Thalassophilia and marine identity: Drivers of 'thick' marine citizenship.

Changing humanity's relationship with the ocean is identified as one of ten key challenges in the UN Decade of Ocean Science for Sustainable Development (2021-2030). Marine citizenship is one potential policy approach for reducing anthropogenic harms to the ocean and promoting ocean recovery, and there is a need to better understand marine citizenship motivating factors and their interactions. To contribute to a more holistic understanding, we approached this problem using an interdisciplinary, mixed methodology, which prioritised the voices and experiences of active marine citizens. An online survey and semi-structured interviews were conducted to examine factors spanning environmental psychology (values, environmental identity) and human geography (place attachment and dependency). Our data uncovered a unique marine place attachment, or thalassophilia, which is a novel conceptualisation of the human capacity to bond with a type of place beyond human settlements or defined localities. It is the product of strong emotional responses to the sensorial experience of the ocean and shared social or cultural understanding of ocean place identifications. A key driver of deeper marine citizenship is marine place dependency, and it is positively influence by stimulation and non-conformity values, environmental identity, and thalassophilia. We map significant motivating factors to identity process theory and describe a novel marine identity concept. We propose this as an operational mechanism of marine citizenship action, potentially filling the value- and knowledge-action gaps in the context of marine environmental action. This research provides a cornerstone in marine citizenship research by analysing together in one study a multitude of variables, which cross human-ocean relationships and experiences. The identification and characterisation of thalassophilia and marine identity process theory will enable research and practice to move forwards with a clearer framework of the role of the ocean as a place in environmental action.

First-in-human trial of the safety, pharmacokinetics and immunogenicity of a PEGylated anti-CD40L antibody fragment (CDP7657) in healthy individuals and patients with systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE). METHODS: This randomized, double-blind, single-dose, dose-escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004-5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5-60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1. RESULTS: Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose-proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657. CONCLUSION: Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE.

Smarter candidate selection--utilizing microdosing in exploratory clinical studies.

Microdosing offers a faster and potentially less expensive approach to obtaining human in vivo PK data in early clinical drug development. It encompasses the use of pharmacologically inactive doses of test drug in the low microgram range along with ultrasensitive assay methods (PET, AMS) to assess human exposure in order to extrapolate the PK of higher, clinically more relevant doses, assuming linear PK. This strategy allows early evaluation of systemic clearance, oral bioavailability as well as sources of intersubject variability and questions of specific metabolite formation. It does take advantage of reduced regulatory requirements of preclinical safety studies, bulk drug synthesis (CMC requirements) and easier formulation options, e.g., as part of an exploratory IND; however, this is counterbalanced by a need to synthesize radiolabeled test compound and the development of a sophisticated analytical method. Ongoing studies will determine the predictability of human PK using Microdosing methods.

Clinical pharmacokinetics of frovatriptan.

OBJECTIVE: To review available data on the clinical pharmacokinetics of frovatriptan. BACKGROUND: Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. METHODS: Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. RESULTS: Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. CONCLUSIONS: Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence.

Frovatriptan: a review of drug-drug interactions.

OBJECTIVE: To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan. BACKGROUND: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans. METHODS: The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials. RESULTS: In vitro, frovatriptan was principally metabolized by cytochrome P-450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase-A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination. CONCLUSIONS: Because it has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins, it is unlikely that frovatriptan will alter the pharmacokinetics of concomitantly administered drugs. Frovatriptan, therefore, appears to have a low risk of interaction with other drugs, and adjustments of dose are unlikely to be required when it is coadministered with other agents.

Tracing functionally identified neurones in a multisynaptic pathway in the hamster and rat using herpes simplex virus expressing green fluorescent protein.

Using a genetically modified herpes simplex virus encoding green fluorescent protein we sought to establish if this viral modification could be used in transneuronal tracing studies of the sympathetic nervous system. The herpes simplex virus encoding green fluorescent protein was injected into the adrenal medulla of three hamsters and six rats. After a suitable survival period, neurones in the sympathetic intermediolateral cell column of the thoracolumbar spinal cord, rostral ventral medulla and paraventricular nucleus of the hypothalamus were clearly identified by the presence of a green fluorescence in the cytoplasm of the neurones of both species. Thus, herpes simplex virus encoding green fluorescent protein labelled chains of sympathetic neurones in the hamster and rat and therefore has the potential to be used in transneuronal tracing studies of autonomic pathways in these species.

Growth-inhibitory effects of the synthetic retinoid CD437 against ovarian carcinoma models in vitro and in vivo.

The activity of CD437¿6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphthalene carboxylic acid¿, a relatively selective activator of RAR-gamma, was evaluated against four human ovarian-carcinoma cell lines : PE01, PE04 (a Pt-resistant in vivo-derived counterpart of PE01), PE01CDDP (a Pt-resistant in vitro-derived model of PE01) and PE014. Growth inhibition was observed after 3 and 6 days of exposure to sub-micromolar concentrations as assessed by a reduction in cell number. IC50 values against PE01, PE04, PE01CDDP and PE014 were 0.09, 0.21, 0.12 and 0.28 microM (day 3) and 0.1, 0.14, 0.07 and 0.17 microM (day 6), respectively. Cisplatin-resistant cell lines were as responsive as cisplatin-sensitive lines, indicating potential activity in resistant disease. CD437 was also evaluated against the PE04 xenograft grown in nude mice using daily doses of 20 (days 0-4) and 10 mg/kg (days 0-4 and 7-11) given either by i.p. delivery or oral administration. Significant growth inhibition (P < 0.05) was obtained for both doses and by both routes. These data provide further support for the view that retinoids have value for the treatment of ovarian cancer.

Repeated topical administration of all-trans-retinoic acid and plasma levels of retinoic acids in humans.

BACKGROUND: Vitamin A ingestion raises plasma levels of several potentially teratogenic retinoic acids (RAs) with all-trans and 13-cis configuration, but definitive data concerning the consequences of topical administration of all-trans-RA are lacking. OBJECTIVE: The study objective was to investigate the potential for inducing systemic activity after topical administration of 0.025% all-trans-RA by measuring plasma retinoid levels. METHODS: Plasma levels of all-trans-RA, 13-cis-RA, and 4-oxo-13-cis-RA were measured in four healthy subjects before, during, and after 14 daily topical applications of all-trans-RA. RESULTS: Topical administration of all-trans-RA did not significantly increase plasma levels of all-trans-RA, 13-cis-RA, and 4-oxo-13-cis-RA. Significant decreases in levels of these RAs observed during the night may reflect diurnal variations of retinoid metabolism or lowered absorption of dietary vitamin A. CONCLUSION: Diurnal and nutritional factors influence plasma levels of endogenous retinoids to a greater extent than topical administration of all-trans-RA at doses used for acne therapy, which on the basis of these results appears unlikely to induce systemic effects.

The potential requirement for HIV counselling and voluntary testing in women of childbearing age.

This paper compares estimates of the potential HIV counselling and testing requirements in a genito-urinary medicine (GUM) clinic, where a formal HIV counselling service is provided, and in an antenatal clinic (ANC), where there is no formal HIV counselling service. Data were collected by means of questionnaires completed by women attending both clinics. Only 31% and 16% of counselling needs were being met at the GUM clinic and antenatal clinic respectively. At the GUM clinic 11% of respondents had had an HIV antibody test, and at the antenatal clinic 1% had been tested. In contrast 68% and 58% of respondents at the GUM and antenatal clinics respectively would accept the offer of an HIV antibody test. In low prevalence areas the universal offer of testing would greatly increase specialist counselling requirements, but alternative models of provision and selective testing may lead to a more efficient use of resources.

Evaluation of the teratogenic risk of cutaneously administered retinoids.

In current cutaneous retinoid therapy systemic exposure is low and the risk of teratogenesis appears to be limited. However, new indications, altered posologies and the introduction of new synthetic retinoids demand continuous assessment of the teratogenic risk. Teratogenicity testing of new substances in animals is only of value if accompanied by detailed pharmacokinetic analysis to establish the relationships between the levels of parent compound and metabolite in both maternal plasma and fetal tissues and teratogenic events. This information should be compared to the maximum of relevant pharmacokinetic data which can be ethically obtained in man or from human tissues. The presence or absence of teratogenic effects following cutaneous administration of retinoids in animals has, as such, little direct bearing on the risk in man. Two special cases exist where teratogenic risk can be evaluated directly in man without reference to animal studies. The first concerns substances whose teratogenic potential has been established in man by other routes of administration permitting a comparison with the cutaneous route on a pharmacokinetic basis. The second concerns the cutaneous administration of endogenously occurring substances and their eventual disturbance of systemic retinoid equilibrium.

Capsaicin-induced bronchoconstriction in the guinea-pig: contribution of vagal cholinergic reflexes, local axon reflexes and their modulation by BW443C81.

1 The objective of the study was to investigate the central vagal and local axon reflex components of bronchoconstrictor responses evoked by inhalation of capsaicin aerosol in anaesthetized guinea-pigs. This was accomplished by comparing the effects of bilateral vagotomy, atropine and the peripherally-acting polar enkephalin analogue, BW443C81, on bronchoconstrictor responses evoked by capsaicin. The effects of codeine were also determined. 2 Aerosols of capsaicin were generated from a 0.9 microgram ml-1 solution. Inhalation of capsaicin aerosol in 5, 10 and 15 breaths evoked dose-related bronchoconstrictor responses. The responses were immediate in onset and of extended duration. 3 Capsaicin-induced bronchoconstrictor responses were significantly inhibited following bilateral vagotomy or atropine (0.3 mg kg-1, i.v.) pretreatment by 46% +/- 14% (P less than 0.05) and 59% +/- 13% (P less than 0.01), respectively. 4 Administration of BW443C81 by intravenous infusion (3, 30 and 100 micrograms kg-1 min-1) caused a significant inhibition of capsaicin-induced bronchoconstrictor responses which achieved a greater maximum than either bilateral vagotomy or atropine. Codeine (100 micrograms kg-1 min-1, i.v.) did not significantly inhibit the bronchoconstrictor responses. 5 Inhibition of capsaicin-induced bronchoconstrictor responses by BW443C81 (30 micrograms kg-1 min-1, i.v.) was significantly (P less than 0.05) reduced by the peripherally-acting opioid antagonist N-methyl nalorphine (100 micrograms kg-1 min-1, i.v.). 6 These results show that capsaicin-induced bronchoconstrictor responses are mediated by at least two mechanisms, a vagal and/or cholinergic reflex pathway and a non-cholinergic pathway. BW443C81, but not codeine, significantly inhibited (P < 0.005) both mechanisms of capsaicin-induced bronchoconstriction probably by an action on peripheral opioid receptors located on vagal sensory nerves.

Randomised controlled trial of day care for hypertension in pregnancy.

Our aim was to assess the effect of the introduction of a day-care unit on the care of women with non-proteinuric hypertension in pregnancy. A randomised controlled trial was carried out on 54 women who presented at 26 weeks of pregnancy or later with non-proteinuric hypertension (systolic blood pressure 150-170 mm Hg and/or diastolic pressure 90-105 mm Hg on two occasions at least 15 min apart). 30 women were allocated to care by the day unit and 24 were managed according to the established practice of their clinicians without access to the day unit (control group). Women in the control group spent on average 4.6 times longer as inpatients (difference in mean stay 4.0 days [95% confidence interval 2.1-5.9 days]) than the day-unit group and were 8.8 times (95% CI 3.0-25.8) more likely to be admitted to hospital. Induction of labour was 4.9 times (95% CI 1.6-13.8) more likely in the control than in the day-unit group and the development of proteinuria 11.4 times (95% CI 1.8-71.4) more likely. The control group had a mean of 1.5 fewer hospital outpatient visits (95% CI 0.36-2.64). The groups did not differ in their use of antihypertensive drugs. Day-unit care for hypertension in pregnancy significantly reduced the need for and the length of antenatal inpatient admissions and the number of medical interventions, at the cost of an increase in outpatient attendances. Our results are further evidence that inpatient care does not improve outcomes or prevent the development of proteinuria in this disorder.

A survey of UK diabetic pregnancy management.

The provision of care and current management strategies for diabetic pregnancy in the United Kingdom were assessed by canvassing British diabetologists. Questionnaires were sent to 376 Consultant Physicians known to have an interest in diabetes, in 239 Health Districts. The response rate was 52% providing information from 182 (76%) Districts. In 66 (36%) Districts, there was an existing combined diabetes/obstetric clinic, with median annual caseloads of 13 (range 1-200) patients. Preconception counselling was offered in 22 clinics. In 153 (84%) of the clinics, the standard WHO diagnostic criteria for diabetes were applied to pregnant patients and 149 (97%) of the clinics using WHO criteria treated patients with 'Impaired Glucose Tolerance' as if they were overtly diabetic. Reflectance meters for home monitoring were employed in 119 (65%) clinics. Target pre-meal blood glucose values were less than or equal to 6.0 (range 3.0-12.0) mmol l-1 (n = 172) and post-meal less than or equal to 8.0 (5.0-10.5) mmol l-1 (n = 139). Insulin was introduced when blood glucose values exceeded 7.0 (5.0-12.0) mmol l-1 (n = 162) pre-meal or 9.0 (5.5-15.0) mmol l-1 (n = 129) post-meal. No unit used oral hypoglycaemic agents during pregnancy. Sixty percent of respondents were unable to provide accurate fetal loss/perinatal mortality rates, usually due to lack of recorded data. Where data were available, fetal loss was almost always intra-uterine. Only 78 (43%) centres allowed pregnancy to progress to term.(ABSTRACT TRUNCATED AT 250 WORDS)

Crohn's disease of the vulva in childhood.

A case of vulval Crohn's disease in childhood is presented. The presentation of this disease as a vulval lesion is well recognised, either as the initial complaint, or as a metastatic lesion. Crohn's disease in childhood is well recognised and up to 49% of sufferers may have perianal disease. Vulval Crohn's disease in children, however, is uncommon, especially when it is the presenting symptom.

Inconsistencies in clinical decisions in obstetrics.

Analysis of the increasing incidence of caesarean section in an English teaching hospital over a 15-year period revealed that emergency caesarean section for the diagnosis of fetal distress in labour made a major contribution to this increasing trend. A retrospective audit of a sample of these operations by the consultants of the hospital indicated that 30% of the operations were unnecessary. There were two other disturbing findings in our audit. First, there was significant disagreement between auditors in the decision whether to do a caesarean section or not. Second, and perhaps more importantly, when faced with identical information at a different time, the auditors were inconsistent in 25% of cases. The disturbing clinical situation highlighted by this study may have implications for medical jurisprudence.

Using Lamicel to expose high cervical lesions during colposcopic examinations.

Women with abnormal cervical cytology and an unsatisfactory colposcopic examination were offered Lamicel in an attempt to expose the entire transformation zone. The sponge, which softens, dilates and effaces the cervix, was passed intracervically in 41 patients in whom the entire squamocolumnar junction could not be seen. After 3-4 h the sponge was removed and colposcopy repeated. In 29 of the 41 patients the lesion and the squamocolumnar junction were now fully visible. Twenty-five of these patients were spared a cone biopsy.

Haemorheological consequences of oestrogen and progestogen therapy.

A clinical investigation was undertaken of the haemorheological effects of short-term administration of synthetic sex hormones. In a randomised controlled investigative trial, groups of 20 women taking ethynyloestradiol, norethisterone, combined norgestrel and ethynyloestradiol or no therapy had their blood viscosity and its major determinants measured before and after 3 months of treatment. Oestrogens and progestogens, singly or in combination, were found to cause a rise in blood viscosity. Oestrogens did so by raising haematocrit and plasma fibrinogen, parameters that are similarly raised in other conditions such as pregnancy and following surgery when venous thromboembolism is common. The synthetic progestogen, on the other hand, raised the blood viscosity by increasing the haematocrit and decreasing erythrocyte deformability, parameters that are similarly altered in occlusive arterial disease. The combined preparation raised blood viscosity by altering all three parameters. These observations indicate the pathways whereby various synthetic oestrogens and progestogens in oral contraceptives or replacement therapy may be associated with different types of cardiovascular pathology.

MEDTUTOR: a microcomputer-based training program for MEDLINE.

MEDTUTOR is an interactive, microcomputer-based training package designed to teach medical and health professionals, as well as librarians and information specialists, how to use MEDLINE effectively. The objective of MEDTUTOR is to provide a comprehensive package for teaching the various commands and search techniques required for utilizing the MEDLINE database through the MEDLARS system. MEDTUTOR's menu-driven design allows novice users to learn about the content and use of MEDLINE, such as author searching, text word searching, MeSH indexing, etc., at their own pace and with considerable program feedback. In addition, MEDTUTOR provides the skilled searcher with a way to reinforce or recall previously-learned search techniques without incurring online charges. MEDTUTOR may be used in place of formal training, as a precursor to or as a refresher following formal training, or for review of a particular concept. It provides inexpensive and easily accessible instruction for searching MEDLINE.

Corticotropin-releasing factor inhibits neurogenic plasma extravasation in the rat paw.

Increased exudation of plasma proteins, as measured by Evans blue leakage into the innervated paw, was produced by antidromic stimulation of the saphenous nerve in the pentobarbital-anesthetized rat. This condition, termed neurogenic plasma extravasation (NPE), was inhibited by morphine, FK 33,824 (a stabilized enkephalin analog), dynorphin (1-13), dynorphin(1-10)amide and corticotropin-releasing factor (CRF) at median effective doses of 2700, 0.45, 1180, 4050 and 5.6 nmol/kg i.v., respectively. The inhibitory effect of CRF was present when injected up to 60 min before electrical stimulation of the nerve. By contrast, the effects of morphine and FK 33,824 were shorter in duration, lasting for only 20 to 30 min before nerve stimulation. Inhibition of NPE by morphine, FK 33,824 dynorphin (1-13) and dynorphin (1-10)amide was blocked by naloxone, 1 mg/kg i.v., but the CRF inhibition was not affected. CRF inhibited NPE in both hypophysectomized and adrenalectomized rats, indicating that its effects were not due to secondary release of endogenous opioid peptides. The inhibitory effect of CRF on NPE was also separable from its hypotensive properties and could be obtained at intradermal doses of CRF into the paw skin which were approximately 11 times lower than the i.v. doses. Intracerebroventricular injection of CRF did not affect the tail-flick latency of rats to warm water. CRF administered i.v. in mice did, however, inhibit writhing responses to phenylbenzoquinone (PBQ), suggesting possible peripheral antinociceptive properties.