Anti-PL-7, anti-Ro/SSA, anti-Mi-2, and anti-TIF1-γ correlate with specific patterns of histopathologic features in dermatomyositis: An analysis of 39 skin biopsy specimens from 25 patients.

BACKGROUND: In dermatomyositis (DM), myositis-specific and myositis-associated antibodies have been correlated with clinical features. It is unknown if histopathologic findings in lesional skin biopsies correlate with serologic subtypes of DM. METHODS: A retrospective chart review of patients with DM was performed. Patients with myositis antibodies and DM lesional skin biopsies were included in the study. Skin biopsies were reviewed by blinded dermatopathologists for 20 histopathologic features. RESULTS: There was a statistically significant (p < 0.05) association between anti-PL-7 serology and decreased degree of vacuolar degeneration, necrotic keratinocytes, and thickening of the epidermal basement membrane. Anti-aminoacyl tRNA synthetase (anti-ARS) antibodies had the same significant negative association with degree of vacuolar degeneration, necrotic keratinocytes, and thickening of the epidermal basement membrane. A similar pattern was seen with an anti-cytoplasmic serology; where there was a significant association with an increased degree of vacuolar degeneration and necrotic keratinocytes, and a nonsignificant trend of minimally thickened epidermal basement membrane. There was a statistically significant association between anti-Ro/SSA serology and increased degree of vacuolar degeneration. Anti-TIF1-γ serology was significantly associated with the increased presence of necrotic keratinocytes and pigment incontinence, and displayed a pattern of increased neutrophils. There was a significant association between anti-Mi-2 antibodies and pigment incontinence, as well as between myositis-specific antibodies and pigment incontinence. A statistically significant positive association was found between nuclear antibodies and degree of vacuolar degeneration, thickened epidermal basement membrane, pigment incontinence, and epidermal atrophy. CONCLUSION: In patients with DM, some specific serotypes, including anti-PL-7, anti-Ro/SSA, anti-Mi-2, and anti-TIF1-γ, may have characteristic histopathologic features.

The Interprofessional Care Access Network (I-CAN): achieving client health outcomes by addressing social determinants in the community.

Four health professions schools at an academic health science university and a partner state university collaborated to develop the Interprofessional Care Access Network (I-CAN), a model of healthcare delivery and interprofessional education that addresses the Triple Aims for vulnerable populations in three underserved neighborhoods. Program goals were achieved through community-based partnerships and the development of a health-care workforce prepared for competent practice in emerging models of care. In the first three years, almost 600 nursing, medicine, dentistry, and pharmacy students worked with clients referred from community partners, providing interprofessional care coordination addressing life instability and social determinants of health. The evaluation has demonstrated substantial improvement of health-related outcomes for clients who began in the first three years of the program and specifically those who completed intake and follow-up documentation (N = 38). There were substantial reductions in the aggregate number of emergency department visits, emergency medical service calls, and hospitalizations when compared to the 6 months prior to starting I-CAN. Estimated cost savings for the 38 clients, based on minimal estimated costs for these indicators alone, were over $224,000. A three-year qualitative review of client progress notes indicated that as a result of interprofessional student team interventions, many clients improved access to health insurance and primary care, and stabilized housing. Since the evaluation was completed, three programs have been added in rural and urban communities, demonstrating the model is scalable and replicable.

Care coordination: Identifying and connecting the most appropriate care to the patients.

Although nurses are increasingly expected to fulfill the role of care coordinator, the knowledge and skills required to be an effective care coordinator are not well understood. The purpose of this study was to describe the knowledge and skills required in care coordination practice using an interpretive phenomenological approach. Fifteen care coordinators from 10 programs were interviewed over a 6-month period. Semi-structured face-to-face interviews were audio recorded, transcribed, and analyzed using interpretive phenomenology. The central theme of care coordination practice was bridging the patient and the healthcare systems. To bridge, care coordinators needed to have knowledge of the patient and healthcare system as well as the skills to identify and negotiate treatments appropriate for the patient. The most salient finding and new to this literature was that care coordinators who used their medical knowledge about available treatment options to discern and negotiate for the most appropriate care to the patient made differences in patient outcomes. Nurses with medical and healthcare system knowledge, combined with the skills to navigate and negotiate with others in an increasingly complex healthcare system, are well situated to be care coordinators and generate optimal outcomes. Further investigations of critical care coordinator competencies are needed to support nurses currently enacting the role of care coordinator and to prepare future nurses to fulfill the role.

Interaction between maternal and postnatal high fat diet leads to a greater risk of myocardial dysfunction in offspring via enhanced lipotoxicity, IRS-1 serine phosphorylation and mitochondrial defects.

Maternal overnutrition is associated with heart diseases in adult offspring. However, combined effect of maternal and postnatal fat intake on cardiac function is unknown. This study was designed to examine the impact of maternal and postnatal fat intake on metabolic, myocardial, insulin and mitochondrial responses in adult offspring. Pregnant FVB mice were fed a low fat (LF) or high fat (HF) diet during gestation and lactation. Weaning male offspring were placed on either LF or HF (calorie-restricted HF-fed mice used as weight control) for 4 months prior to assessment of metabolic indices, myocardial histology, cardiac function, insulin signaling, mitochondrial integrity and reactive oxygen species (ROS) generation. Compared with LF- and HF-fed weight-control mice, postnatal HF intake resulted in obesity, adiposity, dyslipidemia, insulin resistance, cardiac hypertrophy, interrupted cardiac contractile, intracellular Ca(2+) and mitochondrial properties, all of which were significantly accentuated by prenatal fat exposure. Despite the preserved cardiac contractile function, LF offspring from HF-fed dams displayed higher body weights, increased adiposity and glucose intolerance. HF-fed mice with prenatal HF exposure displayed upregulated serine phosphorylation of IRS-1, PTP1B, the rate-limiting fatty acid synthesis enzyme stearoyl-CoA desaturase (SCD1) and hypertrophic markers (calcineurin A, GATA4, ANP, ß-MHC and skeletal α-actin), while suppressing AMP-dependent protein kinase, glucose uptake and PGC-1α levels. Importantly, myocardial and mitochondrial ultrastructural abnormalities were more pronounced in HF-fed offspring with prenatal fat exposure, shown as loss of mitochondrial density and membrane potential, increased ROS generation and apoptosis. Our data suggest that prenatal dietary fat exposure predisposes offspring to postnatal dietary fat-induced cardiac hypertrophy and contractile defect possibly via lipotoxicity, glucose intolerance and mitochondrial dysfunction. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

Findings from an assessment of state Title V workforce development needs.

To describe results of a 2008 assessment of Title V workforce competencies and training needs at the state level, and examine preferences and barriers related to available education and training opportunities. A web-based survey was administered May through August, 2008 to Maternal and Child Health (MCH) and Children and Youth with Special Health Care Needs (CYSHCN) program leaders in all 50 states, and U.S. jurisdictions. Forty-nine MCH (96%) and 44 CYSHCN (86%) programs and four territories completed surveys. A major focus of the survey related to competencies in six core domains: Public Health/Title V Knowledge Base, Communication, Critical Thinking, Management Skills, Family Centered Care and Medical Home, and Leadership Development. The top training needs identified by state Title V programs fall into the global category of critical thinking, including skills in MCH data synthesis and translation, in program evaluation, and in systems thinking. The need to enhance personal rather than organizational leadership skills was emphasized. Blended learning approaches (graduate education), and national conferences with skills building workshops (continuing education) were identified as preferred training modalities. Barriers to training included lack of career opportunities, insufficient agency support, and inability to take leave (graduate education), and travel restrictions, release time limitations, costs, and limited geographic access (continuing education). Both the focus of training and preferred training modalities differed from previous MCH workforce survey findings. Given the changing needs expressed by state Title V leaders as well as their training preferences, it is important that current and future graduate education and continuing education approaches be better aligned to meet these needs and preferences.

"Having a Normal Life": A Qualitative Study on Client Goal-Setting Within a Health Care and Social Needs Navigation Program.

Client goals within healthcare and social needs navigation programs are neither well understood nor incorporated into ambulatory care practices. This study provides a qualitative analysis of client-established goals within the Interprofessional Care Access Network (I-CAN), a community-based health care and social needs navigation program. One hundred eleven client goal lists were analyzed using conventional content analysis. Twenty-two codes were developed and grouped into 4 main categories including Physical/Mental Health, Social/Social Services, Health Care System, and Daily Living. The results of this study offer insight into client goals within health care and social needs navigation programs and provide suggestions for future research.

D1 dopamine receptor activation of NFAT-mediated striatal gene expression.

Exposure to drugs of abuse activates gene expression and protein synthesis that result in long-lasting adaptations in striatal signaling. Therefore, identification of the transcription factors that couple drug exposure to gene expression is of particular importance. Members of the nuclear factor of activated T-cells (NFATc) family of transcription factors have recently been implicated in shaping neuronal function throughout the rodent nervous system. Here we demonstrate that regulation of NFAT-mediated gene expression may also be a factor in drug-induced changes to striatal functioning. In cultured rat striatal neurons, stimulation of D1 dopamine receptors induces NFAT-dependent transcription through activation of L-type calcium channels. Additionally, the genes encoding inositol-1,4,5-trisphosphate receptor type 1 and glutamate receptor subunit 2 are regulated by striatal NFATc4 activity. Consistent with these in-vitro data, repeated exposure to cocaine triggers striatal NFATc4 nuclear translocation and the up-regulation of inositol-1,4,5-trisphosphate receptor type 1 and glutamate receptor subunit 2 gene expression in vivo, suggesting that cocaine-induced increases in gene expression may be partially mediated through activation of NFAT-dependent transcription. Collectively, these findings reveal a novel molecular pathway that may contribute to the enduring modifications in striatal functioning that occur following the administration of drugs of abuse.

Creating international conference submission and review guidelines to facilitate transnational dialogue.

Globally, nurses have much knowledge to share and the increased calls for conference presentation abstracts reflect this. However, a recent literature review revealed no guidelines for presentation submission and review processes for international nursing conferences. During the past decade, one conference, the U.S.-Russian Conference Cruise, has used evaluation data from each conference to shape its submission and review processes in a way that promotes transnational dialogue during the conference. The purpose of this article is to describe the challenges and evolution of designing submission and review processes that support the goal of a scholarly program of intercultural exchange.

Androgen Receptor Expression in Primary Nonsquamous Cell Rare-Variant Carcinomas of the Head and Neck.

OBJECTIVE: Androgen receptor (AR) is a diagnostic immunohistochemical marker for salivary gland duct carcinoma (SDC), but other nonsquamous cell head and neck carcinomas (NSCCs) may also express it. The aim of this preliminary study was to investigate the immunohistochemical expression of AR in rare head and neck NSCCs. STUDY DESIGN: Retrospective analysis of histologic records. SETTING: A large community hospital. SUBJECTS AND METHODS: Twenty-seven patients with NSCC were selected (21 men, 6 women; average age, 69 years). Exclusion criteria were histologically confirmed primary and metastatic head and neck squamous cell carcinomas and thyroid carcinomas. AR immunohistochemistry was done on formalin-fixed, paraffin-embedded tissue blocks. RESULTS: Variable AR expression was found in 5 of 27 (25%) cases of NSCC. All 7 patients with SDC showed intense and extensive positive immunoreactivity. Of 27 NSCC tumors, 15 (56%) had negative staining. CONCLUSION: In the head and neck, expression of AR is not limited to SDCs; other NSCCs also express it. When surgery or radiotherapy is not appropriate for recurrent or metastatic head and neck NSCC, palliative chemotherapy offers poor results. Antiandrogen therapy is well tolerated and is much less toxic than chemotherapy. Since androgen deprivation therapy has been used against SDCs, this therapy may theoretically be used in a small subset of head and neck NSCCs.

6-Hydroxydopamine lesions in female hamsters (Mesocricetus auratus) abolish the sensitized effects of sexual experience on copulatory interactions with males.

This study examined the effects of sexual experience in female hamsters (Mesocricetus auratus) on copulatory interactions with male hamsters. Female sexual experience improved the copulatory efficiency of sexually naive males, an effect that persisted for at least 6 weeks without further sexual behavior testing. In a 2nd study, dopamine lesions made in the region of the nucleus accumbens prior to sexual experience specifically blocked the effects of the female's sexual experience on the hit rate of naive males. These results suggest that sexual experience in female hamsters increases the efficiency of copulatory interactions with males, that these effects persist in the absence of further sexual experience, and that dopamine neurotransmission in the basal forebrain underlies this effect of sexual experience.

Patterns of Relapse in Squamous Cell Carcinoma of the Tonsil - Unilateral vs. Bilateral Radiation in the HPV-Era.

OBJECTIVES:  In the pre-human papillomavirus (HPV) era, unilateral radiation therapy (URT) for tonsil cancer was associated with low contralateral failure rates and had less toxicity than bilateral radiation therapy (BRT). This study explores the validity of URT in HPV-positive tonsil cancers. METHODS:  Tonsil squamous cell carcinomas (SCC) treated (typically with 70 Gy radiation and Cisplatin-based chemotherapy) between 2001 and 2007 were reviewed. Retrospective p16 immunohistochemistry staining was undertaken. Baseline, treatment, and response data were collected. RESULTS:  Of 182 patients, 78% were p16-positive, were younger (predominantly male), mostly former or non-smokers, and had a more advanced nodal stage. With a median follow-up of 68 months, contralateral recurrence (CLR) rates were low (3.5% p16-positive versus 2.5% p16-negative, p=0.63). Overall survival (OS) was 74% for p16-positive versus 54% for p16-negative subjects (p=0.01), but all other outcomes were similar. Analysis amongst only p16-positive subjects revealed URT was delivered to 37%, with CLR rates of 7.5% versus 1.1% for those treated with BRT, p=0.05. Of the four p16-positive subjects treated with URT who developed contralateral recurrences, three were managed with neck dissection (two disease-free and one died of lung metastases) and one received palliative radiation to the neck and distant metastatic site. All disease control and survival outcomes were similar between those treated with URT versus BRT. CONCLUSION:  While CLRs remain rare overall, there appears to be a slightly increased rate among HPV-positive subjects treated with URT. However, overall outcomes do not appear to be impacted, suggesting that URT remains a reasonable approach in HPV-positive subjects.

The Primary Care Practitioner's Role in the Prevention and Management of Alcohol Problems.

Medical practice in the United States has focused on diagnosing and treating alcohol abuse and dependence. A preventative approach to alcohol problems, however, requires that primary care practioners also identify patients whose patterns of alcohol consumption place them at risk for alcohol-related problems.

The NDNQI-Adapted Index of work satisfaction.

The valid measurement of nurses' job satisfaction is critical because job satisfaction is important for the retention of qualified nurses to provide patient care in hospitals. Two studies were conducted to adapt the Stamps Index of Work Satisfaction (1997b) to measure work satisfaction at the patient care unit level for use by the National Database of Nursing Quality Indicators (NDNQI). In Study 1 (n = 918 RNs) exploratory factor analysis of data obtained using the NDNQI-Adapted Index replicated the conceptual dimensions of the Stamps measure. Associations with scores on Job Enjoyment were evidence that the Index measured the intended construct. Using theta, the reliability of the composite subscales was .91. The adapted Work Satisfaction subscale scores explained 46% of the variance in Job Enjoyment, with each subscale contributing uniquely (p < .001). In Study 2 (n = 2277 RNs) confirmatory factor analysis using structural equation modeling supported the 7-subscale structure for the Adapted Index (CFI [719] = .88; RMR = .05). Replication of associations between scores on the Index subscales and Job Enjoyment provided further evidence regarding validity of the data, since the Work Satisfaction subscales explained 56% of the variance in Job Enjoyment. The feasibility of using an on-line version of the Adapted-Index for data collection was demonstrated. The findings from the two studies indicate that the adapted Index of Work Satisfaction has a structure similar to the original instrument and is a reliable and valid measure of work satisfaction at the patient care unit level.

Contemporary systemic therapy for male breast cancer.

BACKGROUND: The use, effectiveness, and tolerability of tamoxifen, aromatase inhibitors, and trastuzumab in early and advanced male breast cancer were examined at a population level. PATIENTS AND METHODS: A total of 158 consecutively referred men with invasive breast cancer diagnosed between 2000 and 2010 were identified. Stage and prognostic factors were compared with a random sample of contemporary female patients. Survival outcomes were compared with a separate female cohort matched 2:1 by prognostic and treatment factors. RESULTS: Men were older (median 69.5 years) than women (median 60 years) and presented with more advanced stage disease. Estrogen receptor was positive in 96% (n = 152) of cases. Tamoxifen was more commonly used than aromatase inhibitors in the curative and metastatic settings. Adherence to adjuvant tamoxifen therapy was generally adequate with estimated actuarial rates of persistence at 1 year and 3.5 years of 89% and 70%, respectively. For the 146 men treated with curative intent, 5-year overall survival, breast cancer-specific survival and progression-free survival were 72%, 86%, and 62%, respectively. Outcomes were similar to matched female patients in univariate and multivariate analyses. CONCLUSIONS: In this large population-based study, outcomes appear similar between male and risk-matched female patients with breast cancer. Side effect profiles, tolerance, adherence, and outcomes after tamoxifen, aromatase inhibitors, and trastuzumab in men appear comparable with those described in the literature for women.

Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function.

Obesity is often associated with reduced plasma insulin-like growth factor 1 (IGF-1) levels, oxidative stress, mitochondrial damage, and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high-fat diet-induced oxidative, myocardial, geometric, and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low- (10%) or high-fat (45%) diet to induce obesity. High-fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin 6, insulin, and triglyceride, as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end-systolic and end-diastolic diameter, increased wall thickness, and cardiac hypertrophy in high-fat-fed FVB mice. High-fat diet promoted reactive oxygen species generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca(2+) dysregulation (including depressed peak shortening and maximal velocity of shortening/relengthening), prolonged duration of relengthening, and dampened intracellular Ca(2+) rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor and postreceptor signaling molecules insulin receptor substrate 1 (tyrosine/serine phosphorylation), Akt, glycogen synthase kinase 3ß, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-γ coactivator 1α and uncoupling protein 2. Intriguingly, IGF-1 mitigated high-fat-diet feeding-induced alterations in reactive oxygen species, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca(2+) handling, and insulin signaling but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high-fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high-fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly because of preserved cell survival, mitochondrial function, and insulin signaling.

Disulfonic stilbene permeation and block of the anion channel from the sarcoplasmic reticulum of rabbit skeletal muscle.

Block of a sarcoplasmic reticulum anion channel (SCl channel) by disulfonic stilbene derivatives [DIDS, dibenzamidostilbene-2,2'-disulfonic acid (DBDS), and 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS)] was investigated in planar bilayers using SO4(2-) as the conducting ion. All molecules caused reversible voltage-dependent channel block when applied to either side of the membrane. DIDS also produced nonreversible channel block from both sides within 1-3 min. Reversible inhibition was associated with a decrease in channel open probability and mean open duration but not with any change in channel conductance. The half inhibitory concentration for cis- and trans-inhibition had voltage dependencies with minima of 190 nM and 33 microM for DBDS and 3.4 and 55 microM for DNDS. Our data supports a permeant blocker mechanism, in which stilbenes block SCl channels by lodging in the permeation pathway, where they may dissociate to either side of the membrane and thus permeate the channel. The stilbenes acted as open channel blockers where the binding of a single molecule occludes the channel. DBDS and DNDS, from opposite sides of the membrane, competed for common sites on the channel. Dissociation rates exhibited biphasic voltage dependence, indicative of two dissociation processes associated with ion movement in opposite directions within the trans-membrane electric field. The kinetics of DNDS and DBDS inhibition predict that there are two stilbene sites in the channel that are separated by 14-24 A and that the pore constriction is approximately 10 A in diameter.

Immunolocalization of NFATc4 in the adult mouse brain.

NFATc4 has recently been identified as playing an important role in variety of activity-dependent neuronal processes, including hippocampal plasticity, axonal growth, neuronal survival, and apoptosis. However, a systematic study examining the distribution of NFATc4 within the nervous system has yet to be conducted. With this in mind, we sought to determine the regional localization of NFATc4 within the adult mouse brain. Interestingly, NFATc4 was expressed broadly, but not uniformly, throughout various brain structures. The highest levels of NFATc4 expression were localized to the hippocampus, olfactory bulb, and various hypothalamic nuclei. Other brain regions that expressed NFATc4 included the cerebellum, striatum, globus pallidus, amygdala, neocortex, and brainstem nuclei. Given NFATc4's widespread expression, these results are consistent with the notion that NFATc4 may underlie activity-dependent neuronal plasticity throughout the adult brain.

Sexual experience alters D1 receptor-mediated cyclic AMP production in the nucleus accumbens of female Syrian hamsters.

Drugs of abuse produce long-term changes in dopamine neurotransmission and receptor-effected intracellular signaling. Similar changes in neuronal activity are mediated by motivated behaviors. To explore cellular mechanisms underlying these neuroadaptations following sexual experience, cyclic AMP accumulation following stimulation of D1 dopamine receptors, G-proteins, and adenylate cyclase was compared in the nucleus accumbens and caudate nucleus of sexually naive and experienced female hamsters following sexual behavior. Direct stimulation of adenylate cyclase with forskolin or indirectly by activation of G-proteins with Gpp(NH)p produced dose-dependent increases in the formation of cyclic AMP in the nucleus accumbens and caudate nucleus, with no effects of sexual experience on these measures. Specific D1 receptor stimulation increased Gpp(NH)p-induced adenylate cyclase activity in the nucleus accumbens and caudate nucleus of all animals. Interestingly, this stimulation was further enhanced only in membranes from the nucleus accumbens, but not from the caudate nucleus, of sexually experienced hamsters compared to the response of naive females. These results demonstrate that sexual behavior experience can sensitize mesolimbic dopamine pathways and that this sensitization occurs through an increase in D1 receptor-mediated signaling.