The effects of loperamide on excitatory and inhibitory neuromuscular function in the human colon.

BACKGROUND: In most animal species, opioids alter colonic motility via the inhibition of excitatory enteric motor neurons. The mechanisms by which opioids alter human colonic motility are unclear. The aim of this study was to describe the effects of loperamide on neuromuscular function in the human colon. METHODS: Tissue specimens of human colon from 10 patients undergoing an anterior resection were divided into three inter-taenial circular muscle strips. Separate organ baths were used to assess: (1) excitatory transmission (selective blockade of inhibitory transmission: L-NOARG/MRS2179); (2) inhibitory transmission (selective blockade of excitatory transmission: hyoscine hydrobromide); and (3) a control bath (no drug additions). Neuromuscular function was assessed using force transducer recordings and electrical field stimulation (EFS; 20 V, 10 Hz, 0.5 ms, 10 s) prior to and following loperamide and naloxone. KEY RESULTS: In human preparations with L-NOARG/MRS2179, loperamide had no significant effects on isometric contractions. In preparations with hyoscine hydrobromide, loperamide reduced isometric relaxation during EFS (median difference + 0.60 g post-loperamide, Z = -2.35, p = 0.019). CONCLUSIONS AND INFERENCES: Loperamide had no effect on excitatory neuromuscular function in human colonic circular muscle. These findings suggest that loperamide alters colonic function by acting primarily on inhibitory motor neurons, premotor enteric neurons, or via alternative non-opioid receptor pathways.

Ending violence against children: What can global agencies do in partnership?

Globally, the range, scale and burden of all forms of violence against children (VAC) have visibly increased. Yet VAC as a physical, mental, public and social health concern is only recently gaining the prominence it deserves. Addressing VAC is critical. Violence experienced early in life can result in short, medium, long-lasting, and/or even inter-generational negative health outcomes. Ample evidence shows that VAC is widespread and the most common forms are usually perpetrated by people with whom children interact every day in their homes, schools and communities. We report on an innovative collaboration between global agencies, led by the International Society for Social Pediatrics and Child Health (ISSOP), the International Society for Prevention of Child Abuse and Neglect (ISPCAN), and the International Pediatric Association (IPA), who were galvanized to respond to VAC using a child-rights and public health lens. This collaboration led to a position statement on VAC with an implementation plan. The strength of the position statement was the explicit incorporation of a rights-based expansive understanding of VAC, with a description of typologies of violence pertinent to children globally, including child labor, children in armed conflict, trafficking of children and gender-based violence; and the identification of strategies both in preventing violence from occurring and ameliorating the effects in its aftermath. We report on the challenges and successes of our collaborative action at regional and supra-national levels, including opportunistic action.

Rights, justice, and equity: a global agenda for child health and wellbeing.

Worldwide challenges to child health and wellbeing are rapidly becoming existential threats to children and childhood. Inequities, armed conflict and violence, nuclear proliferation, forced migration, globalisation, and climate change are among the global issues violating children's rights to optimal survival and development. Child rights-based approaches will be required to enhance the response to the civil-political, social, economic, and cultural determinants of these global child health issues. In this Viewpoint, we present a global agenda for child health and wellbeing as a blueprint for the practice of paediatrics and child health in the domains of clinical care, systems development, and policy formulation. This global agenda is grounded in the principles of rights, justice, and equity and can address the root-cause determinants of health. The 30th anniversary of the UN Convention on the Rights of the Child is a relevant moment to recommit to shared goals for children's health and wellbeing.

Innervation Changes Induced by Inflammation in the Murine Vagina.

Vulvodynia is a prevalent chronic pain disorder associated with high medical costs and often ineffective treatments. The major pathological feature is proliferation of vaginal nerve fibers. This study aimed to develop a highly reproducible animal model to study neuroproliferation in the vagina and aid the identification of appropriately targeted treatments for conditions such as vulvodynia. Mild chronic inflammation was induced using microinjection of complete Freund's adjuvant in the distal vagina of C57Bl/6 mice. Control mice received saline. Inflammation and innervation density were assessed at 7 and 28 days after a single administration or 14 days following repeated administration of complete Freund's adjuvant or saline. Histochemistry and blinded-analysis of images were used to assess vaginal morphology (H & E) and abundance of macrophages (CD68-labeling), mast cells (toluidine blue staining, mast cell tryptase-immunoreactivity), blood vessels (αSMA-immunoreactivity) and nerve fibers immunoreactive for the pan-neuronal marker PGP9.5. Subpopulations of nerve fibers were identified using immunoreactivity for calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY). Single administration of complete Freund's adjuvant resulted in vaginal swelling, macrophage infiltration, vascular proliferation and increased abundance of nerve fibers immunoreactive for CGRP, SP, VIP and/or PGP9.5 but not NPY, evident at seven days. Inflammation further increased following repeated administration of complete Freund's adjuvant but nerve fiber proliferation did not. Nerve fiber proliferation continued to be evident at 28 days. The inter-individual differences within each treatment group were small, indicating that this model may be useful to study mechanisms underlying vaginal nerve fiber proliferation associated with inflammation.

Peptidergic nerve fibers in the urethra: Morphological and neurochemical characteristics in female mice of reproductive age.

BACKGROUND: Peptidergic nerve fibers provide important contributions to urethral function. Urethral innervation of female mice is not well documented. AIMS: To determine the distribution and projection sites of nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY) in the urethra of wild-type control mice and compare innervation characteristics between the proximal and distal urethra of young nullipara and older multipara mice. Furthermore, to identify the location and neurochemical coding of the spinal afferent nerve endings in the urethra, whose sensory neurons reside in lumbosacral dorsal root ganglia (DRG). METHODS: Multiple labeling immunohistochemistry of urethral sections of nulliparous (6-8 weeks old), and multiparous (9-12 months old) mice, and anterograde axonal tracing from L5-S2 (DRG) in vivo. RESULTS: Abundant VIP-, CGRP-, SP-, and NPY-immunoreactive nerve fibers were identified in the adventitia, muscularis, and lamina propria of proximal and distal segments of the urethra. A proportion of fibers were closely associated with blood vessels, glands, and cells immunoreactive for PGP9.5. The epithelium contained abundant nerve fibers immunoreactive for CGRP and/or SP. Epithelial innervation was increased in the distal urethra of multipara mice. Abundant fibers were traced from L5-S2 DRG to all urethral regions. CONCLUSIONS: We present the first identification of spinal afferent endings in the urethra. Peptidergic nerve fibers, including multiple populations of spinal afferents, provide rich innervation of the female mouse urethra. The morphology of fibers in the epithelium and other regions suggests multiple nerve-cell interactions impacting on urethral function.

Disabling chronic conditions in childhood and socioeconomic disadvantage: a systematic review and meta-analyses of observational studies.

OBJECTIVE: To determine the association of socioeconomic disadvantage with the prevalence of childhood disabling chronic conditions in high-income countries. STUDY DESIGN: Systematic review and meta-analyses. DATA SOURCES: 6 electronic databases, relevant websites, reference lists and experts in the field. STUDY SELECTION: 160 observational studies conducted in high-income countries with data on socioeconomic status and disabling chronic conditions in childhood, published between 1 January 1991 and 31 December 2013. DATA EXTRACTION AND SYNTHESIS: Abstracts were reviewed, full papers obtained, and papers identified for inclusion by 2 independent reviewers. Inclusion decisions were checked by a third reviewer. Where reported, ORs were extracted for low versus high socioeconomic status. For studies reporting raw data but not ORs, ORs were calculated. Narrative analysis was undertaken for studies without data suitable for meta-analysis. RESULTS: 126 studies had data suitable for meta-analysis. ORs for risk estimates were: all-cause disabling chronic conditions 1.72 (95% CI 1.48 to 2.01); psychological disorders 1.88 (95% CI 1.68 to 2.10); intellectual disability 2.41 (95% CI 2.03 to 2.86); activity-limiting asthma 2.20 (95% CI 1.87 to 2.85); cerebral palsy 1.42 (95% CI 1.26 to 1.61); congenital abnormalities 1.41 (95% CI 1.24 to 1.61); epilepsy 1.38 (95% CI 1.20 to 1.59); sensory impairment 1.70 (95% CI 1.39 to 2.07). Heterogeneity was high across most estimates (I(2)>75%). Of the 34 studies without data suitable for meta-analysis, 26 reported results consistent with increased risk associated with low socioeconomic status. CONCLUSIONS: The findings indicate that, in high-income countries, childhood disabling chronic conditions are associated with social disadvantage. Although evidence of an association is consistent across different countries, the review provides limited evidence to explain the association; future research, using longitudinal data, will be required to distinguish low socioeconomic status as the cause or consequence of childhood disabling chronic conditions and the aetiological pathways and mechanisms.

Is the onset of disabling chronic conditions in later childhood associated with exposure to social disadvantage in earlier childhood? A prospective cohort study using the ONS Longitudinal Study for England and Wales.

BACKGROUND: The aetiology of disabling chronic conditions in childhood in high income countries is not fully understood, particularly the association with socio-economic status (SES). Very few studies have used longitudinal datasets to examine whether exposure to social disadvantage in early childhood increases the risk of developing chronic conditions in later childhood. Here we examine this association, and its temporal ordering, with onset of all-cause disabling chronic later childhood in children reported as free from disability in early childhood. METHODS: The study comprised a prospective cohort study, using data from the Office for National Statistics Longitudinal Study (ONSLS) for England and Wales. The study sample included 52,839 children with complete data born between 1981-1991 with no disabling chronic condition/s in 1991. Index cases were children with disability recorded in 2001. Comparison cases were children with no recorded disability in 1991. A socio-economic disadvantage index (SDI) was constructed from data on social class, housing tenure and car/van access. Associations were explored with logistic regression modelling controlling sequentially for potentially confounding factors; age, gender, ethnicity and lone parenthood. RESULTS: By 2001, 2049 (4%) had at least one disability. Socio-economic disadvantage, age, gender and lone parenthood but not ethnicity were significantly associated with onset of disabling chronic conditions. The SDI showed a finely graded association with onset of disabling chronic conditions in the index group (most disadvantaged OR 2·11 [CI 1·76 to 2·53]; disadvantaged in two domains OR 1·45 [CI 1·20 to 1·75]; disadvantaged in one domain OR 1·14 [CI 0·93 to 1·39] that was unaffected by age, gender and ethnicity and slightly attenuated by lone parenthood. CONCLUSION: To our knowledge, this is the first study to identify socio-economic disadvantage in earlier childhood as a predisposing factor for onset of all-cause disabling chronic conditions in later childhood. Temporal ordering and gradation of the response indicate socio-economic disadvantage may play a causal role. This suggests that targeting preventative efforts to reduce socio-economic disadvantage in early childhood is likely to be an important public health strategy to decease health inequalities in later childhood and early adulthood.

An experimental method to identify neurogenic and myogenic active mechanical states of intestinal motility.

Excitatory and inhibitory enteric neural input to intestinal muscle acting on ongoing myogenic activity determines the rich repertoire of motor patterns involved in digestive function. The enteric neural activity cannot yet be established during movement of intact intestine in vivo or in vitro. We propose the hypothesis that is possible to deduce indirectly, but reliably, the state of activation of the enteric neural input to the muscle from measurements of the mechanical state of the intestinal muscle. The fundamental biomechanical model on which our hypothesis is based is the "three-element model" proposed by Hill. Our strategy is based on simultaneous video recording of changes in diameters and intraluminal pressure with a fiber-optic manometry in isolated segments of rabbit colon. We created a composite spatiotemporal map (DPMap) from diameter (DMap) and pressure changes (PMaps). In this composite map rhythmic myogenic motor patterns can readily be distinguished from the distension induced neural peristaltic contractions. Plotting the diameter changes against corresponding pressure changes at each location of the segment, generates "orbits" that represent the state of the muscle according to its ability to contract or relax actively or undergoing passive changes. With a software developed in MatLab, we identified twelve possible discrete mechanical states and plotted them showing where the intestine actively contracted and relaxed isometrically, auxotonically or isotonically, as well as where passive changes occurred or was quiescent. Clustering all discrete active contractions and relaxations states generated for the first time a spatio-temporal map of where enteric excitatory and inhibitory neural input to the muscle occurs during physiological movements. Recording internal diameter by an impedance probe proved equivalent to measuring external diameter, making possible to further develop similar strategy in vivo and humans.

Health service use in families where children enter public care: a nested case control study using the General Practice Research Database.

BACKGROUND: At least 3% of children spend some of their childhood in public care and, as a group, have poor outcomes across a range of education, employment, health and social care outcomes. Research, using social care or government datasets, has identified a number of risk factors associated with children entering public care but the utility of risk factors in clinical practice is not established. This paper uses routine primary health care data to see if risk factors for children entering public care can be identified in clinical practice. METHODS: A nested case control methodology using routine primary care data from the United Kingdom. Health service use data were extracted for the 12 months before the case child entered public care and compared with 12 months of data for four control mother child pairs per case pair, matched on the age and sex of the child and the general practice. Exposures of interest were developed from a systematic review of the literature on risk factors associated with children entering public care. RESULTS: Conditional logistic regression was used to investigate the combined effect of more than one exposure of interest. Maternal mental illness (OR 2.51, 95% CI 1.55-4.05), maternal age at birth of the child, socio-economic status (5(th) quintile vs. 1(st) quintile OR 7.14, 95% CI 2.92-17.4), maternal drug use (OR 28.8, 95% CI 2.29-363), non attendance at appointments (OR 2.42, 95% CI 1.42-4.14), child mental illness (OR 2.65, 95% CI 1.42-4.96) and child admission to hospital (OR 3.31, 95% CI 1.21-9.02) were all significantly associated with children entering public care. Maternal use of primary care contraception services was negatively associated with children entering public care (OR 0.52, 95% CI 0.31-0.87). CONCLUSIONS: Differences in health service use can be identified from routine primary care data in mother child pairs where children enter public care after controlling for maternal age and socio-economic status. The interaction between different risk factors needs testing in a cumulative risk model using longitudinal datasets.

Childhood disability and socio-economic circumstances in low and middle income countries: systematic review.

BACKGROUND: The majority of children with disability live in low and middle income (LAMI) countries. Although a number of important reviews of childhood disability in LAMI countries have been published, these have not, to our knowledge, addressed the association between childhood disability and the home socio-economic circumstances (SEC). The objective of this study is to establish the current state of knowledge on the SECs of children with disability and their households in LAMI countries through a systematic review and quality assessment of existing research. METHODS: Electronic databases (MEDLINE; EMBASE; PUBMED; Web of Knowledge; PsycInfo; ASSIA; Virtual Health Library; POPLINE; Google scholar) were searched using terms specific to childhood disability and SECs in LAMI countries. Publications from organisations including the World Bank, UNICEF, International Monetary Fund were searched for. Primary studies and reviews from 1990 onwards were included. Studies were assessed for inclusion, categorisation and quality by 2 researchers. RESULTS: 24 primary studies and 13 reviews were identified. Evidence from the available literature on the association between childhood disability and SECs was inconsistent and inconclusive. Potential mechanisms by which poverty and low household SEC may be both a cause and consequence of disability are outlined in the reviews and the qualitative studies. The association of poor SECs with learning disability and behaviour problems was the most consistent finding and these studies had low/medium risk of bias. Where overall disability was the outcome of interest, findings were divergent and many studies had a high/medium risk of bias. Qualitative studies were methodologically weak. CONCLUSIONS: This review indicates that, despite socially and biologically plausible mechanisms underlying the association of low household SEC with childhood disability in LAMI countries, the empirical evidence from quantitative studies is inconsistent and contradictory. There is evidence for a bidirectional association of low household SEC and disability and longitudinal data is needed to clarify the nature of this association.

A fibre optic catheter for simultaneous measurement of longitudinal and circumferential muscular activity in the gastrointestinal tract.

Diagnostic catheters based on fibre Bragg gratings (FBG's) are proving to be highly effective for measurement of the muscular activity associated with motility in the human gut. While the primary muscular contractions that generate peristalsis are circumferential in nature, it has long been known that there is also a component of longitudinal contractility present, acting in harmony with the circumferential component to improve the overall efficiency of material movement. We report the detection of longitudinal motion in mammalian intestine using an FBG technique that should be viable for similar detection in humans. The longitudinal sensors have been combined with our previously reported FBG pressure sensing elements to form a composite catheter that allows the relative phase between the two components to be detected. The catheter output has been validated using video mapping in an ex-vivo rabbit ileum preparation.

Effects of aging on Ca2+ signaling in murine mesenteric arterial smooth muscle cells.

Pathophysiological changes in arterial smooth muscle structure and function occur with aging and there are a number of reports illustrating reductions in vascular responsiveness with aging. While much is known about arterial remodeling and functional adaptations with aging, very little is known about the biophysical adaptations in individual arterial myocytes. Cytosolic Ca2+ signaling, involving activation of L-type Ca2+ channels on the plasma membrane as well as InsP3 and ryanodine receptors on the sarcoplasmic reticulum, is integral to vascular tone and reactivity. Thus, we tested the hypothesis that aging results in reductions in the functional expression of L-type channels and temporal aspects of ryanodine receptor and InsP3 receptor Ca2+ signaling, in mesenteric arterial smooth muscle cells isolated from 6 and 30 months old C57Bl/6 mice. Comparisons of L-type current activity were made using dialyzed, whole-cell voltage-clamp techniques and Ba2+ as charge carrier. Ca2+ signaling was measured using fura-2 fluorescence microscopy techniques. Cell morphological changes were also investigated using electrophysiological and immunocytochemical approaches. The amplitudes of L-type Ca2+ currents were increased in older mice, but this was associated with membrane surface area increases of approximately 50%, due to increases in cell length not cell width. Consequently, L-type Ca2+ current densities were preserved with age, indicating functional channel expression was unchanged. In contrast, aging was associated with decrements in Ca2+ signaling in response to either ryanodine receptor stimulation by caffeine or InsP3 receptor activation with phenylephrine. These changes with aging may be related to the previously reported depression in myogenic reactivity.

Invasive Haemophilus influenzae disease: an ecological study of sociodemographic risk factors before and after the introduction of Hib conjugate vaccine.

This study examines the impact of H. influenzae type b (Hib) conjugate vaccine on sociodemographic risk factors for invasive H. influenzae disease in the 2 years before and immediately after the introduction of Hib conjugate vaccine. An ecological study design was used and cases were identified using active surveillance employing several surveillance systems. The study population comprised all children aged < 5 years resident in the West Midlands, an English health region, with laboratory confirmed invasive disease 2 years before (1990-1992) and 2 years after (1992-1994) the introduction of Hib conjugate vaccine. Selected sociodemographic variables derived from the UK census were obtained for all census enumeration districts in the region. Each variable was then ranked and divided into six categories. Linear associations between disease rates and sociodemographic variables were examined. Overall, there was a significant reduction in the incidence of invasive H. influenzae disease. In the pre-conjugate vaccine era there were trends of decreasing disease incidence with increasing child population density (p = 0.012) and total population density (p = 0.0023). In the post-conjugate vaccine period, total population density (p = 0.0275) remained significant and a trend of increasing disease incidence with increasing population mobility (p = 0.0012) was seen. Although Hib conjugate vaccine has resulted in a dramatic reduction in disease incidence changes in sociodemographic risk factors were identified in the post-conjugate vaccine period, particularly population mobility. Our results may have implications for current and future vaccine strategies.