Fasciolicides: Efficacy, actions, resistance and its management

The modes of action of fasciolicides are described. Closantel and other salicylanilides interfere with energy metabolism by uncoupling oxidative phosphorylation in the fluke. Other fasciolicides are believed to have a metabolic action-halogenated phenols (via uncoupling) and clorsulon (via inhibition of glycolysis)-but direct evidence is lacking. Benzimidazoles (in particular, riclabendazole) bind to fluke tubulin and disrupt microtubule-based processes. Diamphenethide inhibits protein synthesis in the fluke. Other potential drug actions may contribute to overall drug efficacy. In particular, a number of fasciolicides-salicylanilides, phenols, diamphenethide-induce a rapid paralysis of the fluke, so their action may have a neuromuscular basis, although the actions remain ill-defined. Resistance to salicylanilides and triclabendazole has been detected in the field, although drug resistance does not appear to be a major problem yet. Strategies to minimize the development of resistance include the use of synergistic drug combinations, together with the design of integrated management programmes and the search for alternatives to drugs, in particular, vaccines. (C) 1999 Harcourt Publishers Ltd.

Educational professionals’ understanding of childhood traumatic brain injury

Primary objectives: To determine the understanding of educational professionals around the topic of childhood brain injury and explore the factor structure of the Common Misconceptions about Traumatic Brain Injury Questionnaire (CM-TBI).

Research design: Cross sectional postal survey.

Methods and procedures: The CM-TBI was posted to all educational establishments in one region of the United Kingdom. One representative from each school was asked to complete and return the questionnaire (N = 388).

Main outcomes and results: Differences were demonstrated between those participants who knew someone with a brain injury and those who did not, with a similar pattern being shown for those educators who had taught a child with brain injury. Participants who had taught a child with brain injury demonstrated greater knowledge in areas such as seatbelts/prevention, brain damage, brain injury sequelae, amnesia, recovery, and rehabilitation. Principal components analysis suggested the existence of four factors and the discarding of half the original items of the questionnaire.

Conclusions: In the first European study to explore this issue, we highlight that teachers are ill prepared to cope with children who have sustained a brain injury. Given the importance of a supportive school environment in return to life following hospitalisation, the lack of understanding demonstrated by teachers in this research may significantly impact on a successful return to school.

Synthesis and in Vitro and in Vivo Evaluation of a Series of Dihydroisocoumarin Derivatives Conjugated with Fatty Acids, Alcohols, and Amines as Potential Anticancer Agents

In this paper, we report the synthesis and biological activity of a series of dihydroisocoumarin analogues Conjugated with fatty acids, alcohols, or amines, of varying hydrocarbon chain length and degree of unsaturation, to (he dihydroisocoumarins, kigelin and mellein, at the C-7 and C-8 positions on the core dihydroisocoumarin structure. These compounds were evaluated for their antiproliferative activity against human breast cancer (MCF-7 and MDA-MB-468) and melanoma cells (SK-MEL-28 and Malme-3M) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Two compounds Conjugated with gamma-linolenyl alcohol (18:3 n-6) demonstrated potent antiproliferative activity in vitro with one of these 4-hydroxy-3-oxo-1.3-dihydro-isobenzofuran-5-carboxylic acid octadeca-6,9,12-trienyl ester, demonstrating significant antitumor activity in vivo ill a number of human tumor xenograft models.

Statistical-mechanical description of classical test-particle dynamics in the presence of an external force field: modelling noise and damping from first principles

Aiming to establish a rigorous link between macroscopic random motion (described e.g. by Langevin-type theories) and microscopic dynamics, we have undertaken a kinetic-theoretical study of the dynamics of a classical test-particle weakly coupled to a large heat-bath in thermal equilibrium. Both subsystems are subject to an external force field. From the (time-non-local) generalized master equation a Fokker-Planck-type equation follows as a "quasi-Markovian" approximation. The kinetic operator thus defined is shown to be ill-defined; in specific, it does not preserve the positivity of the test-particle distribution function f(x, v; t). Adopting an alternative approach, previously introduced for quantum open systems, is proposed to lead to a correct kinetic operator, which yields all the expected properties. A set of explicit expressions for the diffusion and drift coefficients are obtained, allowing for modelling macroscopic diffusion and dynamical friction phenomena, in terms of an external field and intrinsic physical parameters.

The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy

Diabetic retinopathy is one of the most common complications of diabetes and is a major cause of new blindness in the working-age population of developed countries. While the exact pathogenic basis of this condition remains ill defined, it is clear that hyperglycaemia is a critical factor in its aetiology. Protein kinase C (PKC) activation is one of the sequelae of hyperglycaemia and it is thought to play an important role in the development of diabetic complications. This review questions the currently held dogma that PKC stimulation in diabetes is solely mediated through the overproduction of palmitate and oleate enriched diacylglycerols. Blood glucose concentrations are closely tracked by changes in the levels of free fatty acids and these, in addition to oxidative stress, may account for the aberrant activation of PKCs in diabetes. Little is known about why PKCs fail to downregulate in diabetes and efforts should be directed towards acquiring such information. Considerable evidence implicates the PKCbeta isoform in the pathogenesis of diabetic retinopathy, but other isoforms may also be of relevance. In addition to PKCs, it is evident that novel diacyglycerol-activated non-kinase receptors could also play a role in the development of diabetic complications. Therapeutic agents have been developed to inhibit specific PKC isoforms and PKCbeta antagonists are currently undergoing clinical trials to test their toxicity and efficacy in suppressing diabetic complications. The likely impact of these drugs in the treatment of diabetic patients is considered.

Change in the use of and attitude to peak flow measurement among general practitioners in Northern Ireland between 1989 and 1994

In 1994 we repeated a study first performed in 1989 to assess the change in general practitioners' use of and attitudes to peak flow measurement. Of 232 general practitioners surveyed, 199 (86%) and 192 (83%) responded in 1989 and 1994 respectively. The percentage who reported having patients using domiciliary peak flow monitoring rose form 58.3 (95% confidence limits 51.4 to 65.2)% to 97.9 (95.9 to 99.9)%. The percentage who reported 'usually' using peak flow measurements for the diagnosis and management of asthma rose from 81.9 (76.5 to 87.3)% to 93.2 (89.6 to 96.8)% and from 83.3 (78.1 to 88.5)% to 95.8 (92.9 to 98.7)% respectively. An unchanged proportion took peak flow meters on house calls. General practitioners have become more aware of the potential of peak flow measurements but are still unlikely to have a meter available to assess patients seen at home. They are therefore likely to be ill-equipped to manage acute exacerbations of asthma in this setting.

Associations between maternal characteristics and pregnancy-related stress among low-risk mothers: An observational cross-sectional study

Background: Pregnancy is viewed as a major life event and, while the majority of healthy, low-risk women adapt well to pregnancy, there are those whose levels of stress are heightened by the experience.

Objectives: To determine the level of pregnancy-related stress experienced by a group of healthy, low-risk pregnant women and to relate the level of stress with a number of maternal characteristics.

Design: An observational cross-sectional study.

Setting: A large, urban maternity centre in Northern Ireland.

Participants: Of the 306 pregnant women who were invited to participate, 278 provided informed consent and were administered one self-complete questionnaire. Due to the withdrawal criteria, 15 questionnaires were removed from the analysis, resulting in a final sample of 263 healthy, low-risk pregnant women.

Methods: Levels of stress were measured using a self-report measure designed to assess specific worries and concerns relating to pregnancy. Maternal characteristics collected included age, marital status, social status, parity, obstetric history, perceived health status and 'wantedness' for the pregnancy. Regression analysis was undertaken using an ordinary linear regression model.

Results: The mean prenatal distress score in the sample was 15.1 (SD = 7.4; range 0-46). The regression model showed that women who had had previous pregnancies, with or without complications, had significantly lower mean prenatal distress scores than primiparous women (p < 0.01). Women reporting poorer physical health had higher mean prenatal distress scores than those who reported at least average health, while women aged 16-20 experienced a mean increase in the reported prenatal distress score (p < 0.05) in comparison to the reference group of 36 years and over.

Conclusions: This study brings to light the prevalence of pregnancy-related stress within a sample representative of healthy, low-risk women. Current antenatal care is ill-equipped to identify women suffering from high levels of stress; yet a growing body of research evidence links stress with adverse pregnancy outcomes. This study emphasises that healthy, low-risk women experience a range of pregnancy-related stress and identification of stress levels, either through the use of a simple stress measurement tool or through the associated factors identified within this research study, provides valuable data on maternal well-being. (C) 2010 Elsevier Ltd. All rights reserved.

Resistance or Resilience? Tracking the Pathway of Recent Arrivals to a ‘New’ Rural Destination

Recent patterns of migration indicate that international migrants are not confined to urban gateways. Instead many migrants have settled in new destination areas located in rural and small town areas. While this might appear to be a positive phenomenon for rural areas struggling with decline and stagnation, the reality is that many of these areas are ill-equipped to manage the rate and pace of change that has been witnessed in recent years. Migration to established, typically urban areas has been the subject of extensive research. However, little is known about the way in which migrants navigate their way through social structures as they settle into destinations with little experience of immigration. Using empirical research, this article considers the way in which migrants navigate their way through social structures to establish life in a so-called ‘new’ migration destination. It analyses the way in which government and civil society respond to their needs of recent arrivals, showing how both NGO’s and the statutory sector play an important role in this process. It considers the ramifications for these different sectors and the implications for so-called ‘new’ destinations as they become more established or ‘mature’ areas of immigration.

Public health education for midwives and midwifery students: a mixed methods study

Background: Current national and international maternity policy supports the importance of addressing public health goals and investing in early years. Health care providers for women during the reproductive and early postnatal period have the opportunity to encourage women to make choices that will impact positively on maternal and fetal health. Midwives are in a unique position, given the emphasis of the philosophy of midwifery care on building relationships and incorporating a holistic approach, to support women to make healthy choices with the aim of promoting health and preventing ill health. However, exploration of the educational preparation of midwives to facilitate public health interventions has been relatively limited. The aim of the study was to identify the scope of current midwifery pre registration educational provision in relation to public health and to explore the perspectives of midwives and midwifery students about the public health role of the midwife.

Methods: This was a mixed methods study incorporating a survey of Higher Educational Institutions providing pre registration midwifery education across the UK and focus groups with midwifery students and registered midwives.

Results: Twenty nine institutions (53% response) participated in the survey and nine focus groups were conducted (59 participants). Public health education was generally integrated into pre registration midwifery curricula as opposed to taught as a discrete subject. There was considerable variation in the provision of public health topics within midwifery curricula and the hours of teaching allocated to them. Focus group data indicated that it was consistently difficult for both midwifery students and midwives to articulate clearly their understanding and definition of public health in relation to midwifery.

Conclusions: There is a unique opportunity to impact on maternal and infant health throughout the reproductive period; however the current approach to public health within midwifery education should be reviewed to capitalise on the role of the midwife in delivering public health interventions. It is clear that better understanding of midwifery public health roles and the visibility of public health within midwifery is required in order to maximise the potential contribution of midwives to achieving short and long term public health population goals.

Removing the threat of diclofenac to critically endangered Asian vultures

Veterinary use of the nonsteroidal anti-inflammatory (NSAID) drug diclofenac in South Asia has resulted in the collapse of populations of three vulture species of the genus Gyps to the most severe category of global extinction risk. Vultures are exposed to diclofenac when scavenging on livestock treated with the drug shortly before death. Diclofenac causes kidney damage, increased serum uric acid concentrations, visceral gout, and death. Concern about this issue led the Indian Government to announce its intention to ban the veterinary use of diclofenac by September 2005. Implementation of a ban is still in progress late in 2005, and to facilitate this we sought potential alternative NSAIDs by obtaining information from captive bird collections worldwide. We found that the NSAID meloxicam had been administered to 35 captive Gyps vultures with no apparent ill effects. We then undertook a phased programme of safety testing of meloxicam on the African white-backed vulture Gyps africanus, which we had previously established to be as susceptible to diclofenac poisoning as the endangered Asian Gyps vultures. We estimated the likely maximum level of exposure (MLE) of wild vultures and dosed birds by gavage (oral administration) with increasing quantities of the drug until the likely MLE was exceeded in a sample of 40 G. africanus. Subsequently, six G. africanus were fed tissues from cattle which had been treated with a higher than standard veterinary course of meloxicam prior to death. In the final phase, ten Asian vultures of two of the endangered species (Gyps bengalensis, Gyps indicus) were dosed with meloxicam by gavage; five of them at more than the likely MLE dosage. All meloxicam-treated birds survived all treatments, and none suffered any obvious clinical effects. Serum uric acid concentrations remained within the normal limits throughout, and were significantly lower than those from birds treated with diclofenac in other studies. We conclude that meloxicam is of low toxicity to Gyps vultures and that its use in place of diclofenac would reduce vulture mortality substantially in the Indian subcontinent. Meloxicam is already available for veterinary use in India.

High-volume haemofiltration for sepsis.

Background: Severe sepsis and septic shock are leading causes of death in the intensive care unit (ICU). This is despite advances in the management of patients with severe sepsis and septic shock including early recognition, source control, timely and appropriate administration of antimicrobial agents, and goal directed haemodynamic, ventilatory and metabolic therapies. High-volume haemofiltration (HVHF) is a blood purification technique which may improve outcomes in critically ill patients with severe sepsis or septic shock. The technique of HVHF has evolved from renal replacement therapies used to treat acute kidney injury (AKI) in critically ill patients in the ICU.

Objectives: This review assessed whether HVHF improves clinical outcome in adult critically ill patients with sepsis in an ICU setting.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 7); MEDLINE (1990 to August 2011), EMBASE (1990 to August 2011); LILACS (1982 to August 2011), Web of Science (1990 to August 2011), CINAHL (1982 to August 2011) and specific websites.

Selection criteria: We included randomized controlled trials (RCTs) and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to standard or usual dialysis therapy; and RCTs and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to no similar dialysis therapy. The studies involved adults in critical care units.

Data collection and analysis: Three review authors independently extracted data and assessed trial quality. We sought additional information as required from trialists.

Main results: We included three randomized trials involving 64 participants. Due to the small number of studies and participants, it was not possible to combine data or perform sub-group analyses. One trial reported ICU and 28-day mortality, one trial reported hospital mortality and in the third, the number of deaths stated did not match the quoted mortality rates. No trials reported length of stay in ICU or hospital and one reported organ dysfunction. No adverse events were reported. Overall, the included studies had a low risk of bias.

Authors' conclusions: There were no adverse effects of HVHF reported.There is insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and or septic shock except as interventions being investigated in the setting of a randomized clinical trial. These trials should be large, multi-centred and have clinically relevant outcome measures. Financial implications should also be assessed.

Considerations for using sucrose to reduce procedural pain in preterm infants

Preterm and critically ill newborns admitted to a NICU undergo repeated skin-breaking procedures that are necessary for their survival. Sucrose is rapidly becoming the accepted clinical standard nonpharmacologic intervention for managing acute procedural pain for these infants. Although shown to be safe in single doses, only 4 studies have evaluated the effects of repeated doses of sucrose over relatively short periods of time. None has examined the use of sucrose throughout the NICU stay, and only 1 study evaluated the neurodevelopmental outcomes after repeated doses of sucrose. In that study, infants born at 10 doses per day in the first week of life were more likely to show poorer attention and motor development in the early months after discharge from the NICU. Results of studies in animal models have suggested that the mechanism of action of sucrose is through opioid pathways; however, in human infants, little has been done to examine the physiologic mechanisms involved, and the findings reported thus far have been ambiguous. Drawing from the growing animal literature of research that has examined the effects of chronic sugar exposure, we describe alternative amine and hormone pathways that are common to the processing of sucrose, attention, and motor development. In addition, a review of the latest research to examine the effects of repeated sucrose on pain processing is presented. These 2 literatures each can inform the other and can provide an impetus to initiate research to examine not only the mechanisms involved in the calming mechanisms of sucrose but also in the long-term neurodevelopmental effects of repeated sucrose in those infants born extremely preterm or critically ill.