Liraglutide attenuates nicotine self-administration as well as nicotine seeking and hyperphagia during withdrawal in male and female rats.

RATIONALE: Nicotine cessation is associated with increased consumption of highly palatable foods and body weight gain in most smokers. Concerns about body weight gain are a major barrier to maintaining long-term smoking abstinence, and current treatments for nicotine use disorder (NUD) delay, but do not prevent, body weight gain during abstinence. Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects of GLP-1R agonist monotherapy on nicotine seeking and withdrawal-induced hyperphagia are unknown. OBJECTIVES: We screened the efficacy of the long-lasting GLP-1R agonist liraglutide to reduce nicotine-mediated behaviors including voluntary nicotine taking, as well as nicotine seeking and hyperphagia during withdrawal. METHODS: Male and female rats self-administered intravenous nicotine (0.03 mg/kg/inf) for ~21 days. Daily liraglutide administration (25 µg/kg, i.p.) started on the last self-administration day and continued throughout the extinction and reinstatement phases of the experiment. Once nicotine taking was extinguished, the reinstatement of nicotine-seeking behavior was assessed after an acute priming injection of nicotine (0.2 mg/kg, s.c.) and re-exposure to conditioned light cues. Using a novel model of nicotine withdrawal-induced hyperphagia, intake of a high fat diet (HFD) was measured during home cage abstinence in male and female rats with a history of nicotine self-administration. RESULTS: Liraglutide attenuated nicotine self-administration and reinstatement in male and female rats. Repeated liraglutide attenuated withdrawal-induced hyperphagia and body weight gain in male and female rats at a dose that was not associated with malaise-like effects. CONCLUSIONS: These findings support further studies investigating the translational potential of GLP-1R agonists to treat NUD.

Proton Compton Scattering from Linearly Polarized Gamma Rays.

Differential cross sections for Compton scattering from the proton have been measured at scattering angles of 55°, 90°, and 125° in the laboratory frame using quasimonoenergetic linearly (circularly) polarized photon beams with a weighted mean energy value of 83.4 MeV (81.3 MeV). These measurements were performed at the High Intensity Gamma-Ray Source facility at the Triangle Universities Nuclear Laboratory. The results are compared to previous measurements and are interpreted in the chiral effective field theory framework to extract the electromagnetic dipole polarizabilities of the proton, which gives α_{E1}^{p}=13.8±1.2_{stat}±0.1_{BSR}±0.3_{theo},ß_{M1}^{p}=0.2∓1.2_{stat}±0.1_{BSR}∓0.3_{theo} in units of 10^{-4} fm^{3}.

Anal cancer screening and prevention: a review for dermatologists.

The incidence of and mortality from anal cancer, predominantly squamous cell carcinoma (SCC), have been increasing since the 1980s, during an era when many common malignancies have seen decreases in mortality. Dermatologists may be more likely to see patients at an increased risk for anal SCC, such as those living with HIV, MSM and those presenting for management of anogenital warts, yet there is little guidance in the field on how to manage these patients. We underwent a project to review the evidence surrounding screening and prevention of anal SCC. HPV vaccination, the main preventative measure for anal SCC, is often underutilized and may not be effective for those most at risk. Screening methods currently include high-risk HPV and anal cytology testing, with high-resolution anoscopy (HRA) reserved for biopsy and confirmatory testing. High-risk HPV testing has been associated with high sensitivity for intraepithelial neoplasia, but low specificity in high-risk groups. Recent meta-analyses examining AIN detection using anal cytology estimate a similarly high sensitivity of 74-87%, with a relatively higher specificity (44-66%) for identifying high-grade AIN. HRA is the gold standard for diagnosis, but its accessibility and cost are deterrents from its use as a screening tool. Cervical cancer screening, initially adopted without significant evidence of its impact, has significantly decreased cervical cancer rates. The argument can be made that rates of anal SCC may also benefit from appropriate screening methods, particularly anal cytology. It is prudent for dermatologists to be aware of the methods available to them in the management of at-risk patients, the data supporting them, and the potential benefits of screening in order to counsel patients appropriately and address the increasing burden of disease.

A human skin equivalent burn model to study the effect of a nanocrystalline silver dressing on wound healing.

In this study, a deep burn wound model was established using a 3D human skin equivalent (HSE) model and this was compared to native skin. HSEs were constructed from dermis derived from abdominoplasty/breast surgery and this dermal template was seeded with primary keratinocytes and fibroblasts. The HSE model was structurally similar to native skin with a stratified and differentiated epidermis. A contact burn (60 °C, 80 °C, 90 °C) was applied with a modified soldering iron and wounds were observed at day 1 and 7 after burn. The HSEs demonstrated re-growth with keratinocyte proliferation and formation of a neo-epidermis after burn injury, whereas the ex vivo native skin did not. To assess the suitability of the 3D HSE model for penetration and toxicity studies, a nanocrystalline silver dressing was applied to the model for 7 days, with and without burn injury. The effect of silver on skin re-growth and its penetration and subcellular localization was assessed in HSEs histologically and with laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS). The silver treatment delayed or reduced skin re-growth, and silver particles were detected on the top of the epidermis, and within the papillary dermis. This novel in vitro 3D multicellular deep burn wound model is effective for studying the pathology and treatment of burn wound injury and is suitable for penetration and toxicity studies of wound healing treatments.

Human and mouse bones physiologically integrate in a humanized mouse model while maintaining species-specific ultrastructure.

Humanized mouse models are increasingly studied to recapitulate human-like bone physiology. While human and mouse bone architectures differ in multiple scales, the extent to which chimeric human-mouse bone physiologically interacts and structurally integrates remains unknown. Here, we identify that humanized bone is formed by a mosaic of human and mouse collagen, structurally integrated within the same bone organ, as shown by immunohistochemistry. Combining this with materials science techniques, we investigate the extracellular matrix of specific human and mouse collagen regions. We show that human-like osteocyte lacunar-canalicular network is retained within human collagen regions and is distinct to that of mouse tissue. This multiscale analysis shows that human and mouse tissues physiologically integrate into a single, functional bone tissue while maintaining their species-specific ultrastructural differences. These results offer an original method to validate and advance tissue-engineered human-like bone in chimeric animal models, which grow to be eloquent tools in biomedical research.

Frailty Exists in Younger Adults Admitted as Surgical Emergency Leading to Adverse Outcomes.

BACKGROUND: Frailty is prevalent in the older adult population (≥65 years of age) and results in adverse outcomes in the emergency general surgical population. OBJECTIVE: To determine whether frailty exists in the younger adult emergency surgical population (<65 years) and what influence frailty may have on patient related outcomes. DESIGN: Prospective observational cohort study. SETTING: Emergency general surgical admissions. PARTICIPANTS: All patients ≥40 years divided into 2 groups: younger adults (40-64.9 years) and older adult comparative group (≥65). MEASUREMENTS: Over a 6-month time frame the following data was collected: demographics; Scottish Index of Multiple Deprivation (SIMD); blood markers; multi-morbidities, polypharmacy and cognition. Frailty was assessed by completion of the Canadian Study of Health and Ageing (CSHA). Each patient was followed up for 90 days to allow determination of length of stay, re-admission and mortality. RESULTS: 82 young adults were included and the prevalence of frailty was 16% (versus older adults 38%; p=0.001) and associated with: multi-morbidity; poly-pharmacy; cognitive impairment; and deprivation. Frailty in older adults was only significantly associated with increasing age. CONCLUSIONS: This novel study has found that frailty exists in 16% of younger adults admitted to emergency general surgical units, potentially leading to adverse short and long-term outcomes. Strategies need to be developed that identify and treat frailty in this vulnerable younger adult population.

Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.

Attenuated kallikrein-related peptidase activity disrupts desquamation and leads to stratum corneum thickening in human skin equivalent models.

BACKGROUND: Epidermal homeostasis is maintained through the balance between keratinocyte proliferation, differentiation and desquamation; however, human skin equivalent (HSE) models are known to differentiate excessively. In native tissue, proteases such as kallikrein-related peptidase (KLK) 5 and KLK7 cleave the extracellular components of corneodesmosomes; proteins corneodesmosin, desmocollin 1 and desmoglein 1, loosening the cellular connections and enabling desquamation. The actions of KLK7 are tightly controlled by protease inhibitors, skin-derived antileucoproteinase (SKALP) and lymphoepithelial Kazal-type-related inhibitor (LEKTI), which also inhibits KLK5, localizing protease activity to the stratum corneum. OBJECTIVES: To investigate the mechanisms that inhibit the desquamation cascade in HSE models. METHODS: Human skin tissue and HSE models were investigated using gene microarray, real-time polymerase chain reaction (PCR), immunohistochemistry and Western blot analysis to examine key components of the desquamation pathway. To elucidate proteolytic activity in HSEs and native skin, in situ and gel zymography was performed. RESULTS: Histological analysis indicated that HSE models form a well-organized epidermis, yet develop an excessively thick and compact stratum corneum. Gene microarray analysis revealed that the desquamation cascade was dysregulated in HSE models and this was confirmed using real-time PCR and immunohistochemistry. Immunohistochemistry and Western blot indicated overexpression of LEKTI and SKALP in HSEs. Although KLK7 was also highly expressed in HSEs, zymography indicated that protease activation and activity was lower than in native skin. CONCLUSIONS: These findings demonstrate that stratum corneum thickening is due to inhibited KLK5 and KLK7 activation and a subsequent lack of corneodesmosome degradation in the HSE model epidermis.

Measurement of Compton scattering from the deuteron and an improved extraction of the neutron electromagnetic polarizabilities.

The electromagnetic polarizabilities of the nucleon are fundamental properties that describe its response to external electric and magnetic fields. They can be extracted from Compton-scattering data-and have been, with good accuracy, in the case of the proton. In contradistinction, information for the neutron requires the use of Compton scattering from nuclear targets. Here, we report a new measurement of elastic photon scattering from deuterium using quasimonoenergetic tagged photons at the MAX IV Laboratory in Lund, Sweden. These first new data in more than a decade effectively double the world data set. Their energy range overlaps with previous experiments and extends it by 20 MeV to higher energies. An analysis using chiral effective field theory with dynamical Δ(1232) degrees of freedom shows the data are consistent with and within the world data set. After demonstrating that the fit is consistent with the Baldin sum rule, extracting values for the isoscalar nucleon polarizabilities, and combining them with a recent result for the proton, we obtain the neutron polarizabilities as αn=[11.55±1.25(stat)±0.2(BSR)±0.8(th)]×10(-4) fm(3) and ßn=[3.65∓1.25(stat)±0.2(BSR)∓0.8(th)]×10(-4) fm(3), with χ(2)=45.2 for 44 degrees of freedom.

Stratum basale keratinocyte expression of the cell-surface glycoprotein CDCP1 during epidermogenesis and its role in keratinocyte migration.

BACKGROUND: Epidermogenesis and epidermal wound healing are tightly regulated processes during which keratinocytes must migrate, proliferate and differentiate. Cell-to-cell adhesion is crucial to the initiation and regulation of these processes. CUB-domain-containing protein (CDCP)1 is a transmembrane glycoprotein that is differentially tyrosine phosphorylated during changes in cell adhesion and survival signalling, and is expressed by keratinocytes in native human skin, as well as in primary cultures. OBJECTIVES: To investigate the expression of CDCP1 during epidermogenesis and its role in keratinocyte migration. METHODS: We examined both human skin tissue and an in vitro three-dimensional human skin equivalent model to examine the expression of CDCP1 during epidermogenesis. To examine the role of CDCP1 in keratinocyte migration we used a function-blocking anti-CDCP1 antibody and a real-time Transwell™ cell migration assay. RESULTS: Immunohistochemical analysis indicated that in native human skin CDCP1 is expressed in the stratum basale and stratum spinosum. In contrast, during epidermogenesis in a three-dimensional human skin equivalent model, CDCP1 was expressed only in the stratum basale, with localization restricted to the cell-cell membrane. No expression was detected in basal keratinocytes that were in contact with the basement membrane. Furthermore, an anti-CDCP1 function-blocking antibody was shown to disrupt keratinocyte chemotactic migration in vitro. CONCLUSIONS: These findings delineate the expression of CDCP1 in human epidermal keratinocytes during epidermogenesis and demonstrate that CDCP1 is involved in keratinocyte migration.

Hydrated silicate minerals on Mars observed by the Mars Reconnaissance Orbiter CRISM instrument.

Phyllosilicates, a class of hydrous mineral first definitively identified on Mars by the OMEGA (Observatoire pour la Mineralogie, L'Eau, les Glaces et l'Activitié) instrument, preserve a record of the interaction of water with rocks on Mars. Global mapping showed that phyllosilicates are widespread but are apparently restricted to ancient terrains and a relatively narrow range of mineralogy (Fe/Mg and Al smectite clays). This was interpreted to indicate that phyllosilicate formation occurred during the Noachian (the earliest geological era of Mars), and that the conditions necessary for phyllosilicate formation (moderate to high pH and high water activity) were specific to surface environments during the earliest era of Mars's history. Here we report results from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) of phyllosilicate-rich regions. We expand the diversity of phyllosilicate mineralogy with the identification of kaolinite, chlorite and illite or muscovite, and a new class of hydrated silicate (hydrated silica). We observe diverse Fe/Mg-OH phyllosilicates and find that smectites such as nontronite and saponite are the most common, but chlorites are also present in some locations. Stratigraphic relationships in the Nili Fossae region show olivine-rich materials overlying phyllosilicate-bearing units, indicating the cessation of aqueous alteration before emplacement of the olivine-bearing unit. Hundreds of detections of Fe/Mg phyllosilicate in rims, ejecta and central peaks of craters in the southern highland Noachian cratered terrain indicate excavation of altered crust from depth. We also find phyllosilicate in sedimentary deposits clearly laid by water. These results point to a rich diversity of Noachian environments conducive to habitability.

Cell/surface interactions and adhesion on Ti-6Al-4V: effects of surface texture.

This paper presents the results of an experimental study of the effects of surface texture on the interactions between human osteo-sarcoma (HOS) cells and Ti-6Al-4V. These include the Ti-6Al-4V with polished (smooth); Al(2)O(3) blasted (rough); and laser micro-grooved geometries with controlled spacings and depths. Immuno-fluorescence staining of adhesion proteins (actin and vinculin) was used to study the spreading and adhesion of HOS cells in 2 day culture experiments. Quantitative measures of adhesion were also obtained using an enzymatic detachment assay. The results are discussed within the context of existing theories of cell adhesion. The implications of the results are also examined for the design of textured surfaces in biomedical systems.

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

Randomized controlled trial of motivational interviewing, cognitive behavior therapy, and family intervention for patients with comorbid schizophrenia and substance use disorders.

OBJECTIVE: Comorbidity of substance abuse disorders with schizophrenia is associated with a greater risk for serious illness complications and poorer outcome. Methodologically sound studies investigating treatment approaches for patients with these disorders are rare, although recommendations for integrated and comprehensive treatment programs abound. This study investigates the relative benefit of adding an integrated psychological and psychosocial treatment program to routine psychiatric care for patients with schizophrenia and substance use disorders. METHOD: The authors conducted a randomized, single-blind controlled comparison of routine care with a program of routine care integrated with motivational interviewing, cognitive behavior therapy, and family or caregiver intervention. RESULTS: The integrated treatment program resulted in significantly greater improvement in patients' general functioning than routine care alone at the end of treatment and 12 months after the beginning of the study. Other benefits of the program included a reduction in positive symptoms and in symptom exacerbations and an increase in the percent of days of abstinence from drugs or alcohol over the 12-month period from baseline to follow-up. CONCLUSIONS: These findings demonstrate the effectiveness of a program of routine care integrated with motivational interviewing, cognitive behavior therapy, and family intervention over routine psychiatric care alone for patients with comorbid schizophrenia and alcohol or drug abuse or dependence.

The concomitant development of poly(vinyl chloride)-related biofilm and antimicrobial resistance in relation to ventilator-associated pneumonia.

Ventilator-associated pneumonia is a major cause of death in intensive care patients and the endotracheal tube, commonly fabricated from poly(vinyl chloride) (PVC), is acknowledged as a significant factor in this. Bacteria colonise the biomaterial, thereby adopting a sessile mode of growth that progresses to the establishment of an antibiotic-resistant biofilm by the accretion of a protective glycocalyx. This study examined the sequential steps involved in the formation of biofilm on PVC by atomic force microscopy and the concomitant development of resistance to an antibiotic (ceftazidime) and to a non-antibiotic antimicrobial agent (hexetidine). Staphylococcus aureus and Pseudomonas aeruginosa isolated from ET tube biofilm were employed. The surface microrugosity of bacteria growing in sessile mode on PVC decreased significantly (p < 0.05) over the period 4, 24, 48 h and 5 d. The progressive accretion of bacterial glycocalyx was readily visualised in micrographs leading to a smoother surface topography with time. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for ceftazidime and hexetidine against planktonic (suspension) S. aureus were lower than for Ps. aeruginosa. Furthermore, sessile populations of S. aureus and Ps. aeruginosa on PVC exhibited greater resistance to both ceftazidime and hexetidine when compared to planktonic bacterial growth. The efficacy of the agents, determined by kill kinetics, against sessile bacteria was dependent on age, with established biofilms (> or = 24 h) significantly more resistant (p < 0.05) than early sessile populations (< or = 4 h). Importantly, for practice, even newly colonised bacteria (1 h) were significantly more resistant to antibiotic than planktonic bacteria. Hexetidine was significantly more active (p < 0.05) than ceftazidime on biofilms of both isolates, irrespective of age, with total kill within 24 h treatment. Hexetidine may offer promise in the resolution of infection associated with PVC endotracheal tubes.

Impact of patient feedback on the interpersonal skills of general practice registrars: results of a longitudinal study.

CONTEXT: A general practice vocational training program. OBJECTIVES: To examine the impacts and implications of different models of systematic patient feedback on the development of general practice (GP) registrars' interpersonal skills as they progressed through a GP vocational training program. DESIGN: A longitudinal study in which GP registrars were randomly assigned to three models of patient feedback: a control group and two intervention groups. The major source of data gathering was through the Doctors' Interpersonal Skills Questionnaire (DISQ) which was administered to patients immediately after their consultation. SUBJECTS: 210 GP registrars, 104 GP supervisors and 28 156 patients. RESULTS: Multivariate analysis techniques (including repeated-measures analysis) tested the effectiveness of the interventions. Findings showed that systematic patient feedback at regular intervals throughout GP training resulted in sustained levels of interpersonal skills. The most significant gains in interpersonal skills for both intervention groups occurred in the earlier stages of general practice training. Most registrars found the experience of patient feedback useful for gaining a better understanding of their interpersonal skills and for identifying areas in which they needed to improve. GP supervisors valued the opportunity to receive patient feedback themselves and found the activity a useful adjunct to their preceptor role. CONCLUSIONS: Patients, by providing feedback on doctors' interpersonal skills, have been able to contribute to improving the quality of the patient-doctor interaction. GP registrars and their supervisors value highly the role of patient feedback in interpersonal skill development.

Combination nicotine replacement therapy for smoking cessation: rationale, efficacy and tolerability.

Currently available nicotine replacement therapy (NRT) medications provide effective treatment for tobacco dependence, typically doubling success rates compared with placebo. A strategy for further improving the efficacy of NRT is to combine one medication that allows for passive nicotine delivery (e.g. transdermal patch) with another medication that permits ad libitum nicotine delivery (e.g. gum, nasal spray, inhaler). The rationale for combining NRT medications is that smokers may need both a slow delivery system to achieve a constant concentration of nicotine to relieve cravings and tobacco withdrawal symptoms, as well as a faster acting preparation that can be administered on demand for immediate relief of breakthrough cravings and withdrawal symptoms. This article reviews 5 published studies that have examined the effectiveness of combination NRT compared with monotherapy in providing withdrawal relief and smoking cessation, and examines other factors relevant to the promotion of combination NRT for treating tobacco dependence. The data show that there are conditions under which combinations of NRT products provide greater efficacy in relieving withdrawal and enabling cessation than monotherapy, but the findings are not robust and additional research is warranted to better understand the magnitude and generality of the benefits of combination therapy. There are also regulatory and commercial obstacles that must be considered. Nonetheless, combination NRT has the potential to provide effective treatment of tobacco dependence in persons whose dependence is refractory to currently available treatments.