Early-life risperidone alters locomotor responses to apomorphine and quinpirole in adulthood.

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.

Value of cognitive interviewing in the development of the weight stigma in healthcare inventory.

BACKGROUND: Despite the detrimental effects of weight stigma in healthcare, there is no widely validated measure comprehensively examining such experiences. OBJECTIVE: We aimed to develop and pilot test an inventory to measure patient experiences of weight stigma in healthcare, and to ensure our items were easily understood. PATIENT INVOLVEMENT: During our iterative design process, patients assessed whether our inventory items were easy to understand and we included an open-ended comments question. METHODS: We compiled items from pre-existing tools assessing experiences of weight stigma in healthcare, and developed our own novel items. We conducted field pre-testing with a convenience sample of 48 patients at a Midwest academic internal medicine clinic. We utilized an iterative design process whereby respondents provided feedback on our inventory, we analyzed the data and made revisions, and then repeated the cycle. RESULTS: Respondents found some of the language in our items confusing; expressed reluctance to speculate on the motivations of healthcare providers; had difficulty with "double-barreled" questions; found some questions vague; and expressed the desire to have weight addressed in clinical encounters neither too much nor too infrequently. We altered items appropriately, and in subsequent rounds of data collection they were easier to understand. DISCUSSION: Patients found many common weight stigma survey items and some of our novel items confusing. Our modified inventory reduces patient confusion and enhances data quality. PRACTICAL VALUE: Our study demonstrates the value of cognitive interviewing. Furthermore, the WSHCI will be a useful tool for clinicians and research teams seeking to measure weight stigma in healthcare but first needs to be validated in a larger sample. FUNDING: This study was supported by the Physician Scientist Training Program, Diabetes Center T32 (DK112751), and the Clinical and Translational Science Award grant funded from the National Institutes of Health (UL1TR002537).

Obesity treatment initiation, retention, and outcomes in the Veterans Affairs MOVE! Program among rural and urban veterans.

Objective: Rural veterans have high obesity rates. Yet, little is known about this population's engagement with the Veterans Affairs (VA) weight management program (MOVE!). The study objective is to determine whether MOVE! enrollment, anti-obesity medication use, bariatric surgery use, retention, and outcomes differ by rurality for veterans with severe obesity. Methods: This is a retrospective cohort study using Veterans Health Administration patient databases, including VA patients with severe obesity during 2015-2017. Patients were categorized using Rural-Urban Commuting Area codes. Primary outcomes included proportion of patients and risk-adjusted likelihood of initiating VA MOVE!, anti-obesity medication, or bariatric surgery and risk-adjusted highly rural|Hazard Ratio (HR) of any obesity treatment. Secondary outcomes included treatment retention (≥12 weeks) and successful weight loss (5%) among patients initiating MOVE!, and risk-adjusted odds of retention and successful weight loss. Results: Among 640,555 eligible veterans, risk-adjusted relative likelihood of MOVE! treatment was significantly lower for rural and HR veterans (HR = 0.83, HR = 0.67, respectively). Initiation rates of anti-obesity medication use were significantly lower as well, whereas bariatric surgery rates, retention, and successful weight loss did not differ. Conclusions: Overall treatment rates with MOVE!, bariatric surgery, and anti-obesity medications remain low. Rural veterans are less likely to enroll in MOVE! and less likely to receive anti-obesity medications than urban veterans.

Vitamin D deficiency exacerbates UV/endorphin and opioid addiction.

The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.

Reduced MC4R signaling alters nociceptive thresholds associated with red hair.

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.

Bone Health and Osteoporosis Prevention and Treatment.

Postmenopausal osteoporosis is a common condition and is associated with increased risk of fracture, including hip and vertebral fractures that in turn can have devastating consequences on morbidity and mortality. In this article, we review the pathogenesis and diagnostic approach to postmenopausal osteoporosis. We review available nonpharmacologic and pharmacologic therapies and we discuss their clinical efficacy and complications, with a detailed discussion of atypical femur fractures and osteonecrosis of the jaw.

A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells.

The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer's. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244-372, reproduces much of the aggregation behaviour of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro. We show that this peptide lacks the ability to seed aggregation of tau244-372 in cells. However, as the hexapeptide is gradually extended to 31 residues, the peptides aggregate more slowly and gain potent activity to induce aggregation of tau244-372 in cells. X-ray fibre diffraction, hydrogen-deuterium exchange and solid-state NMR studies map the beta-forming region to a 25-residue sequence. Thus, the nucleus for self-propagating aggregation of tau244-372 in cells is packaged in a remarkably small peptide.

Skin ß-endorphin mediates addiction to UV light.

UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, ß-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in ß-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. Although primordial UV addiction, mediated by the hedonic action of ß-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in humans.

Sildenafil use and increased risk of incident melanoma in US men: a prospective cohort study.

IMPORTANCE: The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk. OBJECTIVE: To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States. DESIGN, SETTING, AND PARTICIPANTS: Our study is a prospective cohort study. In 2000, participants in the Health Professionals' Follow-up Study were questioned regarding sildenafil use for erectile dysfunction. Participants who reported cancers at baseline were excluded. A total of 25,848 men remained in the analysis. MAIN OUTCOMES AND MEASURES: The incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed. RESULTS: We identified 142 melanoma, 580 SCC, and 3030 BCC cases during follow-up (2000-2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95% CI, 1.04-3.22). In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95% CI, 0.59-1.20) or BCC (1.08; 0.93-1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR, 1.92; 95% CI, 1.14-3.22). A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95% CI, 1.05-4.78) for sildenafil use at baseline and 2.77 (1.32-5.85) for ever use. CONCLUSIONS AND RELEVANCE: Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association.

Tanning as a substance abuse.

While few people would deny the appeal of a day in the sun there are some who seem to take it too far. In recent years the concept of 'tanning addiction' has become popular and several studies have supported the notion of viewing exposure to UV radiation as a form of substance abuse. In this article we will review some of the literature on sun seeking behavior.

A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway.

Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect noncoding regions. A SNP within an intron of the gene encoding Interferon Regulatory Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. Here, we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a noncoding polymorphism that affects a phenotype by modulating a developmental gene regulatory network.

An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background.

People with pale skin, red hair, freckles and an inability to tan--the 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.

Lineage-specific transcriptional regulation of DICER by MITF in melanocytes.

DICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression--an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER's transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17 approximately 92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development.

Thyroid state and tolerance of mammalian myocardium to hypoxia.

Thyroid hormone is known to affect myocardial glycogen stores and thereby possibly limit anaerobic performance of mammalian cardiac muscle. Thyroid hormone administration (3,5,3'-triiodo-L-thyroxine, 300 microg/kg/day, sc) for 10 days decreased left ventricle (LV) glycogen concentration relative to euthyroid animals (2.78+/-0.46 vs. 4.28+/-0.29 mg/g of LV (mean+/-SEM)) while increasing the percent of V(1) myosin isozyme, contractile activity and cardiac mass. In contrast, thyroidectomy increased myocardial glycogen stores (8.50+/-0.56 mg/g of LV) and shifted the myosin isozyme toward V(3), prolonged contractile activity and decreased LV mass. Thyroxine administration for 3, 7 and 10 days to thyroidectomized animals progressively decreased contractile duration and increased LV mass. Thyroxine administration for 3 or 7 days to thyroidectomized rats did not reduce glycogen stores (7.75+/-1.02 and 9.62+/-1.16 mg/g of LV, respectively), whereas myocardial glycogen declined to 3.30+/-0.58 mg/g of LV after 10 days of treatment. During hypoxia, cardiac muscle from thyroidectomized rats maintained greater active force and developed less contracture relative to euthyroid and, to a greater extent, than hyperthyroid rats. Removal of glucose from the bath decreased anaerobic performance and impaired recovery; however, myocardium from thyroidectomized rats remained more tolerant to hypoxia than the euthyroid group. Overall, the intrinsic LV glycogen content was positively correlated to anaerobic performance. These data demonstrate that the thyroid state profoundly affects myocardial growth, contractility and anaerobic performance of rat myocardium. Although energy demand may affect function during hypoxia, anaerobic substrate reserve (cardiac glycogen concentration) appears to be the primary factor determining tolerance to hypoxic stress.

Specification and loss of melanocyte stem cells.

The melanocyte stem cells of the hair follicle provide an attractive system for the study of stem cells. The stem cells exist in an anatomically defined niche clearly separated from their differentiated progeny, differentiated progeny can be selected against by treatment with an inhibitor of Stem Cell Factor signaling, perturbations which affect survival and differentiation have clearly visible pigmentation phenotypes, and genetic mutations can impair or completely abolish this lineage without lethality. In mice several coat color mutants have been shown to have impaired specification or survival of melanocyte stem cells. Furthermore understanding of the normal regulation and behaviors of melanocytes and melanocyte stem cells will allow development of better strategies for cancer treatment. This article will review the discovery and behaviors of melanoctye stem cells as well as some aspects of melanocyte biology.

L-arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat.

BACKGROUND: The effects of long-term oral administration of L-arginine, a substrate for nitric oxide (NO) production, on left ventricular (LV) remodeling, myocardial function and the prevention of heart failure (HF) was compared to the angiotensin-converting enzyme (ACE) inhibitor captopril in a rat model of hypertensive HF (aged spontaneously hypertensive rat (SHR)). METHODS: SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats were assigned to either no treatment, treatment with L-arginine (7.5 g/l in drinking water) or captopril (1 g/l in drinking water) beginning at 14 months of age, a time when SHRs exhibit stable compensated hypertrophy with no hemodynamic impairment; animals were studied at 23 months of age or at the time of HF. RESULTS: In untreated SHR, relative to WKY, there was significant LV hypertrophy, myocardial fibrosis, and isolated LV muscle performance and response to isoproterenol (ISO) were depressed; and, 7 of 10 SHRs developed HF. Captopril administration to six SHRs attenuated hypertrophy and prevented impaired inotropic responsiveness to ISO, contractile dysfunction, fibrosis, increased passive stiffness, and HF. In contrast, L-arginine administration to SHR increased LV hypertrophy and myocardial fibrosis while cardiac performance was depressed; and 7 of 9 SHRs developed HF. In WKY, L-arginine treatment but not captopril resulted in increased LV weight and the contractile response to ISO was blunted. Neither L-arginine nor captopril treatment of WKY changed fibrosis and HF did not occur. CONCLUSION: These data demonstrate that in contrast to captopril, long-term treatment with L-arginine exacerbates age-related cardiac hypertrophy, fibrosis, and did not prevent contractile dysfunction or the development of HF in aging SHR.

Mature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience.

PURPOSE: The purpose of this article is to describe the features, treatment, and risk factors for relapse of children with mature teratoma (MT) and immature teratoma (IT) to assist future treatment plans. PATIENTS AND METHODS: Patients were younger than 16 years of age and referred to the UK Children's Cancer Study Group centers with biopsy-proven extracranial MT and IT and no prior chemotherapy. Complete excision, with the coccyx in sacrococcygeal patients, and follow-up, including serum alpha-fetoprotein monitoring for early detection of malignant yolk sac tumor (YST) recurrence, were recommended. Carboplatin, etoposide, and bleomycin (JEB) were given for YST relapse, whereas relapsed MT and IT were treated at clinicians' discretion, usually surgically. Pathology was reviewed and treatments, outcome, and prognostic features assessed. RESULTS: There were 351 patients, 227 with MT, 124 with IT. Tumor sites were: testis (n = 53), ovary (n = 130), sacrococcygeal region (n = 98), thorax (n = 23), and other (n = 47). Surgical resection was incomplete in 26% of MT and 40% of IT patients; 5-year event-free survival was 92.2% and 85.9%, respectively, and 5-year overall survival was 99% and 95.1%. Poorer outcome occurred with incomplete resection, tumor rupture, nongonadal site (particularly sacrococcygeal), young age, higher stage and grade, and gliomatosis peritonei, but not with cyst fluid aspiration/spillage, tumor enucleation, nodal gliomatosis, or microfoci of YST in the tumor (Heifetz lesions). JEB was effective for YST recurrence, but not for MT or IT. CONCLUSION: Treatment remains primarily surgical, with JEB chemotherapy for YST relapse. No definite response followed JEB for pure MT and IT. Adjuvant chemotherapy after surgery for sacrococcygeal patients is not advocated.

Who is providing what type of psychotherapy to eating disorder clients? A survey.

OBJECTIVE: Little is known about the psychotherapies delivered to eating-disordered clients by community therapists. We sought to describe the education and training of psychotherapists working with eating-disordered clients, the psychotherapeutic approaches used, and the reasons for use. METHOD: Eligible Calgary clinicians were identified and asked to complete a 25-item telephone interview. RESULTS: The response rate was 74%. Educational backgrounds and fields of specialization of clinicians who completed the survey (n = 52) varied widely, as did the psychotherapies used. The most common primary therapeutic orientations of respondents were eclectic therapy (50%), cognitive-behavioral therapy (CBT; 33%), and addiction-based therapy (6%). Most clinicians (87%) reported frequently using CBT techniques with eating-disordered clients. The reasons given for using primary therapeutic approaches varied by clinicians' preferred therapeutic approach and education level. CONCLUSION: Clinicians generally choose to tailor treatment to individual needs rather than base decisions on the level of empirical support. These findings have implications for dissemination of empirically supported psychotherapies.

Heart failure after long-term supravalvular aortic constriction in rats.

BACKGROUND: Pressure overload in humans follows a chronic and progressive course, often resulting in eventual cardiac decompensation and death. Animal models of heart failure generally fail to mimic the temporal features observed in human disease often covering a major portion of the life span, and findings of short-term studies are of uncertain applicability. The purpose was to determine whether chronic pressure overload introduced gradually in young normotensive rats would lead predictably to heart failure and to characterize specific phenotype features that have been well documented in another model of heart failure. METHODS: Rats underwent banding of the ascending aorta at 7 weeks of age such that the hemodynamic load increased gradually with ontogenic growth. Two groups of hypertrophied hearts from aortic-banded rats, with and without signs of heart failure, were compared with those of control rats at a mean age of 11 months. RESULTS: Hearts of aorta-banded rats underwent a transition from stable compensated hypertrophy to heart failure that was characterized by augmented hypertrophy, depressed contractile function, elevated fibrosis, increased myocardial stiffness, and marked alterations in the expression of genes encoding contractile, regulatory, and extracellular matrix proteins. CONCLUSIONS: Gradual constriction of the rat aorta resulted in heart failure after a variable length of time (3 to 18 months). Despite differences in genotype, the ultimate phenotype associated with the transition to failure in the aorta-banded rat is nearly identical to that observed in the aged spontaneously hypertensive rat (SHR), with a few notable differences. The findings suggest that a common heart failure phenotype follows long-term pressure overload regardless of the underlying etiology.