Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice.

BACKGROUND: The use of electronic cigarettes has increased over the past decade. To determine how the abuse liability of electronic cigarette liquids (e-liquids) differs from nicotine alone, and to determine the impact of flavor, we compared nicotine-containing fruit- and tobacco-flavored e-liquids, and their nicotine-free versions, to nicotine alone in mouse models of oral consumption, reward and aversion. METHODS: Adult male C57BL/6 J mice voluntarily consumed oral nicotine, equivalent nicotine concentrations of fruit- and tobacco-flavored e-liquid, and equivalent dilutions of the nicotine-free versions in 2-bottle choice tests. Conditioned place preference and place aversion were assessed with peripherally administered e-liquids or nicotine. Serum nicotine and cotinine levels were measured after subcutaneous injections of e-liquid or nicotine. RESULTS: Mice showed higher consumption and preference for the fruit-flavored e-liquid compared with nicotine alone. This increase was not due to the flavor itself as consumption of the nicotine-free fruit-flavored e-liquid was not elevated until the highest concentration tested. The increased consumption and preference were not observed with the tobacco-flavored e-liquid. The conditioned place preference, place aversion and nicotine pharmacokinetics of the fruit-flavored e-liquid were not significantly different from nicotine alone. CONCLUSIONS: Our data suggest that fruit, but not tobacco flavor, increased the oral consumption of e-liquid compared with nicotine alone. Moreover, this enhancement was not due to increased consumption of the flavor itself, altered rewarding or aversive properties after peripheral administration, or altered pharmacokinetics. This flavor-specific enhancement suggests that some flavors may lead to higher nicotine intake and increased use of e-liquids compared with nicotine alone.

Similar precipitated withdrawal effects on intracranial self-stimulation during chronic infusion of an e-cigarette liquid or nicotine alone.

The FDA recently extended their regulatory authority to electronic cigarettes (ECs). Because the abuse liability of ECs is a leading concern of the FDA, animal models are urgently needed to identify factors that influence the relative abuse liability of these products. The ability of tobacco products to induce nicotine dependence, defined by the emergence of anhedonia and other symptoms of nicotine withdrawal following cessation of their use, contributes to tobacco abuse liability. The present study compared the severity of precipitated withdrawal during chronic infusion of nicotine alone or nicotine-dose equivalent concentrations of three different EC refill liquids in rats, as indicated by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Because these EC liquids contain constituents that may enhance their abuse liability (e.g., minor alkaloids), we hypothesized that they would be associated with greater withdrawal effects than nicotine alone. Results indicated that the nicotinic acetylcholine receptor antagonist mecamylamine precipitated elevations in ICSS thresholds in rats receiving a chronic infusion of nicotine alone or EC liquids (3.2mg/kg/day, via osmotic pump). Magnitude of this effect did not differ between formulations. Our findings indicate that nicotine alone is the primary CNS determinant of the ability of ECs to engender dependence. Combined with our previous findings that nicotine alone and these EC liquids do not differ in other preclinical addiction models, these data suggest that product standards set by the FDA to reduce EC abuse liability should primarily target nicotine, other constituents with peripheral sensory effects (e.g. flavorants), and factors that influence product appeal (e.g., marketing).

Abuse liability assessment of an e-cigarette refill liquid using intracranial self-stimulation and self-administration models in rats.

BACKGROUND: The popularity of electronic cigarettes (ECs) has increased dramatically despite their unknown health consequences. Because the abuse liability of ECs is one of the leading concerns of the Food and Drug Administration (FDA), models to assess it are urgently needed to inform FDA regulatory decisions regarding these products. The purpose of this study was to assess the relative abuse liability of an EC liquid compared to nicotine alone in rats. Because this EC liquid contains non-nicotine constituents that may enhance its abuse liability, we hypothesized that it would have greater abuse liability than nicotine alone. METHODS: Nicotine alone and nicotine dose-equivalent concentrations of EC liquid were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, acquisition of self-administration, reinforcing efficacy (i.e., elasticity of demand), blockade of these behavioral effects by mecamylamine, nicotine pharmacokinetics and nicotinic acetylcholine receptor binding and activation. RESULTS: There were no significant differences between formulations on any measure, except that EC liquid produced less of an elevation in ICSS thresholds at high nicotine doses. CONCLUSIONS: Collectively, these findings suggest that the relative abuse liability of this EC liquid is similar to that of nicotine alone in terms of its reinforcing and reinforcement-enhancing effects, but that it may have less aversive/anhedonic effects at high doses. The present methods may be useful for assessing the abuse liability of other ECs to inform potential FDA regulation of those products.

An Unusual "Collision Tumour" of the Prostate Gland and Rectum.

Collision tumours of two different histopathological processes are rare. We describe a case of a patient with known low grade prostate adenocarcinoma developing a rectal GIST, which was diagnosed with combined imaging modalities of MR and ultrasound and confirmed by transrectal ultrasound guided biopsy.

Selective effects of a morphine conjugate vaccine on heroin and metabolite distribution and heroin-induced behaviors in rats.

Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines.

Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats.

Preclinical models of nicotine vaccine pharmacology have relied on i.v. or s.c. administration of nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. Nicotine vaccine effects were examined in rats using two cigarette smoke exposure models: a 10 min nose-only exposure (NSE) producing serum nicotine levels equivalent to the nicotine boost from 1 cigarette in a smoker, and a 2h whole-body exposure (WBE) producing serum nicotine levels similar to those associated with regular mid-day smoking. Vaccination prior to 10min smoke NSE reduced nicotine distribution to brain by 90%, comparable to its effect on nicotine administered i.v. Vaccination prior to 2 h smoke WBE reduced nicotine distribution to brain by 35%. The nicotine concentration in broncheoalveolar lavage (BAL) fluid obtained after 2 h WBE was increased by 230% in vaccinated rats but was also increased in rats passively immunized with a nicotine-specific monoclonal antibody, and so was likely due to transfer of antibody from serum rather than local production at the pulmonary mucosa. Nicotine-specific IgA was not detectable in BAL fluid, but titers in serum were appreciable at 21-25% of the IgG titer and could contribute to vaccine efficacy. Both vaccination and passive immunization are effective in reducing nicotine distribution to brain in rats when nicotine is delivered via inhaled cigarette smoke. These data validate results previously obtained in rodents for nicotine vaccines using i.v. or s.c. nicotine dosing and provide a quantitative method for studying aspects of nicotine exposure which are unique to cigarette smoke inhalation.

Mullerian duct anomalies: from diagnosis to intervention.

The purpose of this study was to review the embryology, classification, imaging features and treatment options of Müllerian duct anomalies. The three embryological phases will be described and the appearance of the seven classes of Müllerian duct anomalies will be illustrated using hysterosalpingography, ultrasound and MRI. This exhibit will also review the treatment options, including interventional therapy. The role of imaging is to help detect, classify and guide surgical management. At this time, MRI is the modality of choice because of its high accuracy in detecting and accurately characterising Müllerian duct anomalies. In conclusion, radiologists should be familiar with the imaging features of the seven classes of Müllerian duct anomalies, as the appropriate course of treatment relies upon the correct diagnosis and categorisation of each anomaly.

Radiological features of synovial cell sarcoma.

Synovial cell sarcoma is an uncommon soft-tissue malignant tumour. These tumours have common radiological features with a variety of both benign and malignant lesions. However, there is a variety of imaging findings that can suggest a pre-biopsy diagnosis of synovial cell sarcoma. This pictorial review aims to describe the imaging features of synovial sarcoma in a series of cases with various age ranges and tumour locations. In addition, the pathology, staging, prognosis and management of synovial sarcoma is briefly discussed.

Radiological imaging features of non-uterine leiomyosarcoma.

Leiomyosarcomas are unusual soft-tissue tumours that occur in the retroperitoneum, peripheral soft tissues, gastrointestinal and genito-urinary tracts, vessels and (rarely) in bone. The aim of this pictonal review is to delineate the more specific radiological features that would suggest a radiological diagnosis of leiomyosarcoma prior to biopsy.

The imaging features of gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GISTs) are a rare group of mesenchymal neoplasms that occur predominantly in the gastrointestinal tract. Previously GISTs were classified as smooth muscle tumours referred to as leiomyomas, leiomyosacromas or leiomyoblastomas. However, with the advent of immunohistochemistry, GISTs are now defined by the identification of cKit positivity. This is now used to select patients with metastatic disease who may respond to chemotherapeutic agents such as the tyrosine kinase inhibitor, STI-571. In this pictorial essay we have attemped to describe the range of imaging findings of GISTs that can suggest a pre-biopsy diagnosis.

Double dissociation in the neural substrates of acute opiate dependence as measured by withdrawal-potentiated startle.

The basolateral amygdala and portions of the "extended" amygdala (i.e. central nucleus of the amygdala, bed nucleus of the stria terminalis and shell of the nucleus accumbens) have been implicated in the aversive aspects of withdrawal from chronic opiate administration. Given that similar withdrawal signs are observed following a single opiate exposure, these structures may also play a role in "acute opiate dependence." In the current study, drug-naïve rats underwent naloxone-precipitated withdrawal from acute morphine (10 mg/kg) exposure on two successive days. On either the first or second day of testing, the basolateral amygdala, central nucleus of the amygdala, bed nucleus of the stria terminalis, or nucleus accumbens was temporarily inactivated immediately prior to naloxone injection by microinfusion of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulfonamide (3 microg/0.5 microl). On the first day, inactivation of the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis, but not the nucleus accumbens blocked withdrawal-potentiated startle, a behavioral measure of the anxiogenic effects of withdrawal. On the second day, inactivation of the nucleus accumbens, but not the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis disrupted the withdrawal effect. Effects of structural inactivations on withdrawal-potentiated startle were not influenced by differences in withdrawal severity on the two days of testing. A fear-potentiated startle procedure provided functional confirmation of correct cannulae placement in basolateral amygdale- and central nucleus of the amygdala-implanted animals. Our findings indicate a double dissociation in the neural substrates of withdrawal-potentiated startle following a first versus second morphine exposure, and may reflect a reorganization of the neural circuitry underlying the expression of withdrawal-induced negative affect during the earliest stages of opiate dependence.

Synovial osteochondromatosis: the spectrum of imaging findings.

Imaging plays a vital role in the diagnosis and management of synovial osteochondromatosis, a proliferative disorder of the synovium with associated loose body formation. The aim of this pictorial review is to illustrate the radiographic, computed tomographic and magnetic resonance appearances of various stages of the disease.

Leiomyosarcoma of the distal femur in a patient with a history of bilateral retinoblastoma: a case report and review of the literature.

We report a case of primary leiomyosarcoma of the distal femoral shaft arising in a patient who had undergone bilateral orbital enucleation for bilateral retinoblastoma several years previously. Radiography demonstrated an osteolytic, expansive lesion with cortical destruction anteriorly in the distal femoral shaft, and these findings were confirmed on CT. MR imaging revealed an expansive intramedullary lesion with cortical breakthrough and soft tissue extension. The occurrence of a second malignancy in patients with a history of bilateral retinoblastoma is well documented. Many different histological types have been described, with osteosarcoma and leiomyosarcoma occurring with the greatest frequency.

Ct findings in blunt renal trauma.

Computed tomography (CT) can provide essential anatomic and physiologic information required to determine management of intraabdominal and retroperitoneal injuries sustained during blunt abdominal trauma. It can help in evaluation of the type and severity of parenchymal injury, the extent of perirenal hemorrhage and parenchymal devascularization, and the presence of urinary extravasation. CT can help confirm the presence of major injuries to the vascular pedicle and depict occult renal pathologic conditions. Principal indications for the use of CT in the evaluation of blunt renal trauma include (a) the presence of gross hematuria, (b) microscopic hematuria associated with shock (systolic blood pressure <90 mm Hg), and (c) microscopic hematuria associated with a positive result of diagnostic peritoneal lavage. The majority of renal injuries sustained during blunt abdominal trauma are contusions and minor parenchymal lacerations amenable to nonoperative management. Deep parenchymal lacerations, urinary extravasation, and mild to moderate degrees of parenchymal devascularization may also be treated conservatively. Radiologists should look for coexisting renal lesions such as tumors and traumatic false aneurysms that may alter management.

Odontoid fracture following an epileptic seizure.

Fractures of the thoracic and lumber spine are well recognized following an epileptic seizure. Fractures of the cervical spine are not. The rare occurrence of a displaced odontoid fracture type 2, secondary to a grand mal seizure is presented. To our knowledge, this association has not been described previously in the English literature.