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Biomedical subjects

D L Bennett

Publications and source records attributed to D L Bennett.

At least 19 recordsLinked to original sources
PubMed2004

MDCT of tendon abnormalities using volume-rendered images.

OBJECTIVE: Our objectives were to report tendon abnormalities diagnosed on 3D volume-rendered images from MDCT data and to validate the clinical usefulness of this technique. CONCLUSION: We present 18 tendon abnormalities from 16 patients that were diagnosed on 3D volume-rendered MDCT images generated by commercially available software. Certain abnormalities such as avulsions, partial tears, and dislocations of tendons are clearly shown by this technique. This technique may prove useful in the evaluation of tendon abnormalities when MRI or sonography cannot be used.

Achilles Tendon↗
PubMed2003

Clinical assessment, management and outcomes of a group of adolescents presenting with complex medico-psychosocial conditions.

BACKGROUND: Adolescents with complex medico-psychosocial presentations are often seen as a management challenge. The Medical Family Therapy model provides a useful framework for working with these patients in the context of a multidisciplinary approach to treatment. MATERIALS AND METHODS: A retrospective case analysis of 38 patients referred over a two-year period to the Department of Adolescent Medicine was carried out. These patients met DSM-IV criteria for somatoform disorder or had a diagnosis of chronic fatigue syndrome (CFS). Duration of symptomatology, diagnosis, the presence of psychiatric conditions in the young person and their immediate family and the type and duration of the intervention were examined in relation to outcome. Two case presentations illustrate the complexity of the assessment and treatment process. RESULTS: Clinicians rated 47% of patients who engaged with the service as improved. There was no relationship between diagnosis, length of intervention and outcome. No significant differences emerged between the group of young people diagnosed with CFS and those with somatoform disorders in terms of outcome. Nine patients presented with symptoms which were similar or identical to those of one of their parents. Physical illness was more likely to be reported as a precipitating factor in the CFS group. Poor school attendance and psychiatric morbidity were linked to poor outcome. CONCLUSIONS: A comprehensive evaluation of presenting symptomatology and focussed intervention with measurable outcomes are important aspects of the clinical approach to complex medico-psychosocial conditions in adolescents. Families' beliefs about the presenting symptomatology and experiences of illness should be explored.

Adolescent↗
PubMed2003

Art and "the language of well-being" in adolescent health care.

Feeling effective as a young person depends on a capacity to draw upon one's own resources in the service of healthy living and development. In adolescent health care, there is the need to call upon the talents and creativity of young people, to introduce new and exciting experiences, and to facilitate involvement in their own care in order to nurture optimal growth and development on a physical and psychological level. While hospitalisation can represent a major crisis point in adolescence, the provision of a stimulating environment and the opportunity for creative activities offers an exciting, transformative and healing experience. Art allows adolescents to use alternative languages beyond illness, to engage in endeavours that are distanced from overt therapeutic intent, and to embrace attributes of self-esteem and resilience. Through the process and production of art, and the inclusion of music, poetry, film or theatre, young people can experience personal growth, acquire skills, develop socially and contribute to environmental change. In seeking to illustrate the value and importance of such approaches, this paper draws upon the experiences of a youth arts program attached to an adolescent ward. In a project called Art Injection, art students worked with adolescents to make sculptures from old hospital equipment, with startling results. More recently, the development of personal totem poles and an imaginative mosaic mural has powerfully engaged creativity and community in care. Group and individual art sessions, including the media arts project Creative Well, are offered on weekdays as part of the general hospital routine, enabling hospitalised young people to experience creativity as a daily part of their lives.

Adolescent↗
PubMed2001

Neurotrophic factors: important regulators of nociceptive function.

Neurotrophic factors have an established developmental role in regulating the survival and specification of sensory neurons. However, these factors continue to exert an important influence on sensory neurons throughout the postnatal period and into adult life. In adulthood, approximately one-half of nociceptors are dependent on nerve growth factor (NGF) for trophic support, whereas the other half are sensitive to glial cell line-derived neurotrophic factor (GDNF). It is now known that many chronic pain states are maintained by widespread changes in the anatomy, neurochemistry, and function of the sensory nervous system both at the level of the primary sensory neuron and the dorsal horn of the spinal cord. Trophic factors appear to orchestrate many of these dynamic changes. This review highlights some of the key roles played by these molecules and in particular the role of NGF in the peripheral sensitization of nociceptors and brain-derived neurotrophic factor (BDNF) as a central pain modulator.

Animals↗
PubMed2001

Adolescent health in a globalised world: a picture of health inequalities.

More than half of the world's population of 6 billion people is under age 25 years. Of the estimated 1.2 billion adolescents worldwide (1 in every 5 people is an adolescent), about 85% live in developing countries and the remainder in the industrialised world. Changing social, political, and economic realities are having a major and dramatic impact on young people and their families. In this context, however, the health of young people in developing countries has been largely ignored. Of particular concern are the implications of poverty, health inequality, gender discrimination, economic instability, and political unrest. These troubling dimensions create scenarios that challenge paediatricians and other health workers to become more active and courageous as advocates for the health rights and health care of young people. In this chapter, we outline and describe some of the key issues involved, recognise a number of initiatives being undertaken, and propose additional measures for consideration.

Adolescent↗
PubMed2000

Potent analgesic effects of GDNF in neuropathic pain states.

Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.

Action Potentials↗
PubMed2000

The glial cell line-derived neurotrophic factor family receptor components are differentially regulated within sensory neurons after nerve injury.

Glial cell line-derived neurotrophic factor (GDNF) has potent trophic effects on adult sensory neurons after nerve injury and is one of a family of proteins that includes neurturin, persephin, and artemin. Sensitivity to these factors is conferred by a receptor complex consisting of a ligand binding domain (GFRalpha1-GFRalpha4) and a signal transducing domain RET. We have investigated the normal expression of GDNF family receptor components within sensory neurons and the response to nerve injury. In normal rats, RET and GFRalpha1 were expressed in a subpopulation of both small- and large-diameter afferents projecting through the sciatic nerve [60 and 40% of FluoroGold (FG)-labeled cells, respectively]. GFRalpha2 and GFRalpha3 were both expressed principally within small-diameter DRG cells (30 and 40% of FG-labeled cells, respectively). Two weeks after sciatic axotomy, the expression of GFRalpha2 was markedly reduced (to 12% of sciatic afferents). In contrast, the proportion of sciatic afferents that expressed GFRalpha1 increased (to 66% of sciatic afferents) so that virtually all large-diameter afferents expressed this receptor component, and the expression of GFRalpha3 also increased (to 66% of sciatic afferents) so that almost all of the small-diameter afferents expressed this receptor component after axotomy. There was little change in RET expression. The changes in the proportions of DRG cells expressing different receptor components were mirrored by alterations in the total RNA levels within the DRG. The changes in GFRalpha1 and GFRalpha2 expression after axotomy could be largely reversed by treatment with GDNF.

Animals↗
PubMed2000

Na/K pump alpha subunit expression in rabbit ventricle and regional variations of intracellular sodium regulation.

We examined the isoform distribution and expression of the alpha subunit of the Na/K-ATPase in the left ventricular muscle of rabbit heart in order to determine whether previously reported regional differences in intracellular sodium regulation derive from differences in pump expression. Immunohistochemical techniques show that only the alpha1 isoform is present in rabbit ventricle; therefore, regional variation in isoform distribution is not possible. Western blots of samples taken from subendocardial and sub-epicardial regions confirm the absence of alpha2 and alpha3 isoforms but also show that levels of the alpha1 isoform do not differ significantly in the two regions. The ratio of densitometric readings from blot bands was 1.18+/-0.17 (epicardial:endocardial; mean +/-SEM). Measurements of fully activated pump current in voltage-clamped cells were achieved by dialysing the cell via the patch pipette with 50 mM Na and applying 1 mM dihydroouabain. The current measured was 0.16+/-0.02 pA/pF in epicardial cells and 0.17+/-0.02 pA/pF in endocardial cells. These results indicate that the capacity of cells from the two regions to generate sodium efflux is identical. Regional differences in intracellular sodium regulation, therefore, are more likely to arise from differences in influx of sodium.

Animals↗
PubMed1999

Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord.

The primary sensory neurons that respond to noxious stimulation and project to the spinal cord are known to fall into two distinct groups: one sensitive to nerve growth factor and the other sensitive to glial cell-line-derived neurotrophic factor. There is currently considerable interest in the ways in which these factors may regulate nociceptor properties. Recently, however, it has emerged that another trophic factor-brain-derived neurotrophic factor (BDNF)-may play an important neuromodulatory role in the dorsal horn of the spinal cord. BDNF meets many of the criteria necessary to establish it as a neurotransmitter/neuromodulator in small-diameter nociceptive neurons. It is synthesized by these neurons and packaged in dense core vesicles in nociceptor terminals in the superficial dorsal horn. It is markedly up-regulated in inflammatory conditions in a nerve growth factor-dependent fashion. Postsynaptic cells in this region express receptors for BDNF. Spinal neurons show increased excitability to nociceptive inputs after treatment with exogenous BDNF. There are both electrophysiological and behavioral data showing that antagonism of BDNF at least partially prevents some aspects of central sensitization. Together, these findings suggest that BDNF may be released from primary sensory nociceptors with activity, particularly in some persistent pain states, and may then increase the excitability of rostrally projecting second-order systems. BDNF released from nociceptive terminals may thus contribute to the sensory abnormalities associated with some pathophysiological states, notably inflammatory conditions.

Animals↗
PubMed1999

Molecular cloning and immunolocalization of a novel vertebrate trp homologue from Xenopus.

We report the sequence, structure and distribution of a novel transient receptor potential (trp) homologue from Xenopus, Xtrp, determined by screening an oocyte cDNA library. On the basis of sequence similarity and predicted structure, Xtrp appears to be a homologue of mammalian trp1 proteins. Two polyclonal antibodies raised against distinct regions of the Xtrp sequence revealed Xtrp expression in various Xenopus tissues, and the localization of Xtrp at the plasma membrane of Xenopus oocytes and HeLa cells. Since capacitative calcium entry into Xenopus oocytes has been shown previously to be substantially inhibited by trp1 antisense oligonucleotides [Tomita, Kaneko, Funayama, Kondo, Satoh and Akaike (1998) Neurosci. Lett. 248, 195-198] we suggest that Xtrp may underlie capacitative calcium entry in Xenopus tissues.

Amino Acid Sequence↗
PubMed1999

Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord.

Central sensitization, the hyperexcitability of spinal processing that often accompanies peripheral injury, is a major component of many persistent pain states. Here we report that the neurotrophin, brain-derived neurotrophic factor (BDNF), is a modulator of excitability within the spinal cord and contributes to the mechanism of central sensitization. BDNF, localized in primary sensory neuron cell bodies and central terminals, potentiates nociceptive spinal reflex responses in an in vitro spinal cord preparation and induces c-fos expression in dorsal horn neurons. NMDA receptor-mediated responses, known as a major contributor to central sensitization, were significantly enhanced by exogenous BDNF. Systemic NGF treatment, a procedure that mimics peripheral inflammatory states, raises BDNF levels in sensory neurons and increases nociceptive spinal reflex excitability. This increased central excitability is reduced by trkB-IgG, a BDNF "antagonist." We also show directly that inflammatory pain-related behavior depends on BDNF release in vivo. Thus behavioral nociceptive responses induced by intraplantar formalin and by intraplantar carageenan are significantly attenuated by trkB-IgG. Hence BDNF is appropriately localized and regulated in inflammatory states and is sufficient and necessary for the expression of central sensitization in the spinal cord. We propose that BDNF may function as a modulator of central sensitization in pathological states, and our results suggest that pharmacological antagonism of BDNF may prove an effective and novel analgesic strategy for the treatment of persistent inflammatory pain states.

Animals↗
PubMed1999

Strophanthidin-induced gain of Ca2+ occurs during diastole and not systole in guinea-pig ventricular myocytes.

We have investigated the effects of inhibiting the Na-K pump with strophanthidin on the intracellular Ca2+ concentration ([Ca2+]i), sarcoplasmic reticulum (s.r.) Ca2+ content and membrane currents. s. r. Ca2+ content was measured by integrating the Na-Ca exchange current resulting from application of 10 mM caffeine. The application of strophanthidin increased both diastolic and systolic [Ca2+]i. This was accompanied by an increase of s.r. Ca2+ content from a resting value of 17.9+/-1.5 micromol/l to 36.9+/-3.3 micromol/l (n=16) after 5 min. Systolic fluxes of Ca2+ into and out of the cell before and during strophanthidin application were also measured. Ca2+ efflux (measured as the integral of the Na-Ca exchange tail current) rose steadily in the presence of strophanthidin, while Ca2+ influx (the integral of the L-type Ca2+ current) was reduced. In spite of this, s.r. Ca2+ content rose substantially. In the presence of Cd2+ (100 microM), which inhibits the L-type Ca2+ current, strophanthidin had negligible effects on current suggesting that Ca2+ influx via Na-Ca exchange during depolarization does not account for the increase of s.r. Ca2+ content. This suggests that changes of Ca2+ flux during systole are not responsible for the strophanthidin-induced increase of s.r. Ca2+. We conclude that the primary mechanism by which the cardiac cell gains Ca2+ when the Na-K pump is inhibited is by a net influx during diastole.

Animals↗
PubMed1999

Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin.

Evidence suggests that nerve growth factor (NGF) is an important mediator in inflammatory pain states: NGF levels increase in inflamed tissue, and neutralization of endogenous NGF prevents the hyperalgesia which normally develops during inflammation of the skin. Here we asked whether NGF contributes to sensitization of primary afferent nociceptors, which are an important component of pain and hyperalgesia in inflamed tissue. An in vitro skin nerve preparation of the rat was used to directly record the receptive properties of thin myelinated (Adelta) and unmyelinated (C) nociceptors innervating normal hairy skin, carrageenan-inflamed skin and carrageenan-inflamed skin where endogenous NGF had been neutralized by application of a trkA-IgG (tyrosine kinase Aimmunoglobulin G) fusion molecule. Following carrageenan inflammation, there was a marked increase in the proportion of nociceptors which displayed ongoing activity (50% of nociceptors developed spontaneous activity compared to 4% of nociceptors innervating normal uninflamed skin), and this was reflected in a significant increase in the average ongoing discharge activity. Spontaneously active fibres were sensitized to heat and displayed a more than twofold increase in their discharge to a standard noxious heat stimulus. Furthermore, the number of nociceptors responding to the algesic mediator bradykinin increased significantly from 28% to 58%. By contrast, the mechanical threshold of nociceptive afferents did not change during inflammation. When the NGF-neutralizing molecule trkA-IgG was coadministered with carrageenan at the onset of the inflammation, primary afferent nociceptors did not sensitize and displayed essentially normal response properties, although the inflammation as evidenced by tissue oedema developed normally. We therefore conclude that NGF is a crucial component for the sensitization of primary afferent nociceptors associated with tissue inflammation.

Animals↗
PubMed1998

A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury.

Several lines of evidence suggest that neurotrophin administration may be of some therapeutic benefit in the treatment of peripheral neuropathy. However, a third of sensory neurons do not express receptors for the neurotrophins. These neurons are of small diameter and can be identified by the binding of the lectin IB4 and the expression of the enzyme thiamine monophosphatase (TMP). Here we show that these neurons express the receptor components for glial-derived neurotrophic factor (GDNF) signaling (RET, GFRalpha-1, and GFRalpha-2). In lumbar dorsal root ganglia, virtually all IB4-labeled cells express RET mRNA, and the majority of these cells (79%) also express GFRalpha-1, GFRalpha-2, or GFRalpha-1 plus GFRalpha-2. GDNF, but not nerve growth factor (NGF), can prevent several axotomy-induced changes in these neurons, including the downregulation of IB4 binding, TMP activity, and somatostatin expression. GDNF also prevents the slowing of conduction velocity that normally occurs after axotomy in a population of small diameter DRG cells and the A-fiber sprouting into lamina II of the dorsal horn. GDNF therefore may be useful in the treatment of peripheral neuropathies and may protect peripheral neurons that are refractory to neurotrophin treatment.

Age Factors↗
PubMed1998

Ca2+ entry into PC12 cells initiated by ryanodine receptors or inositol 1,4,5-trisphosphate receptors.

Capacitative Ca2+ entry (CCE) is a universal mechanism for refilling intracellular Ca2+ stores in electrically non-excitable cells. The situation in excitable cells is less clear, however, since they may rely on other entry mechanisms for Ca2+-store refilling. In the present study we investigated CCE in intact PC12 cells, using acetylcholine to bring about activation of InsP3 receptors (InsP3Rs), caffeine to activate ryanodine receptors (RyRs) and thapsigargin to inhibit sarco/endoplasmic reticulum Ca2+-ATPase pumps. We found that depletion of the InsP3-, caffeine- or thapsigargin-sensitive stores promoted Ca2+ entry, suggesting that stimulation of either InsP3Rs or RyRs can activate CCE. The CCE pathways activated by InsP3Rs, RyRs and thapsigargin appeared to be independent at least in part, since their effects were found to be additive. However, CCE triggered by caffeine, acetylcholine or thapsigargin progressively diminished with time. The decay of CCE caused by one agent also inhibited subsequent responses to the others, suggesting that some component of the CCE pathway is common to all intracellular Ca2+ stores. The magnitude of CCE stimulated by InsP3Rs or RyRs was related to the size of the stores; the InsP3-sensitive store was smaller than the RyR-sensitive store and triggered a smaller entry component. However, both stores filled with a similar half time (about 1 min), and both could be filled more rapidly by depolarization-induced Ca2+ entry through voltage-operated channels. A significant basal Ca2+ influx was apparent in PC12 cells. The basal entry component may be under the control of the InsP3-sensitive Ca2+ store, since short incubations in Ca2+-free medium depleted this store.

Acetylcholine↗
PubMed1998

Endogenous nerve growth factor regulates the sensitivity of nociceptors in the adult rat.

Nerve growth factor (NGF) has a well characterized role in the development of the nervous system and there is evidence that it interacts with nociceptive primary afferent fibres. Here we applied a synthetic tyrosine kinase A IgG (trkA-IgG) fusion molecule for 10-12 days to the innervation territory of the purely cutaneous saphenous nerve in order to bind, and thereby neutralize endogenous NGF in adult rats. Using neurophysiological analysis of 152 nociceptors we now show that sequestration of NGF results in specific changes of their receptive field properties. The percentage of nociceptors responding to heat dropped significantly from a normal 57% to 32%. This was accompanied by a rightward shift and a reduced slope of the stimulus response function relating the intracutaneous temperature to the neural response. The number of nociceptors responding to application of bradykinin was also significantly reduced from a normal of 28% to 8%. In contrast, the threshold for mechanical stimuli and the response to suprathreshold stimuli remained unaltered, as did the percentage of nociceptors responding to noxious cold. The reduced sensitivity of primary afferent nociceptors was accompanied by a reduction in the innervation density of the epidermis by 44% as assessed with quantitative immunocytochemical analysis of the panaxonal marker PGP 9.5. This demonstrates that endogenous NGF in the adult specifically modulates the terminal arborization of unmyelinated fibres and the sensitivity of primary afferent nociceptors to thermal and chemical stimuli in vivo.

Afferent Pathways↗