retrospective cohort study collected data for patients with AEH or EMCA who had an endometrial sample after receiving conservative therapy utilizing either Megestrol acetate or Levonorgestrel Intrauterine device (IUD). Immunohistochemistry (IHC) was performed on pre- and post- treatment biopsy samples to assess androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) expression. IHC scores (1-12) were calculated based on staining intensity and percentage of positive cells., Results and Analysis: We identified 15 patients with AEH and EMCA between 2015 and 2023 with the majority of African American ethnicity (53 %). Fourteen patients (93 %) received Megestrol acetate, and 1 patient received Levonorgestrel IUD alone. Three patients ultimately underwent hysterectomy. Seven (46.6 %) endometrial samples had strong positivity for AR, PR and ER expression on pre-treatment biopsies, and only 3 (20 %) of them maintained strong positivity for the 3 receptors in the post-treatment. Patients who successfully responded to the treatment demonstrated a significantly greater decrease in IHC scores after the treatment compared to those who did not respond (p = 0.009)., Conclusion: Steroid receptor expression could be used as a possible biomarker for response to progestin therapy in patients undergoing conservative management for AEH and EMCA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Tooth decay is the most common chronic disease in children, and children often see their primary care practitioners more frequently than dentists (Adjaye-Gbewonyo and Black 2019-2020; National Center for Health Statistics 2019-2020). This Infant Oral Health Education Program included two online training sessions for trainees in social work, nursing, medicine, and dentistry. Trainees were assessed on anticipated changes to their practice related to children's oral health. During the first training session, trainees received a lecture on infant oral health, and then discussed a case study in interprofessional groups to reinforce the content. Trainees in medicine and nursing completed training to receive Medicaid reimbursement for performing preventive oral health services. The second training session was profession specific with tailored instructions in the form of videos, as well as a demonstration on fluoride varnish application. Of the 78 trainees (22 social work, 4 pediatric nurse practitioner, 38 pediatric medicine residents, and 14 pediatric dentistry residents), 91% (n=70) reported that they were introduced to at least one new health information resource or tool. Four-fifths of the eligible trainees (n=16/20, 80%) who completed the evaluation had fulfilled the State's requirements to receive Medicaid reimbursement for performing preventive oral health services. Three-fourths of trainees (n=22/29, 75%) reported that they are likely to promote children's oral health in future clinical practice. Trainees from all four professions provided positive feedback about the content.

Objective: Adolescent relationship abuse (ARA) is associated with myriad negative health outcomes. Pediatric primary care presents an opportunity to engage adolescents and parents, who can be protective against ARA, in ARA prevention; however, no family-focused, health care-based ARA interventions exist. The purpose of this study is to explore the perspectives of adolescents, parents, and health care providers (HCPs) on incorporating ARA prevention into primary care, including 1) current discussions around ARA, 2) how to best include ARA prevention education, and 3) how to address implementation barriers., Methods: We conducted individual, semi-structured interviews with HCPs, adolescents ages 11 to 15, and parents recruited through convenience sampling. Transcripts were individually coded by 4 study team members (with every third transcript co-coded to assess discrepancies) and analyzed via thematic analysis., Results: Participants identified a need for pediatric HCPs to involve younger adolescents and parents in universal, inclusive ARA prevention and noted that HCPs require training, techniques, and resources around ARA. Participants acknowledged multilevel barriers to implementing primary care-based ARA prevention. They suggested that ARA education be intentionally integrated into HCP and clinic workflows and recommended strategies to garner adolescent and parent buy-in to facilitate ARA-focused conversations., Conclusions: Pediatric primary care is a promising environment to involve parents and adolescents in universal ARA-prevention. Future research should contextualize these results with larger samples across multiple practice settings and integrate relevant partners in the development and evaluation of evidenced-based ARA prevention for pediatric primary care., (Copyright © 2023. Published by Elsevier Inc.)

Mental healthcare disparities are routinely documented, yet they remain wider than in most other areas of healthcare services and common mental disorders (depression and anxiety) continue to be one of the highest health burdens for older people of color. To address disparities in mental health services for older people of color, the narrative must move beyond simply documenting these inequities and attain a better understanding of the internalized, interpersonal, systemic, and medical racism that have harmed these communities and excluded them from its services in the first place. It is imperative that researchers, clinicians, and policymakers acknowledge the realities of racism and discrimination as leading causes of mental healthcare disparities. Therefore, this review is a call-to-action. Authors adopt an antiracist and health equity lens in evaluating the differing needs of Blacks/African-Americans, Asian Americans, and Latinos by exploring psychiatric comorbidity, experiences with seeking, accessing, and engaging in treatment, and the unique cultural and psychosocial factors that affect treatment outcomes for these diverse groups. Further, authors offer researchers and practitioners tangible tools for developing and implementing culturally-sensitive, mental health focused interventions for older people of color with special attention placed on cultural adaptations, models of care, prevention, and practical strategies that can be implemented to reduce disparities and increase equity in mental healthcare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: To demonstratefull-thickness excision of the affected muscularis along the submucosal plane., Design: Stepwise demonstration of LRSD technique with narrated video footage., Setting: LRSD takes advantage of the submucosal layer of the bowel wall and uses it as an easier line of excision for rectal endometriosis compared with the very difficult traditional line of excision of irregular disease-muscularis interface. The expansion of the submucosal layer by the injection separates the affected muscularis away from the mucosa, making it safer to excise the lesion with less chance of entering the bowel lumen. Excision of disease is more complete with LRSD because the full-thickness excision of the muscularis layer includes the healthy deep muscularis, which will form the disease-free deep excision margin., Intervention: This video will highlight anatomic and technical aspects of LRSD including the following key steps: 1. Mobilization of diseased bowel segment 2. Submucosal injection 3. Circumferential incision of the muscularis 4. Submucosal dissection along the submucosal plane 5. Bowel wall integrity test 6. Muscularis defect repair CONCLUSION: Rectal shaving by LRSD appears to be easier, safer, and more complete in excision of bowel endometriosis than the classical rectal shaving technique. This modification requires further evaluation to confirm its potential in the surgical management of rectosigmoid deep infiltrative endometriosis., (Copyright © 2021 AAGL. All rights reserved.)

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na + channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid β-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with inherited forms of Parkinson's disease (PD), causing disease by a gain of kinase function. Here, we describe a series of isogenic iPSC lines with any of five pathogenic mutations (N1437H, R1441C, Y1699C, G2019S and I2020T); two hypothesis testing mutations (GTP binding null, T1348N, and kinase dead, K1906M) and two LRRK2 knockouts. This resource could be used to assess effects of mutations on the function of endogenous LRRK2 and/or to study LRRK2 interactors and substrates in iPSC-derived cellular models., (Published by Elsevier B.V.)

Objective: Scalable, deliberate practice training strategies to administer evidence-based recommendations are necessary to improve human papillomavirus (HPV) vaccination rates. We sought to characterize resident clinicians' perceptions regarding the usability of the HPV Vaccine: Same Way, Same Day smartphone application (app). Usability, a critical aspect of digital programs to promote behavior change, was evaluated., Methods: Fifteen third-year pediatric residents were recruited to complete a usability evaluation of the HPV Vaccine: Same Way, Same Day app, which includes simulated role-play scenarios in which users interact, as a pediatrician avatar, with an animated parent hesitant to accept the vaccine for her child. The app provides information about the vaccine and utilizes deliberate practice, a purposeful and systematic approach to improve performance, to teach evidence-based vaccine recommendation practices, including motivational interviewing skills. Data were derived from in-depth, semistructured interviews with pediatric residents. We used a constructivist general inductive approach to illuminate perspectives via inductive coding and pattern identification. Garrison's theoretical construct on self-directed learning was used to cluster themes into conceptual categories., Results: We classified interview data in 3 conceptual categories: self-management, internal monitoring and motivational principles. Residents described the app as interactive, easy to use, succinct, informative, engaging, and practical. All residents would recommend the HPV Vaccine: Same Way, Same Day app to a colleague. Residents suggested adding more complex cases for future iterations., Conclusions: From their perspective, pediatric residents reported that an app using deliberate practice principles has the potential to inform and advance providers' counseling skills regarding the HPV vaccine., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Treating and reusing greywater for agricultural irrigation is becoming increasingly prevalent in water-scarce regions such as the Middle East. However, the potential for antibiotic-resistant bacteria to be introduced into food systems or the environment via greywater reuse is a potential area of concern. It is known that off-grid treated greywater often has elevated levels of bacteria, however, little is known regarding the prevalence of antibiotic-resistant bacteria in this water source. To address this knowledge gap, samples (n = 61) of off-grid, household greywater (influent), treated greywater effluent, and irrigation pond water were collected between October 2017 and June 2018 from four farms in the West Bank, Palestinian Territories. Samples were tested for pH, turbidity, dissolved oxygen, electrical conductivity, and oxidation reduction potential. Standard membrane filtration was used to enumerate presumptive Escherichia coli, and isolates (n = 88) were purified, confirmed using 16S rRNA sequencing, and subjected to antimicrobial susceptibility testing using microbroth dilution. The majority of influent (76.5%) and effluent (70.6%) samples had detectable presumptive E. coli. Interestingly, the majority of the isolates were confirmed as Klebsiella sp. (n = 37), followed by E. coli (n = 32), and the remainder were classified as other Enterobacteriaceae (n = 19). A higher percentage of effluent isolates were fully susceptible to all tested antibiotics when compared to influent isolates (28.6% vs 18.6%). Resistance was most commonly observed against ampicillin (69.3% of all isolates), trimethoprim-sulfamethoxazole (11.4%), tetracycline (9.1%), and cefazolin (7.9%), and 7.9% of isolates were observed to be multidrug-resistant. While most water quality parameters were within Israeli and Palestinian wastewater reuse requirements, E. coli levels in effluent violated available standards. These findings suggest that, despite observed decreases in bacteria and an overall decrease in isolates expressing antibiotic resistance from influent to effluent, off-grid greywater treatment systems are still a potential source of both susceptible and antibiotic-resistant bacteria in the agricultural environment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Study Objective: To demonstrate laparoscopic shaving of deeply infiltrative endometriosis affecting the rectosigmoid colon, with particular emphasis on the anatomic and technical aspects of the procedure., Design: Stepwise demonstration of the technique with narrated video footage., Setting: Intestinal involvement in deep endometriosis is estimated to occur in 8% to 12% of patients, with 90% of occurrences being located in the colorectal segment. Deep endometriosis of the rectosigmoid is defined as endometriosis involving the muscular layer of the bowel wall, usually >5 mm deep, thus excluding superficial lesions that only affect the serosal layer. In cases in which medical therapy is unsatisfactory, rectosigmoid deep endometriosis can be surgically managed by 3 recognized surgical techniques: (1) rectal shaving, (2) disc excision, and (3) segmental resection. There are helpful recommendations for different approaches on the basis of the characteristics of the lesion, including the size, length, depth of invasion, involved rectal circumference, and number of lesions, among other factors [1]. Rectal shaving is well suited for smaller lesions, typically <3 cm, and involves "shaving" the lesion in the affected muscular layer of the bowel wall off the mucosa, ideally without entering the bowel lumen. It is associated with lower rates of perioperative complications and lower probability of long-term postoperative bladder and bowel dysfunctions [2]., Interventions: This video demonstrates and highlights the anatomic and technical aspects of the following important steps of the rectal shaving procedure: (1) suspension of ovaries; (2) mobilization of the diseased segment of the rectum; (3) shaving of the lesions, with pertinent comments at different stages of nodule excision; (4) checking for the integrity of the bowel wall; and (5) suture of the muscularis defect after excision of the lesions from the muscularis layer of the bowel., Conclusion: Compared with other alternatives, shaving for bowel endometriosis is a more conservative procedure with lower rates of perioperative complications, and it is less likely to result in long-term bladder and bowel dysfunctions. Therefore, shaving is preferable and recommended for appropriate lesions., (Copyright © 2019 AAGL. All rights reserved.)

Cognitive behavioral therapy (CBT) is an efficacious treatment for child anxiety disorders, but 40%-50% of youth do not respond fully to treatment, and time commitments for standard CBT can be prohibitive for some families and lead to long waiting lists for trained CBT therapists in the community. SmartCAT 2.0 is an adjunctive mobile health program designed to improve and shorten CBT treatment for anxiety disorders in youth by providing them with the opportunity to practice CBT skills outside of session using an interactive and gamified interface. It consists of an app and an integrated clinician portal connected to the app for secure 2-way communication with the therapist. The goal of the present study was to evaluate SmartCAT 2.0 in an open trial to establish usability, feasibility, acceptability, and preliminary efficacy of brief (8 sessions) CBT combined with SmartCAT. We also explored changes in CBT skills targeted by the app. Participants were 34 youth (ages 9-14) who met DSM-5 criteria for generalized, separation, and/or social anxiety disorder. Results demonstrated strong feasibility and usability of the app/portal and high satisfaction with the intervention. Youth used the app an average of 12 times between each therapy session (M = 5.8 mins per day). At posttreatment, 67% of youth no longer met diagnostic criteria for an anxiety disorder, with this percentage increasing to 86% at 2-month follow-up. Youth showed reduced symptom severity over time across raters and also improved from pre- to posttreatment in CBT skills targeted by the app, demonstrating better emotion identification and thought challenging and reductions in avoidance. Findings support the feasibility of combining brief CBT with SmartCAT. Although not a controlled trial, when benchmarked against the literature, the current findings suggest that SmartCAT may enhance the utility of brief CBT for childhood anxiety disorders., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: The population in United States aged 65 and older has rapidly grown and is projected to grow faster than any other segment of the population. Despite this demographic shift, the nation's geriatric workforce is shrinking., Aim: The primary goal of the fellowship was to form a learning collaborative that would help trainees in medicine, nursing, social work, pharmacy and occupational/physical therapy understand the roles of each discipline involved in the provision of geriatric mental healthcare and to enhance basic knowledge of common geriatric syndromes., Methods: Faculty from the University of Pittsburgh developed a format for the mini-fellowship. Trainees from five disciplines were recruited for participation in the mini-fellowship. This was offered annually over four-year period, hosted by the John A. Hartford Foundation Centers of Excellence in Geriatric Psychiatry at the University of Pittsburgh and University of California at San Diego., Results: Eighty-one participants across five schools of the health sciences completed the mini-fellowship. Feedback was positive: most participants appreciated learning from other team members, endorsed appreciation of the contributions of other disciplines to patient care, and reported improved understanding of three major geriatric syndromes., Conclusion: Conducting an interdisciplinary mini-fellowship in geriatric mental health was feasible and well received by trainees. The fellowship enabled better appreciation for the provision of geriatric mental health care within the context of an interprofessional team. However, decanal and faculty leadership across the schools needs to place greater emphasis on the importance of interprofessional team-based learning and to free up time for such activity., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Enduring cognitive models of anxiety posit that negative biases in information processing are implicated in the etiology, maintenance, and recurrence of anxiety disorders in youth and adults. Specifically, the vigilance-avoidance model of attention is an influential hypothesis proposed to explain anxious individuals' attentional patterns. The vigilance-avoidance model posits that anxious individuals, relative to nonanxious individuals, initially orient more quickly to threatening stimuli and then later avoid threatening stimuli. However, a large body of empirical research examining attentional mechanisms in anxious individuals uses paradigms that do not allow the measurement of the time course of attention. Furthermore, existing reviews that examine the time course of attention only include studies with adults. We systematically review in depth the literature that compares anxious and non-anxious children that takes advantage of research designs that allow the examination of the time course of attention. Across studies, there is not robust support for the vigilance-avoidance model in samples of anxious youth. Future research examining attention biases across time should employ tasks that more directly measure multiple stages of attention, in order to assess if vigilance-avoidance patterns emerge based on sample characteristics or task variables, and to inform intervention efforts., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Children who are fearful and anxious are at heightened risk for developing depression in adolescence. Treating anxiety disorders in pre-/early adolescence may be one mechanism through which depressive symptoms later in adolescence can be prevented. We hypothesized that anxious youth who responded positively to cognitive-behavioral therapy (CBT) for anxiety would show reduced onset of depressive symptoms 2 years later compared to treatment nonresponders, and that this effect would be specific to youth treated with CBT compared to an active supportive comparison treatment., Method: Participants were 80 adolescents ages 11 to 17 years who had previously completed a randomized trial comparing predictors of treatment response to CBT and child-centered therapy (CCT). Youth met DSM-IV criteria for generalized, separation, and/or social anxiety disorder at the time of treatment. The present study was a prospective naturalistic 2-year follow-up examining trajectories toward depression, in which participants were reassessed for depressive symptoms 2 years after anxiety treatment. Treatment response was defined as a 35% reduction in independent evaluator-rated anxiety severity on the Pediatric Anxiety Rating Scale after treatment., Results: As hypothesized, lower levels of depressive symptoms were observed in anxious youth who responded to CBT for anxiety (β = -0.807, p = .004) but not CCT (β = 0.254, p = .505). Sensitivity analyses showed that the effects were driven by girls., Conclusion: Findings suggest that CBT for anxiety is a promising approach to preventing adolescent depressive symptomatology, especially among girls. The results highlight the need for better early screening for anxiety and better dissemination of CBT programs targeting anxiety in youth., (Copyright © 2019 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

To determine how obstetricians and gynecologists (OB/GYNs) perceive the gynecologic health effects of obesity and to identify perceived obstacles to counseling. OB/GYNs with 3 St. Louis health systems were emailed a 46-question survey regarding physicians' role in counseling women on the health risks of obesity and barriers faced in achieving this counseling. Differences between respondents' gender, age, practice type, years in practice, and body mass index were assessed using Chi-square or Fisher's exact tests as appropriate. Of 318 OB/GYNs emailed, 134 completed surveys, including 82 generalists and 52 subspecialists. 93% of respondents believed it was necessary to educate patients on health risks of obesity. 90% and 75%, respectively, cited diagnoses of endometrial hyperplasia and cancer as teachable moments for counseling. The most frequently cited barriers to successful counseling were lack of time, referral services, and patient tools/information. Most did not believe they had adequate reimbursement (65%), training (53%) or educational resources (50%) to counsel patients. Survey answers differed by practice setting, gender, and provider age. Although most OB/GYN providers consider obesity counseling important, execution is hindered by perceived barriers that differ by provider gender, age, and practice type. For OB/GYNs, more effective weight management counseling will require better training and practice-specific strategies. Based on survey responses, better reimbursement combined with increased resources for appropriate referrals and cancer prevention counseling are needed in order to improve weight management implementation in OB/GYN. •The majority of OB/GYNs believe obesity counseling is important•Perceptions of obesity counseling differ based on provider/practice characteristics.•Lack of time, referral services, and patient tools are the biggest cited barriers to counseling.•Improved obesity counseling could improve downstream OB/GYN morbidities.

Mitochondria are best known for their role in ATP generation. However, studies over the past two decades have shown that mitochondria do much more than that. Mitochondria regulate both necrotic and apoptotic cell death pathways, they store and therefore coordinate cellular Ca 2+ signaling, they generate and metabolize important building blocks, by-products and signaling molecules, and they also generate and are targets of free radical species that modulate many aspects of cell physiology and pathology. Most estimates suggest that although the brain makes up only 2 percent of body weight, utilizes about 20 percent of the body's total ATP. Thus, mitochondrial dysfunction greatly impacts brain functions and is indeed associated with numerous neurodegenerative diseases. Furthermore, a number of abnormal disease-associated proteins have been shown to interact directly with mitochondria, leading to mitochondrial dysfunction and subsequent neuronal cell death. Here, we discuss the role of mitochondrial dynamics impairment in the pathological processes associated with neurodegeneration and suggest that a therapy targeting mitochondrialdysfunction holds a great promise., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Competing Interests: None declared.

Humans express an enzyme that degrades chitin, called chitotriosidase, despite the fact that we do not produce chitin. One possible explanation for this is that chitinase also degrades hyaluronan, a polysaccharide that is abundant in human tissues and shares structural attributes in common with chitinase. The objective of this study was to determine whether human chitotriosidase is capable of hydrolyzing hyaluronan. Hyaluronan of various sizes under a range of pH conditions displayed no degradation when incubated with various chitinases over a period of 5 days, while commercial hyaluronidase readily digested the hyaluronan. Under the same conditions, recombinant chitinase but not our negative control chitinase, was able to digest chitosan. We conclude that human chitinase does not digest hyaluronan. Because chitin is a prominent component of certain fungi and insects, it seems likely that human chitinase evolved for roles in host defense rather than serving to catabolize the endogenous polymer hyaluronan., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Peripheral artery disease (PAD) is a multifactorial disease initially triggered by reduced blood supply to the lower extremities due to atherosclerotic obstructions. It is considered a major public health problem worldwide, affecting over 200 million people. Management of PAD includes smoking cessation, exercise, statin therapy, antiplatelet therapy, antihypertensive therapy and surgical intervention. Although these pharmacological and non-pharmacological interventions usually increases blood flow to the ischemic limb, morbidity and mortality associated with PAD continue to increase. This scenario raises new fundamental questions regarding the contribution of intrinsic metabolic changes in the distal affected skeletal muscle to the progression of PAD. Recent evidence suggests that disruption of skeletal muscle mitochondrial quality control triggered by intermittent ischemia-reperfusion injury is associated with increased morbidity in individuals with PAD. The mitochondrial quality control machinery relies on surveillance systems that help maintaining mitochondrial homeostasis upon stress. In this review, we describe some of the most critical mechanisms responsible for the impaired skeletal muscle mitochondrial quality control in PAD. We also discuss recent findings on the central role of mitochondrial bioenergetics and quality control mechanisms including mitochondrial fusion-fission balance, turnover, oxidative stress and aldehyde metabolism in the pathophysiology of PAD, and highlight their potential as therapeutic targets., Competing Interests: Daria Mochly-Rosen filed patents on ALDH2 activators and is in a process of licensing these. The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca(2+) transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases., Competing Interests: All authors have read and approved the final article. Authors reports no conflicts, (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Parasitic diseases cause ∼ 500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase) and TRACK (Trypanosoma receptor for activated C-kinase). We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase), may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs.

Background/objectives: We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy are unknown and should be established to determine the optimal time window for drug treatment., Methods: Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H₂O₂ release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats., Results: We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H₂O₂ release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24h after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats., Conclusion: Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction cardiomyopathy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Kidney Disease Outcome Quality Initiative guidelines recommend permanent access in dialysis patients aged 0 to 19 years who weigh >20 kg and are unlikely to receive a transplant within 1 year. Unfortunately, >80% of these patients currently receive dialysis through a permanent catheter and are exposed to the associated risks and shortcomings. With a clear imperative to increase the incident use of permanent access in pediatric patients, our objective was to examine the long-term outcomes of pediatric arteriovenous fistulas (AVFs)., Methods: A retrospective review was performed of all AVFs created in a hemodialysis (HD) population aged 0 to 19 years at a single institution from 1999 to 2012. Data abstracted included age, weight, etiology of renal failure, time on dialysis, central venous catheter history, and transplantation history. Data were analyzed to determine the influence of these variables on primary and secondary patency., Results: During the study period, 101 AVFs were performed in 93 patients, of whom 65 patients (70%) were male. Mean patient age was 14 years (range, 3-19 years), and mean weight was 51 kg (range, 12-131 kg). At the time of AVF creation, 66 patients (82%) were already receiving HD, with a mean length of HD dependence of 18 months. At the time of surgery, 78% of patients had a previous central venous catheter, and 24% had two or more catheters. Procedures performed included 43 radiocephalic fistulas, 29 brachiocephalic fistulas, 20 basilic vein transpositions, and 9 femoral vein transpositions. Mean follow-up was 2.5 years. The 2-year and 4-year primary and secondary patency rates were 83% and 92%, and 65% and 83%, respectively. Increasing age was correlated with improved primary patency (P = .02) but had no effect on secondary patency. Weight, etiology, catheter location, and catheter history were not significantly associated with primary or secondary patency. During the postoperative period, 68 patients (75%) received a renal transplant, with a mean time to transplant of 556 days., Conclusions: AVFs demonstrate excellent long-term patency with minimal complications in pediatric HD patients, regardless of weight. Concerted efforts should be made to improve the incident use of AVFs in all pediatric patients with end-stage renal disease., (Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: This study examines how communication patterns vary across racial and ethnic patient-clinician dyads in mental health intake sessions and its relation to continuance in treatment, defined as attending the next scheduled appointment., Methods: Observational study of communication patterns among ethnically/racially concordant and discordant patient-clinician dyads. Primary analysis included 93 patients with 38 clinicians in race/ethnic concordant and discordant dyads. Communication was coded using the Roter Interaction Analysis System (RIAS) and the Working Alliance Inventory Observer (WAI-O) bond scale; continuance in care was derived from chart reviews., Results: Latino concordant dyad patients were more verbally dominant (p<.05), engaged in more patient-centered communication (p<.05) and scored higher on the (WAI-O) bond scale (all p<.05) than other groups. Latino patients had higher continuance rates than other patients in models that adjusted for non-communication variables. When communication, global affect, and therapeutic process variables were adjusted for, differences were reversed and white dyad patients had higher continuance in care rates than other dyad patients., Conclusion: Communication patterns seem to explain the role of ethnic concordance for continuance in care., Practice Implications: Improve intercultural communication in cross cultural encounters appears significant for retaining minorities in care., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Pervious biochemical and hemodynamic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias., Methods: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30 min stabilization period, 15 min of no-flow ischemia, followed by 20 min reperfusion. Peptides (0.5 μM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); (b) εPKC agonist (TAT-ψεRACK); (c) εPKC antagonist (TAT-εV1)., Results: Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P<0.05) and (VF, 70%, P < 0.05). However, the highest incidence of VT (100%, P < 0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20 min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (P < 0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P < 0.5) of hearts in control. At 20 min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2 ± 9 ms) compared to exacerbated dispersion (115.4 ± 42 ms, P < 0.05) in εPKC antagonist and control (67 ± 20 ms, P<0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control., Conclusion: The results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents., (Published by Elsevier Inc.)

Cyclic ADP-ribose (cADPR) is a second messenger that acts on ryanodine receptors to mobilize Ca(2+). cADPR has a net negative charge at physiological pH making it not passively membrane permeant thereby requiring it to be injected, electroporated or loaded via liposomes. Such membrane impermeance of other charged intracellular messengers (including cyclic AMP, inositol 1,4,5-trisphosphate and nicotinic acid adenine dinucleotide phosphate) and fluorescent dyes (including fura-2 and fluorescein) has been overcome by synthesizing masked analogs (prodrugs), which are passively permeant and hydrolyzed to the parent compound inside cells. We now report the synthesis and biological activity of acetoxymethyl (AM) and butoxymethyl (BM) analogs of cADPR. Extracellular addition of cADPR-AM or cADPR-BM to neuronal cells in primary culture or PC12 neuroblastoma cells induced increases in cytosolic Ca(2+). Pre-incubation of PC12 cells with thapsigargin, ryanodine or caffeine eliminated the response to cADPR-AM, whereas the response still occurred in the absence of extracellular Ca(2+). Combined, these data demonstrate that masked cADPR analogs are cell-permeant and biologically active. We hope these cell-permeant tools will facilitate cADPR research and reveal its diverse physiological functions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Herein is described an anterior approach to uterine artery ligation during laparoscopic myomectomy and total laparoscopic hysterectomy. The anterior leaf of the broad ligament is opened and the uterine artery is clipped lateral to its crossing over the ureter. Outcome measures were completion of the procedure laparoscopically and the need for transfusion postoperatively. Thirty-eight myomectomies and 28 difficult total laparoscopic hysterectomies (primarily uteri with large myomas) were performed, with 1 conversion to laparotomy during myomectomy and 1 during hysterectomy, and 1 transfusion after total laparoscopic hysterectomy. The anterior approach to uterine artery ligation is an alternative method for treatment of uterine artery occlusion during laparoscopic myomectomy or hysterectomy performed to treat large myomas., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Background: Emerging evidence showed that resistin induces vascular smooth muscle cell (VSMC) migration, a critical step in initiating vascular restenosis. Adhesion molecule expression and cytoskeletal rearrangement have been observed in this progress. Given that matrix metalloproteinases (MMPs) also regulate cell migration, we hypothesized that MMPs may mediate resistin-induced VSMC migration., Methods: Human VSMCs were treated with recombinant human resistin at physiologic (10 ng/mL) and pathologic (40 ng/mL) concentrations for 24 hours. Cell migration was determined by the Boyden chamber assay. MMP and tissue inhibitor metalloproteinase (TIMP) mRNA and protein levels were measured with real-time PCR and ELISA. MMP enzymatic activity was measured by zymography. In another experiment, neutralizing antibodies against MMP-2 and MMP-9 were coincubated with resistin in cultured VSMCs. The regulation of MMP by protein kinase C (PKC) was determined by εV1-2, a selective PKCε inhibitor., Results: Resistin-induced smooth muscle cell (SMC) migration was confirmed by the Boyden chamber assay. Forty nanograms/milliliter resistin increased SMC migration by 3.7 fold. Additionally, resistin stimulated MMP-2 and -MMP9 mRNA and protein expressions. In contrast, the TIMP-1 and TIMP-2 mRNA levels were inhibited by resistin. Neutralizing antibodies against MMP-2 and MMP-9 effectively reversed VSMC migration. Furthermore, resistin activated PKCε, but selective PKCε inhibitor suppressed resistin-induced MMP expression, activity, and cell migration., Conclusions: Our study confirmed that resistin increased vascular smooth muscle cell migration in vitro. In terms of mechanism, resistin-stimulated cell migration was associated with increased MMP expression, which was dependent on PKCε activation., (Published by Mosby, Inc.)

In this study, differences in sensitivity between Long-Evans (L-E; dioxin sensitive) and Han/Wistar (H/W; dioxin resistant) rats following long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were statistically and quantitatively investigated. Sensitivity differences were analyzed by comparing benchmark doses (BMDs) for the two strains considering a number of toxicological endpoints including data on body and organ weights, hepatic foci, hepatic CYP1A1 induction, as well as tissue retinoid levels. Dose-response relationships for L-E and H/W rats, described by the Hill function, were assumed to be parallel, which was supported according to statistical analysis. It was concluded that L-E and H/W rats differed statistically in their response to TCDD treatment for most of the parameters investigated. Differences between the strains were most pronounced for hepatic foci; L-E rats were approximately 20-40 times more sensitive than H/W rats. For body and organ weight parameters, L-E rats were approximately 10-20 times more sensitive than H/W rats. For retinoid parameters and hepatic CYP1A1 induction, estimated differences between the strains were generally about 5-fold, and associated with a low uncertainty. In conclusion, the present study employs a dose-response modeling approach suitable for statistical evaluation of strain and species differences in sensitivity to chemical exposure. The study demonstrates quantitatively the differences in sensitivity between the L-E and H/W rat strains following long-term TCDD exposure., (Copyright 2010 Elsevier Inc. All rights reserved.)

Heart failure (HF) in which the blood supply does not match the body's needs, affects 10% of the population over 65 years old. The protein kinase C (PKC) family of kinases has a key role in normal and disease states. Here we discuss the role of PKC in HF and focus on the use of specific PKC regulators to identify the mechanism leading to this Pathology and potential leads for therapeutics.

Cardiac mitochondria, the main source of energy as well as free radicals, are vital organelles for normal functioning of the heart. Mitochondrial number, structure, turnover and function are regulated by processes such as mitochondrial protein quality control, mitochondrial fusion and fission and mitophagy. Recent studies suggest that abnormal changes in these mitochondrial regulatory processes may contribute to the pathology of heart failure (HF). Here we discuss these processes and their potential as therapeutic targets.

Objective: Stigma associated with mental illness continues to be a significant barrier to help seeking, leading to negative attitudes about mental health treatment and deterring individuals who need services from seeking care. This study examined the impact of public stigma (negative attitudes held by the public) and internalized stigma (negative attitudes held by stigmatized individuals about themselves) on racial differences in treatment-seeking attitudes and behaviors among older adults with depression., Method: Random digit dialing was utilized to identify a representative sample of 248 African American and white older adults (older than 60 years) with depression (symptoms assessed by the Patient Health Questionnaire-9). Telephone-based surveys were conducted to assess their treatment-seeking attitudes and behaviors and the factors that impacted these behaviors., Results: Depressed older adult participants endorsed a high level of public stigma and were not likely to be currently engaged in or did they intend to seek mental health treatment. Results also suggested that African American older adults were more likely to internalize stigma and endorsed less positive attitudes toward seeking mental health treatment than their white counterparts. Multiple regression analysis indicated that internalized stigma partially mediated the relationship between race and attitudes toward treatment., Conclusion: Stigma associated with having a mental illness has a negative influence on attitudes and intentions toward seeking mental health services among older adults with depression, particularly African American elders. Interventions to target internalized stigma are needed to help engage this population in psychosocial mental health treatments.

Background: We aimed to compare two techniques of heterotopic heart transplantation in rats. Non-volume-loaded (NL) and volume-loaded (VL) models were tested for their physiologic and immunologic properties to assess their suitability for transplant studies., Methods: Syngeneic heterotopic heart transplants were performed according to the techniques previously described by Ono (NL) and Yokoyama (VL). Grafts were followed over 90 days with sequential echocardiography. Ex-vivo Langendorff perfusion was used to gain functional data. Allogeneic heart transplants were done to determine whether chronic allograft vasculopathy (CAV) develops at a different pace in both transplant models., Results: The ischemic time during surgery was significantly longer using the VL model (p<0.001). The LV diameter of NL hearts decreased over time while that of the VL model significantly increased (p=0.004 on POD 90). Mean LV developed pressure and (dP/dt)max were significantly higher with the NL model (61.1+/-8.5 mmHg and 4261.7+/-419.6 mmHg/s) than with VL hearts (19.9+/-16.5 mmHg; p=0.011 and 924.8+/-605.6 mmHg/s; p<0.001). The mean weight of NL hearts (0.45+/-0.03 g) was significantly less than that of VL hearts (1.21+/-0.16 g, p<0.001). Histology of syngeneic NL grafts showed healthy, but partly atrophic myocardium, whereas the LV myocardium of VL hearts showed dilation and scarring typical for chronic ischemic injury. Heart allografts similarly developed CAV with luminal narrowing of 37.2+/-16.6% (NL) and 34.4+/-21.4% (VL), respectively by POD 90 (p=0.807)., Conclusions: Since the coronary arteries in the VL model get perfused with partly deoxygenated blood, the myocardium suffers from chronic ischemic injury. We recommend using the NL model in preclinical transplant studies., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Objectives: The aging opioid-addicted cohort from the 1970s has begun to alter the demographic characteristics of individuals in need of services for heroin addiction. Yet, despite clear trends that indicate the population of older methadone patients is increasing, little is known about their well-being and service needs. The goal of this study was to assess the physical and mental health status of older methadone patients., Design: Face-to-face interviews were conducted with study participants., Setting: This study was conducted at a free-standing methadone clinic in a Midwestern industrial city., Participants: A clinic sample of 140 adult methadone patients over the age of 50 was recruited for face-to-face interviews., Measures: Mental health status was assessed by the Composite International Diagnostic Interview. The SF-12v2 was administered to measure a range of physical health issues. Participants were also asked about a variety of chronic conditions. In addition, respondents provided access to their drug screen results from monthly urine tests for illegal drug use for 1 year before and 1 year after the interview., Results: Findings revealed that over half (57.1%) of respondents had at least one mental health disorder in the past year. In the year before the interview, the most prevalent mental health disorder experienced by older adult patients was major depressive episode (32.9%). The most prevalent anxiety disorders were posttraumatic stress disorder (27.8%) and generalized anxiety disorder (29.7%). Additionally, women experienced significantly higher levels of depression than males (43.8% versus 27.2%), and nearly twice the prevalence rate of agoraphobia and panic disorders. Regarding physical health, respondents reported high rates of health problems in the past year, including arthritis (54.3%) and hypertension (44.9%). The majority of respondents reported having fair to poor physical health (57.7%). When examining the entire 24-month period during which urine data were collected, three quarters (76.4%) of the respondents had at least 1 month where the urine screen detected illegal drug use., Conclusions: In the next decade, the growing and aging substance abusing population will require clinicians trained in both geriatrics and substance abuse. Health and mental health professionals have the opportunity to address the specialized needs of this population and prepare for the shifting service needs these older patients will require.

NAADP (nicotinic acid adenine dinucleotide phosphate) is a recently discovered second messenger, and as such, we have much yet to learn about its functions in health and disease. A bottleneck in this basic research is due to NAADP, like all second messengers, being charged to prevent it from leaking out of cells. This makes for effective biology, but imposes difficulties in experiments, as it must be injected, loaded via liposomes, or electroporated, techniques that are highly technically demanding and are possible only in certain single cell preparations. For the better understood second messenger inositol 1,4,5-trisphosphate, great success has been obtained with cell-permeant derivatives where the charged groups are masked through esterification. We now report NAADP-AM as a cell-permeant analogue of NAADP that is taken up into cells and induces NAADP-mediated Ca(2+) signalling. NAADP-AM is a powerful chemical tool that will be of enormous biological utility in a wide range of systems and will greatly facilitate research into the role of NAADP in health and disease.

Current treatment for acute myocardial infarction (AMI) is aimed at limiting the duration of ischemia by either mechanical (balloon catheters) or enzymatic (thrombolytics) means to disrupt the occlusion. While these treatments are effective in limiting the duration of ischemia, no therapeutic treatment is currently available to prevent ischemic injury and to reduce reperfusion injury, which occurs after these interventions. The development of rationally designed PKC isozyme-selective regulator peptides has permitted investigation into the role of specific PKC isozymes in ischemia-reperfusion (IR) injury. Based on these studies, it is now evident that epsilon and deltaPKC have distinct temporal and opposing roles in regulating myocardial damage induced by IR. Activation of epsilonPKC before ischemia protects the heart by mimicking preconditioning, whereas inhibition of deltaPKC during reperfusion protects the heart from reperfusion-induced damage. These cardioprotective effects have been observed in isolated cardiomyocytes, isolated perfused hearts and in vivo in all species tested including mouse, rat and pig and may provide the basis for future therapeutic agents. Having established the efficacy of PKC isozyme-specific regulators in reducing IR injury, the next challenge is to outline the molecular mechanisms regulated by delta and epsilonPKC isozymes that result in enhanced tolerance to IR. In this review, we discuss progress that has been made in establishing cytoprotective mechanisms, which arise as a consequence of epsilonPKC activation or deltaPKC inhibition, and how they may lead to protection in the setting of myocardial ischemia reperfusion.

Protein kinase C (PKC) is a family of kinases that are critical in many cellular events. These enzymes are activated by lipid-derived second messengers, are dependent on binding to negatively charged phospholipids and some members also require calcium to attain full activation. The interaction with lipids and calcium activators is mediated by binding to the regulatory domains C1 and C2. In addition, many protein-protein interactions between PKC and other proteins have been described. These include interactions with adaptor proteins, substrates and cytoskeletal elements. Regulation of the interactions between PKC, small molecules and other proteins is essential for signal transduction to occur. Finally, a number of auto-inhibitory intra-molecular protein-protein interactions have also been identified in PKC. This chapter focuses on mapping the sites for many of these inter- and intra-molecular interactions and how this information may be used to generate selective inhibitors and activators of PKC signaling.

Study Objective: To identify the volume and type of laparoscopic surgery being performed. To review the incidence, nature of associated complications, and reasons for conversion to laparotomy., Design: A multicenter, prospective case load analysis and chart review, identifying operations performed by 6 advanced laparoscopic surgeons over a 12-month period (1/1/05 to 12/31/05)., Setting: Surgical cases were performed in 5 hospitals in Sydney, New South Wales., Patients: One thousand two hundred sixty-five women underwent a variety of major and advanced operative procedures., Measurements and Main Results: A total of 1265 major and advanced laparoscopic procedures were performed. Laparoscopic hysterectomy accounted for 364 cases (28.8%), pelvic floor repair and Burch colposuspension 280 cases (22.2%), excisional endometriosis surgery 354 cases (28%), adnexal surgery 177 cases (13.9%), adhesiolysis 75 cases (5.9%), and miscellaneous cases 15 (1.2%). Overall major complications in terms of bowel, urologic, or major vessel injuries accounted for 8 cases (0.6%). There were 4 injuries of the bowel, 2 injuries to the bladder, and 2 injuries to ureters. There were no major vessel injuries. There were no injuries associated with primary trocar or Veres needle insertion. The most common perioperative morbidity reported was the requirement for blood transfusion (11 cases [0.9%]), and the second most common was venous thromboembolism (4 patients [0.3%]). Six (0.5%) cases were converted to laparotomy, 2 as a result of a complication and 4 for technical reasons. Six of the 8 complications were managed laparoscopically, and a multidisciplinary input was sought only in 4 of the 8 complications., Conclusions: Despite the advanced nature of laparoscopic procedures performed by our group, the complication rate and conversion to laparotomy remain low. There is an increasing feasibility to perform traditional open operations laparoscopically. An increasing number of these complications are now being managed laparoscopically by the gynecologist.