Extraskeletal Ewing sarcoma of the sciatic nerve.

Extraskeletal Ewing sarcoma (EES) is a rare tumor diagnosed in children or young adults and is even more unusual in individuals over 30 years of age. Due to its rare occurrence and low index of suspicion, this tumor can pose diagnostic and therapeutic challenges. We present a case of a 60-year-old male with EES of the sciatic nerve, an unexpected entity given the patient's age, tumor type, and tumor location. This can mimic a nerve sheath tumor on imaging.

Improved economic and clinical outcomes with oritavancin versus a comparator group for treatment of acute bacterial skin and skin structure infections in a community hospital.

BACKGROUND: Oritavancin is a lipoglycopeptide antibiotic with in vitro bactericidal activity against gram-positive pathogens indicated for use in adults with acute bacterial skin and skin structure infections (ABSSSI). Its concentration-dependent activity and prolonged half-life provide a convenient single-dose alternative to multi-dose daily therapies for ABSSSI. This retrospective cohort study was conducted to quantify the clinical and economic advantages of using oritavancin compared to other antibiotic agents that have been historically effective for ABSSSI. METHODS: Seventy-nine patients received oritavancin who had failed previous outpatient antibiotic therapy (OPAT) for cellulitis or abscess and were subsequently readmitted to the hospital as an inpatient between 2016 and 2018. These patients were compared to a cohort of 28 patients receiving other antibiotics following OPAT failure and subsequent hospitalization for these two infection types. The primary clinical end point was average length of stay (aLOS) and secondary endpoints included readmission rates for the same indication at 30 and 90 days after discharge and the average hospital cost (aHC). RESULTS: A total of 107 patients were hospitalized for treatment of cellulitis or abscess. Demographic characteristics of both the oritavancin and comparator groups were similar except for the presence of diabetes. The primary clinical endpoint showed a non-significant decrease in aLOS between the oritavancin group versus comparator (2.12 days versus 2.59 days; p = 0.097). The secondary endpoints revealed lower readmission rates associated with oritavancin treatment at 30 and 90 days; the average hospital cost was 5.9% lower for patients that received oritavancin. CONCLUSION: The results of this study demonstrate that oritavancin provides not only a single-dose alternative to multi-day therapies for skin and skin structure infections, but also a clinical and economic advantage compared to other antibiotic agents.

Ruxolitinib: a new treatment for myelofibrosis.

Myelofibrosis (MF) is a blood cancer characterized by fibrotic bone marrow and altered hematopoiesis. Although the prevalence of MF is low, its severe symptoms have a significantly negative impact on patient quality of life, and its ability to transform into leukemia increases morbidity. Conventional drug therapies provide modest symptom palliation, but allogeneic stem cell transplantation has been the only treatment capable of affecting MF's natural history. Ruxolitinib (Jakafi®) is a new targeted therapy indicated to treat patients with intermediate- and high-risk MF. Although the research is conflicted regarding ruxolitinib's ability to affect survival or induce remission, studies show that it offers dramatic improvements in symptom management. However, ruxolitinib carries some potentially life-threatening adverse effects. This article reviews ruxolitinib, discusses its risks and benefits, and describes the vital role of oncology nurses in education, monitoring, and support.

Assessment of voluntary ethanol consumption and the effects of a melanocortin (MC) receptor agonist on ethanol intake in mutant C57BL/6J mice lacking the MC-4 receptor.

BACKGROUND: The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent evidence shows that chronic exposure to ethanol significantly blunts central MC peptide immunoreactivity and MC receptor (MCR) agonists protect against high ethanol intake characteristic of C57BL/6J mice. Here, we assessed the role of the MC-4 receptor (MC4R) in voluntary ethanol intake and in modulating the effects of the nonselective MCR agonist melanotan-II (MTII) on ethanol consumption. METHODS: To assess the role of the MC4R, MC4R knockout (Mc4r(-/-) ) and littermate wild-type (Mc4r(+/+) ) mice on a C57BL/6J background were used. Voluntary ethanol (3, 5, 8, 10, 15, and 20%, v/v) and water intake were assessed using standard two-bottle procedures. In separate experiments, Mc4r(-/-) and Mc4r(+/+) mice were given intracerebroventricular (i.c.v.) infusion of MTII (0, 0.5, or 1.0 µg/1 µl) or intraperitoneal (i.p.) injection of MTII (0 or 5 mg/kg/5 ml). The effects of MTII (0 or 0.5 µg/1 µl, i.c.v.) on 10% sucrose and 0.15% saccharin intake were assessed in C57BL/6J mice. RESULTS: Mc4r(-/-) mice showed normal consumption of ethanol over all concentrations tested. I.c.v. infusion of MTII significantly reduced ethanol drinking in Mc4r(+/+) mice, but failed to influence ethanol intake in Mc4r(-/-) mice. When administered in an i.p. injection, MTII significantly reduced ethanol drinking in both Mc4r(-/-) and Mc4r(+/+) mice. MTII attenuated consumption of caloric (ethanol, sucrose, and food) and noncaloric (saccharin) reinforcers. CONCLUSIONS: When given centrally, the MCR agonist MTII reduced ethanol drinking by signaling through the MC4R. On the other hand, MTII-induced reduction of ethanol drinking did not require the MC4R when administered peripherally. Together, the present observations show that the MC4R is necessary for the central actions of MCR agonists on ethanol drinking and that MTII blunts the consumption natural reinforcers, regardless of caloric content, in addition to ethanol.

Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism.

Alcoholism is a chronic disorder characterized by cycling periods of excessive ethanol consumption, withdrawal, abstinence and relapse, which is associated with progressive changes in central corticotropin-releasing factor (CRF) receptor signaling. CRF and urocortin peptides act by binding to the CRF type 1 (CRF1R) or the CRF type 2 (CRF2R) receptors, both of which have been implicated in the regulation of neurobiological responses to ethanol. The current review provides a comprehensive overview of preclinical evidence from studies involving rodents that when viewed together, suggest a promising role for CRFR antagonists in the treatment of alcohol abuse disorders. CRFR antagonists protect against excessive ethanol intake resulting from ethanol dependence without influencing ethanol intake in non-dependent animals. Similarly, CRFR antagonists block excessive binge-like ethanol drinking in non-dependent mice but do not alter ethanol intake in mice drinking moderate amounts of ethanol. CRFR antagonists also protect against increased ethanol intake and relapse-like behaviors precipitated by exposure to a stressful event. Additionally, CRFR antagonists attenuate the negative emotional responses associated with ethanol withdrawal. The protective effects of CRFR antagonists are modulated by CRF1R. Finally, recent evidence has emerged suggesting that CRF2R agonists may also be useful for treating alcohol abuse disorders.

CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis.

Recent evidence suggests that corticotropin-releasing factor (CRF) receptor (CRFR) signaling is involved in modulating binge-like ethanol consumption in C57BL/6J mice. In this report, a series of experiments were performed to further characterize the role of CRFR signaling in binge-like ethanol consumption. The role of central CRFR signaling was assessed with intracerebroventricular (i.c.v.) infusion of the nonselective CRFR antagonist, alpha-helical CRF(9-41) (0, 1, 5, 10 microg/1 microl). The contribution of central CRF type 2 receptor (CRF(2)R) signaling was assessed with i.c.v. infusion of the selective CRF(2)R agonist, urocortin (Ucn) 3 (0, 0.05, 0.1, or 0.5 microg/1 microl). The role of the hypothalamic-pituitary-adrenal (HPA) axis was assessed by pretreating mice with intraperitoneal (i.p.) injection of (1) the corticosterone synthesis inhibitor, metyrapone (0, 50, 100, 150 mg/kg) or (2) the glucocorticoid receptor antagonist, mifepristone (0, 25, 50 mg/kg), and (3) by using radioimmunoassay to determine whether binge-like ethanol intake influenced plasma corticosterone levels. Finally, we determined whether the ability of the CRF(1)R antagonist, CP-154,526 (CP; 0, 10, 15 mg/kg, i.p.), to blunt binge-like drinking required normal HPA axis signaling by comparing the effectiveness of CP in adrenalectomized (ADX) and normal mice. Results showed that i.c.v. infusion of a 1 microg dose of alpha-helical CRF(9-41) significantly attenuated binge-like ethanol consumption relative to vehicle treatment, and i.c.v. infusion of Ucn 3 dose-dependently blunted binge-like drinking. On the other hand, metyrapone nonselectively reduced both ethanol and sucrose consumption, mifepristone did not alter ethanol drinking, and binge-like drinking did not correlate with plasma corticosterone levels. Finally, i.p. injection of CP significantly attenuated binge-like ethanol intake in both ADX and normal mice. Together, these results suggest that binge-like ethanol intake in C57BL/6J mice is modulated by CRF(1)R and CRF(2)R signaling, such that blockade of CRF(1)R or activation of CRF(2)R effectively reduces excessive ethanol intake. Furthermore, normal HPA axis signaling is not necessary to achieve binge-like drinking behavior.

Effects of food availability and administration of orexigenic and anorectic agents on elevated ethanol drinking associated with drinking in the dark procedures.

BACKGROUND: Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations reaching levels that have measurable affects on physiology and/or behavior. The present study determined if increased ethanol drinking associated with DID procedures may be motivated by caloric need rather than by the postingestive pharmacological effects of ethanol. To this end, food availability was manipulated or mice were given peripheral administration of orexigenic or anorectic agents during DID procedures. METHODS: C57BL/6J had 2-hours of access to the 20% (v/v) ethanol solution beginning 3-hours into the dark cycle on days 1 to 3, and 4-hours of access to the ethanol bottle on day 4 of DID procedures. In Experiment 1, the effects of food deprivation on ethanol consumption during DID procedures was assessed. In Experiments 2 and 3, mice were given intraperitoneal (i.p.) injection of the orexigenic peptide ghrelin (0, 10 or 30 mg/kg) or the anorectic protein leptin (0 or 20 microg/g), respectively, before access to ethanol on day 4 of DID procedures. In Experiment 4, hourly consumption of food and a 0.05% saccharin solution were assessed over a period of hours that included those used with DID procedures. RESULTS: Consistent with previous research, mice achieved blood ethanol concentrations (BECs) that ranged between 100 and 150 mg% on day 4 of DID experiments. Neither food deprivation nor administration of orexigenic or anorectic compounds significantly altered ethanol drinking with DID procedures. Interestingly, mice exhibited their highest level of food and saccharin solution consumption during hours that overlapped with DID procedures. CONCLUSIONS: The present observations are inconsistent with the hypothesis that C57BL/6J mice consume large amounts of ethanol during DID procedures in order to satisfy a caloric need.

Blockade of the corticotropin releasing factor type 1 receptor attenuates elevated ethanol drinking associated with drinking in the dark procedures.

BACKGROUND: Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations (BECs) reaching levels that have measurable affects on physiology and/or behavior. The present experiments determined whether the increased ethanol drinking caused by DID procedures can be attenuated by pretreatment with CP-154,526; a corticotropin releasing factor type-1 (CRF1) receptor antagonist. METHODS: In Experiment 1, male C57BL/6J mice received ethanol (20% v/v) in place of water for 4 hours, beginning with 3 hours into the dark cycle. On the fourth day, mice were given an intraperitoneal injection of one of the 4 doses of CP-154,526 (0, 1, 3, 10 mg/kg) 30 minutes before receiving their ethanol bottle. In Experiment 2, C57BL/6J mice had 2 hours of access to the 20% ethanol solution, beginning with 3 hours into the dark cycle on days 1 to 3, and 4 hours of access to the ethanol bottle on day 4 of DID procedures. Mice were given an intraperitoneal injection of one of the 4 doses of CP-154,526 (0, 1, 3, 10 mg/kg) 30 minutes before receiving their ethanol bottle on day 4. Tail blood samples were collected immediately after the 4-hour ethanol access period on the fourth day of each experiment. Additional control experiments assessed the effects of CP-154,526 on 4-hour consumption of a 10% (w/v) sucrose solution and open-field locomotor activity. RESULTS: In Experiment 1, the vehicle-treated group consumed approximately 4.0 g/kg/4 h of ethanol and achieved BECs of approximately 30 mg%. Furthermore, pretreatment with the CRF1 receptor antagonist did not alter ethanol consumption. On the other hand, procedures used in Experiment 2 resulted in vehicle-treated mice consuming approximately 6.0 g/kg/4 h of ethanol with BECs of about 80 mg%. Additionally, the 10 mg/kg dose of CP-154,526 significantly reduced ethanol consumption and BECs to approximately 3.0 g/kg/4 h and 27 mg%, respectively, relative to vehicle-treated mice. Importantly, the 10 mg/kg dose of the CRF1R antagonist did not significantly alter 4-hour sucrose consumption or locomotor activity. CONCLUSIONS: These data indicate that CRF1R signaling modulates high, but not moderate, levels of ethanol drinking associated with DID procedures.

The CRF-1 receptor antagonist, CP-154,526, attenuates stress-induced increases in ethanol consumption by BALB/cJ mice.

BACKGROUND: Corticotropin-releasing factor (CRF) signaling modulates neurobiological responses to stress and ethanol, and may modulate observed increases in ethanol consumption following exposure to stressful events. The current experiment was conducted to further characterize the role of CRF1 receptor (CRF1R) signaling in stress-induced increases in ethanol consumption in BALB/cJ and C57BL/6N mice. METHODS: Male BALB/cJ and C57BL/6N mice were given continuous access to 8% (v/v) ethanol and water for the duration of the experiment. When a baseline of ethanol consumption was established, animals were exposed to 5 minutes of forced swim stress on each of 5 consecutive days. Thirty minutes before each forced swim session, animals were given an intraperitoneal injection of a 10 mg/kg dose of CP-154,526, a selective CRF1R antagonist, or an equal volume of vehicle. The effect of forced swim stress exposure on consumption of a 1% (w/v) sucrose solution was also investigated in an ethanol-naïve group of BALB/cJ mice. RESULTS: Exposure to forced swim stress significantly increased ethanol consumption by the BALB/cJ, but not of the C57BL/6N, mice. Stress-induced increases in ethanol consumption were delayed and became evident approximately 3 weeks after the first stressor. Additionally, forced swim stress did not cause increases of food or water intake and did not promote delayed increases of sucrose consumption. Importantly, BALB/cJ mice pretreated with the CRF1R antagonist showed blunted stress-induced increases in ethanol intake, and the CRF1R antagonist did not influence the ethanol drinking of non-stressed mice. CONCLUSIONS: The present results provide evidence that CRF1R signaling modulates the delayed increase of ethanol consumption stemming from repeated exposure to a stressful event in BALB/cJ mice.

Limited-access consumption of ascending ethanol concentrations in alcohol-preferring, nonpreferring, and Sprague-Dawley rats.

BACKGROUND: Ethanol intake and preference differences between the selectively bred alcohol-preferring (P) and nonpreferring (NP) rats have generally been studied in a continuous-access paradigm using 10% ethanol. Little is known about the consumption of lower concentrations of ethanol in these lines or consumption of a wide range of ethanol concentrations in limited-access paradigms. Recently, limited-access paradigms have been used to study the biological and pharmacological mechanisms of ethanol consumption in animal models. Such research would be informed by studies investigating ethanol oral self-administration within a limited-access context. Therefore, the current study addressed P, NP, and Sprague-Dawley (SD) rats' consumption of a wide range of ethanol concentrations in a 2-bottle-choice, limited-access procedure. METHODS: Male P, NP, and SD rats were given concurrent access to water and ethanol solutions for 1 h/d, 7 d/wk. Ethanol solutions were presented in an ascending series ranging from 0.01 to 20% (v/v) over 55 days. Ethanol intakes (g/kg), volumes of solutions consumed (mL/kg), and preference ratios were assessed for each rat line at each concentration. RESULTS: Clear differences among the 3 types of rats emerged at an ethanol concentration of 4%, although differences between P and NP rats emerged at concentrations as low as 1.8%. Alcohol-preferring rats almost exclusively preferred ethanol solutions over water at ethanol concentrations of 4% and above, whereas SD and NP rats' preference ratios were more variable. CONCLUSIONS: The results suggest that differences between P and NP rats exist at ethanol concentrations lower than those previously studied in continuous-access paradigms. They also provide a current description of the ranges of ethanol concentrations preferred by P, NP, and SD rats.