Degradation, cyclic adenosine monophosphate production, insulin secretion, and glycemic effects of two novel N-terminal Ala(2)-substituted analogs of glucose-dependent insulinotropic polypeptide with preserved biological activity in vivo

Glucose-dependent insulinotropic polypeptide (GIP) has significant potential in diabetes therapy due to its ability to serve as a glucose-dependent activator of insulin secretion. However, its biological activity is severely compromised by the ubiquitous enzyme dipeptidylpeptidase IV (DPP IV), which removes the N-terminal Tyr(1)-Ala(2) dipeptide from GIP. Therefore, 2 novel N-terminal Ala(2)-substituted analogs of GIP, with Ala substituted by 2-aminobutyric acid (Abu) or sarcosine (Sar), were synthesized and tested for metabolic stability and biological activity both in vitro and in vivo. Incubation with DPP IV gave half-lives for degradation of native GIP, (Abu(2))GIP, and (Sar(2))GIP to be 2.3, 1.9, and 1.6 hours, respectively, while in human plasma, the half-lives were 6.2, 7.6, and 5.4 hours, respectively. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, native GIP, (Abu(2))GIP, and (Sar(2))GIP dose-dependently stimulated cyclic adenosine monophosphate (camp) production with EC50 values of 18.2, 38.5, and 54.6 nmol/L, respectively. In BRIN-BD11 cells, both (Abu(2))GIP and (Sar(2))GIP (10(-13) to 10(-8) mol/L) dose-dependently stimulated insulin secretion with significantly enhanced effects at 16.7 mmol/L compared with 5.6 mmol/L glucose. In obese diabetic (ob/ob) mice, GIP and (Sar(2))GIP significantly increased (1.4-fold to 1.5-fold; P <.05) plasma insulin concentrations, whereas (Abu(2))GIP exerted only minor effects. Changes in plasma glucose were small reflecting the severe insulin resistance of this mutant. The present data show that substitution of the penultimate N-terminal Ala(2) in GIP by Abu or Sar results in analogs with moderately reduced metabolic stability and biological activity in vitro, but with preserved biological activity in vivo. (C) 2003 Elsevier Inc. All rights reserved.

A phase I study of the p-glycoprotein antagonist Tarquidar in combination with Vinorelbine.

P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. EXPERIMENTAL DESIGN: Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. RESULTS: Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. CONCLUSIONS: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Restorative Justice as a Response to Sexual Offending – Addressing the Failings of Current Punitive Approaches

This article explores the use of restorative justice as a response to sexual crime. The management of high risk sex offenders, particularly in the community post-release, has been a key focus of contemporary popular and political debates on sexual offending. Many offenders fail to come to the attention of the criminal justice system. For those that do, there is the almost blanket application of recent control in the community measures such as sex offender registries and community notification which have failed to prevent reoffending. The response by the media and the public to the presence of sex offenders in the community may also impede offender rehabilitation. The use of punishment alone via formal criminal justice is, therefore, an inadequate deterrent for sexual crimes. Although controversial, this article advocates the use of restorative practices with sexual crime as a proactive, holistic response to the problem and ultimately as a more effective means of reducing the incidence of sexual offences and sex offender recidivism.

The L Pack: Addressing the Sexual Health Needs of Young Lesbians

Concerns about the sexual health of women who identify as other than heterosexual have been highlighted in numerous research reports, yet access to information, advice and services remains limited within Northern Ireland. In response to this, a group of young women have produced a sexual health resource (‘‘The L Pack’’) specifically for those who identify as lesbian or bisexual. This article discusses the issue of lesbian sexual health and the rationale for the production of The L Pack. Drawing upon discussions with the young women involved and the various partners, it outlines the participatory process of producing information for young women by young women, the meaning and value of this and the nature of learning for all involved. Illustrating feminist and related principles through practice examples, the article outlines how the project moved from a focus on individual learning to one where the young women involved gained the knowledge, skills and confidence to take their learning to their peers and others.

Reactivity of ammonium chloride/mercuric chloride mixtures with monel containers. The new compounds (NH4)(2)(NH3)(x)[Ni(NH3)(2)Cl-4] and (NH4)(5)Cl-2[CuCl2][CuCl4]

Ammonium chloride/mercuric chloride mixtures (molar ratio 2: 1) react at 350degreesC with Monel (Cu68Ni32) to yield (NH4)NiCl3 and mercury and copper amalgam, respectively. With larger amounts of (NH4)Cl in the reaction mixture, dark green (NH4)(2)(NH3)(x)[Ni(NH3)(2)Cl-4] (x approximate to 0.77) (1) is also formed as a main product. Light blue crystals of the mixed-valent copper(I,II) chloride (NH4)(5)Cl-5[CuCl2][CuCl4] (2) were obtained as a minor byproduct from a 4:1 reaction mixture. The crystal structures were determined from single crystal X-ray data; (1): tetragonal, I4/mmm, a = 770.9(1), e = 794.2(2) pm, 190 reflections, R-1 = 0.0263; (2): tetragonal, I4/mcm, a = 874.8(1), c = 2329.2(3) pm, 451 reflections, R-1 = 0.0736. In (1) Ni2+ resides in trans-[Ni(NH3)(2)Cl-4](2-) octahedra, and in (2) copper(l) is linearly two-coordinated in ECUC121- and copper(II) resides in a flattened tetrahedron [CuCl4](2-) with a tetrahedricity of 89%. (C) 2001 Elsevier Science.

Interaction of water, hydrogen and their mixtures with SnO2 based materials: the role of surface hydroxyl groups in detection mechanisms

DRIFTS, TGA and resistance measurements have been used to study the mechanism of water and hydrogen interaction accompanied by a resistance change (sensor signal) of blank and Pd doped SnO2. It was found that a highly hydroxylated surface of blank SnO2 reacts with gases through bridging hydroxyl groups, whereas the Pd doped materials interact with hydrogen and water through bridging oxygen. In the case of blank SnO2 the sensor signal maximum towards H-2 in dry air (R-0/R-g) is observed at similar to 345 degrees C, and towards water, at similar to 180 degrees C, which results in high selectivity to hydrogen in the presence of water vapors (minor humidity effect). In contrast, on doping with Pd the response to hydrogen in dry air and to water occurred in the same temperature region (ca. 140 degrees C) leading to low selectivity with a high effect of humidity. An increase in water concentration in the gas phase changes the hydrogen interaction mechanism of Pd doped materials, while that of blank SnO2 is unchanged. The interaction of hydrogen with the catalyst doped SnO2 occurs predominantly through hydroxyl groups when the volumetric concentration of water in the gas phase is higher than that of H-2 by a factor of 1000.

Bronzino’s allegory of ‘Venus and Cupid’: An exemplary image for contemporary sexual health promotion?

Recent sexual health promotion strategies have veered between a negative emphasis on the deleterious consequences of sexually transmitted infections, and a more positive, eroticized approach to safer sex. The differences in approach are starkly reflected in the images chosen to illustrate them. We note that there are problems with both approaches. The main purpose of this review is to demonstrate how this dichotomy was transcended by the sixteenth century Florentine Mannerist painter, Agnolo Bronzino, in his allegory on syphilis

Vetting Sexual Offenders: State Over-extension, the Punishment Deficit and the Failure to Manage Risk

This article examines the state regulation of sexual offenders in the particular context of pre-employment vetting. A successive range of statutory frameworks have been put in place, culminating in the Safeguarding Vulnerable Groups Act 2006, to prevent unsuitable individuals from working with the vulnerable, and children in particular. Contemporary legislative and policy developments are set against a backdrop of broader concerns in the area of crime and justice, namely risk regulation, preventative governance and ‘precautionary logic.’ Proponents of these approaches have largely ignored concerns over their feasibility. This article specifically addresses this fissure within the specific field of vetting. It is argued that ‘hyper innovation’ and state over-extension in this area are particularly problematic and have resulted in exceptionally uncertain and unsafe policies. These difficulties relate principally to unrealistic public expectations about the state’s ability to control crime; unintended and ambiguous policy effects; and ultimately the failure of the state to deliver on its self-imposed regulatory mandate to effectively manage risk.

Managing Risk: From Regulation to the Reintegration of Sexual Offenders

In the last number of years the management of the dangerous in the community, particularly sex offenders, has generated enormous concern. This concern has been reflected at a number of different levels - in media and popular responses to the risk posed by released sex offenders in the community and in official discourses where an abundance of legislation and policy reforms have been enacted within a relatively short period of time. This analysis seeks to critically evaluate these developments within the context of contemporary criminal justice policy and practice in relation to the management of sex offenders in the community. The article analyses the contemporary focus on risk management or preventative governance which underpins the current regulatory framework and has been reflected in both the sentencing options and in control in the community initiatives for sex offenders. In this respect, the article highlights the gap between policy and practice in terms of the effective risk management of sex offenders. Given the failure of the traditional justice system with respect to these types of offences, it will be argued that the retributive framework could usefully be supplemented by the theory and practice of reintegrative or restorative community justice, and public education in particular, in order to better manage the risk presented by sex offenders in the community.

Sexual division of antibacterial resource defence in breeding burying beetles, Nicrophorus vespilloides

A key component of parental care involves defending resources destined for offspring from a diverse array of potential interspecific competitors, such as social parasites, fungi and bacteria. 2. Just as with other aspects of parental care, such as offspring provisioning or brood defence, sexual conflict between parents may arise over how to share the costs of this form of care. There has been little previous work, however, to investigate how this particular burden might be shared. 3. Here, we describe a hitherto uncharacterized form of parental care in burying beetles Nicrophorus vespilloides, a species which prepares carrion for its young and faces competition from microbes for this resource. We found that parents defend the carcass with antibacterial anal exudates, and that the antibacterial activity of these exudates is only upregulated following the discovery of a corpse. At the same time, phenoloxidase activity in the anal exudates is downregulated, indicating parallels with the internal insect immune system. 4. In unmanipulated breeding pairs, females had higher antibacterial activity in their anal exudates than males, suggesting sex-specific roles in this aspect of parental care. 5. When we experimentally widowed males, we found that they increased levels of antibacterial activity in their anal exudates. Experimentally widowing females, however, led them to decrease levels of antibacterial activity in their anal exudates. Widowed beetles of each sex thus produced anal exudates of comparable antibacterial activity. We suggest that this flexible division of antibacterial activity may be coordinated by Juvenile Hormone. © 2009 British Ecological Society.

Negotiation of risk in sexual relationships and reproductive decision-making amongst HIV sero-different couples

The paper focuses on the ways in which medical discourses of HIV transmission risk, personal bodily meanings and reproductive decision-making are re-negotiated within the context of sero-different relationships, in which one partner is known to be HIV-positive. Eighteen in-depth interviews were conducted with 10 individuals in Northern Ireland during 2008–2009. Drawing on an embodied sociological approach, the findings show that physical pleasure, love, commitment, a desire to conceive without medical interventions and a dislike of condoms within regular ongoing relationships, shaped individuals' sense of biological risk. In addition, the subjective logic that a partner had not previously become infected through unprotected sex prior to knowledge of HIV status and the added security of an undetectable viral load significantly impacted upon women's and, especially, men's decisions to have unprotected sex in order to conceive. The findings speak to the importance of reframing public health campaigns and clinical counselling discourses on HIV risk transmission to acknowledge how couples negotiate this risk, alongside pleasure and commitment within ongoing relationships.

Scaling of Food-Web Properties with Diversity and Complexity Across Ecosystems

Trophic scaling models describe how topological food-web properties such as the number of predator prey links scale with species richness of the community. Early models predicted that either the link density (i.e. the number of links per species) or the connectance (i.e. the linkage probability between any pair of species) is constant across communities. More recent analyses, however, suggest that both these scaling models have to be rejected, and we discuss several hypotheses that aim to explain the scale dependence of these complexity parameters. Based on a recent, highly resolved food-web compilation, we analysed the scaling behaviour of 16 topological parameters and found significant power law scaling relationships with diversity (i.e. species richness) and complexity (i.e. connectance) for most of them. These results illustrate the lack of universal constants in food-web ecology as a function of diversity or complexity. Nonetheless, our power law scaling relationships suggest that fundamental processes determine food-web topology, and subsequent analyses demonstrated that ecosystem-specific differences in these relationships were of minor importance. As such, these newly described scaling relationships provide robust and testable cornerstones for future structural food-web models.

Association of impulsivity with sleep duration and insomnia in an employee population

Clinical studies have linked impulsivity and insomnia in patients, but little is known about this association in non-clinical settings. This study examined whether impulsive temperament is associated with sleep duration and insomnia complaints in a large cohort of hospital employees (535 men and 4014 women). Linear regression models were related to prospective data from two surveys conducted in 1998 and 2000. Adjustments were made for age, marital status, education, shift work, smoking, alcohol consumption, body mass index, physical activity, minor psychiatric morbidity, social support, somatic disease, depression and other psychiatric disease in 1998. In men, higher impulsivity predicted shorter sleep duration and waking up several times per night independent of baseline characteristics. In women, higher impulsivity predicted having difficulty falling asleep and waking up feeling tired after the usual amount of sleep after adjustment for most of covariates. However, these associations turned out to be non-significant after adjustment for somatic and psychiatric disease. These results support the hypothesis that impulsive temperament could be a risk factor for insomnia in men. (c) 2007 Elsevier Ltd. All rights reserved.

Individual and Public-Program Adaptation: Coping with Heat Waves in Five Cities in Canada

Heat Alert and Response Systems (HARS) are currently undergoing testing and implementation in Canada. These programs seek to reduce the adverse health effects of heat waves on human health by issuing weather forecasts and warnings, informing individuals about possible protections from excessive heat, and providing such protections to vulnerable subpopulations and individuals at risk. For these programs to be designed effectively, it is important to know how individuals perceive the heat, what their experience with heat-related illness is, how they protect themselves from excessive heat, and how they acquire information about such protections. In September 2010, we conducted a survey of households in 5 cities in Canada to study these issues. At the time of the survey, these cities had not implemented heat outreach and response systems. The study results indicate that individuals' recollections of recent heat wave events were generally accurate. About 21% of the sample reported feeling unwell during the most recent heat spell, but these illnesses were generally minor. Only in 25 cases out of 243, these illnesses were confirmed or diagnosed by a health care professional. The rate at which our respondents reported heat-related illnesses was higher among those with cardiovascular and respiratory illnesses, was higher among younger respondents and bore no relationship with the availability of air conditioning at home. Most of the respondents indicated that they would not dismiss themselves as