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Biomedical subjects

Michael S Gold

Publications and source records attributed to Michael S Gold.

At least 19 recordsLinked to original sources

Anaphylaxis: diagnosis and management.

Anaphylaxis is a serious, rapid-onset, allergic reaction that may cause death. Severe anaphylaxis is characterised by life-threatening upper airway obstruction, bronchospasm and/or hypotension. Anaphylaxis in children is most often caused by food. Bronchospasm is a common symptom, and there is usually a background of atopy and asthma. Venom- and drug-induced anaphylaxis are more common in adults, in whom hypotension is more likely to occur. Diagnosis can be difficult, with skin features being absent in up to 20% of people. Anaphylaxis must be considered as a differential diagnosis for any acute-onset respiratory distress, bronchospasm, hypotension or cardiac arrest. The cornerstones of initial management are putting the patient in the supine position, administering intramuscular adrenaline into the lateral thigh, resuscitation with intravenous fluid, support of the airway and ventilation, and giving supplementary oxygen. If the response to initial management is inadequate, intravenous infusion of adrenaline should be commenced. Use of vasopressors should be considered if hypotension persists. The patient should be observed for at least 4 hours after symptom resolution and referred to an allergist to assist with diagnosis, allergen avoidance measures, risk assessment, preparation of an action plan and education on the use of self-injectable adrenaline. Provision of a MedicAlert bracelet should also be arranged.

Airway Obstruction↗

Intracellular calcium regulation among subpopulations of rat dorsal root ganglion neurons.

Primary afferent neurons are functionally heterogeneous. To determine whether this functional heterogeneity reflects, in part, heterogeneity in the regulation of the concentration of intracellular Ca(2+) ([Ca(2+)](i)), the magnitude and decay of evoked Ca(2+) transients were assessed in subpopulations of dorsal root ganglion (DRG) neurons with voltage clamp and fura-2 ratiometric imaging. To determine whether differences in evoked Ca(2+) transients among subpopulations of DRG neurons reflected differences in the contribution of Ca(2+) regulatory mechanisms, pharmacological techniques were employed to assess the contribution of influx, efflux, release and uptake pathways. Subpopulations of DRG neurons were defined by cell body size, binding of the plant lectin IB(4) and responsiveness to the algogenic compound capsaicin (CAP). Ca(2+) transients were evoked with 30 mm K(+) or voltage steps to 0 mV. There were marked differences between subpopulations of neurons with respect to both the magnitude and decay of the Ca(2+) transient, with the largest and most slowly decaying Ca(2+) transients in small-diameter, IB(4)-positive, CAP-responsive neurons. The smallest and most rapidly decaying transients were in large-diameter, IB(4)-negative and CAP-unresponsive DRG neurons. These differences were not due to a differential distribution of voltage-gated Ca(2+) currents. However, these differences did appear to reflect a differential contribution of other influx, efflux, release and uptake mechanisms between subpopulations of neurons. These results suggest that electrical activity in subpopulations of DRG neurons will have a differential influence on Ca(2+)-regulated phenomena such as spike adaptation, transmitter release and gene transcription. Significantly more activity should be required in large-diameter non-nociceptive afferents than in small-diameter nociceptive afferents to have a comparable influence on these processes.

Animals↗

Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation.

Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage-gated calcium channel (VGCC) alpha2delta1 subunit (Ca(v)alpha2delta1) in sensory neurons and dorsal spinal cord by peripheral nerve injury has been suggested to contribute to neuropathic pain. To investigate the mechanisms without the influence of other injury factors, we have created transgenic mice that constitutively overexpress Ca(v)alpha2delta1 in neuronal tissues. Ca(v)alpha2delta1 overexpression resulted in enhanced currents, altered kinetics and voltage-dependence of VGCC activation in sensory neurons; exaggerated and prolonged dorsal horn neuronal responses to mechanical and thermal stimulations at the periphery; and pain behaviors. However, the transgenic mice showed normal dorsal horn neuronal responses to windup stimulation, and behavioral responses to tissue-injury/inflammatory stimuli. The pain behaviors in the transgenic mice had a pharmacological profile suggesting a selective contribution of elevated Ca(v)alpha2delta1 to the abnormal sensations, at least at the spinal cord level. In addition, gabapentin blocked VGCC currents concentration-dependently in transgenic, but not wild-type, sensory neurons. Thus, elevated neuronal Ca(v)alpha2delta1 contributes to specific pain states through a mechanism mediated at least partially by enhanced VGCC activity in sensory neurons and hyperexcitability in dorsal horn neurons in response to peripheral stimulation. Modulation of enhanced VGCC activity by gabapentin may underlie at least partially its antihyperalgesic actions.

Animals↗

Testosterone and estrogen have opposing actions on inflammation-induced plasma extravasation in the rat temporomandibular joint.

The present study was designed to test the hypothesis that estrogen exacerbates inflammation of the temporomandibular joint (TMJ). Evans blue dye was used to quantify plasma extravasation (PE) around the rat TMJ. In an initial set of experiments, TMJ PE was compared in naïve intact male and female rats, as well as in both groups after complete Freund's adjuvant (CFA)-induced inflammation of the TMJ. In contrast to our hypothesis, TMJ PE was significantly greater in both naïve and CFA-inflamed male rats than in females. To determine whether these differences were due to gonadal hormones, four additional groups of rats were studied: gonadectomized (Gx) males and females, Gx males with chronic testosterone (T) replacement, and Gx females with chronic estrogen (E) replacement. The sex difference in baseline TMJ PE appeared to reflect the actions of T. However, in the presence of TMJ inflammation, T augmented TMJ PE in males, while E attenuated TMJ PE in females. Changes in PE were also assessed in the contralateral TMJ. Results from this analysis indicated that there is a transient contralateral increase in TMJ PE in females but not males. Given that there is an inverse relationship between PE and joint damage, our results suggest that testosterone may mitigate, but estrogen may exacerbate, TMJ damage, particularly in the presence of overt inflammation. Importantly, our results may help explain both the higher prevalence and severity of temporomandibular disorder pain in females than males.

Animals↗

Inflammatory hyperalgesia: a role for the C-fiber sensory neuron cell body?

UNLABELLED: Peripheral nerve injury increases the chemosensitivity and excitability of injured afferents, resulting in ectopic activity arising from within dorsal root ganglia. Studies of dissociated sensory ganglion neurons in vitro suggest afferent somata might be sensitized by persistent inflammation. However, it is unknown whether this inflammation-induced sensitization is manifest in somata within the intact ganglia. To explore this possibility, intracellular electrophysiologic recording was used with a sciatic nerve-L4-dorsal root ganglia preparation to compare excitability and chemosensitivity of cutaneous C-fiber somata from control and inflamed rats. Cutaneous afferents were identified with the retrograde dye DiI. Excitability was assessed before and after the application of inflammatory soup (IS) containing bradykinin, serotonin, and prostaglandin E2 all at a pH of 7.0. Persistent inflammation decreased the excitability of cutaneous afferents in intact ganglia and had no significant influence on the magnitude of IS-induced increase in excitability. Opposite to the effects observed in intact ganglia, excitability was greater in dissociated cutaneous nociceptors obtained from inflamed rats, although the magnitude of the IS-induced increase in excitability was not significantly affected by inflammation. These results suggest that the cell bodies of putative cutaneous nociceptors in the intact ganglia contribute minimally to pain and hyperalgesia associated with persistent inflammation. PERSPECTIVE: Results of the present study suggest that inflammation-induced changes in afferent somata are minimal. However, they also suggest that inflammatory mediator-induced increase in the excitability of sensory neuron somata might contribute to global changes in nociception observed under high systemic inflammatory mediator loads.

Animals↗

The role of sodium channels in chronic inflammatory and neuropathic pain.

UNLABELLED: Clinical and experimental data indicate that changes in the expression of voltage-gated sodium channels play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic. Clinical and experimental data also suggest that changes in voltage-gated sodium channels may play a role in inflammatory pain, and here too sodium-channel blockers may have therapeutic potential. The sodium-channel blockers of interest include local anesthetics, used at doses far below those that block nerve impulse propagation, and tricyclic antidepressants, whose analgesic effects may at least partly be due to blockade of sodium channels. Recent data show that local anesthetics may have pain-relieving actions via targets other than sodium channels, including neuronal G protein-coupled receptors and binding sites on immune cells. Some of these actions occur with nanomolar drug concentrations, and some are detected only with relatively long-term drug exposure. There are 9 isoforms of the voltage-gated sodium channel alpha-subunit, and several of the isoforms that are implicated in neuropathic and inflammatory pain states are expressed by somatosensory primary afferent neurons but not by skeletal or cardiovascular muscle. This restricted expression raises the possibility that isoform-specific drugs might be analgesic and lacking the cardiotoxicity and neurotoxicity that limit the use of current sodium-channel blockers. PERSPECTIVE: Changes in the expression of neuronal voltage-gated sodium channels may play a key role in the pathogenesis of both chronic neuropathic and chronic inflammatory pain conditions. Drugs that block these channels may have therapeutic efficacy with doses that are far below those that impair nerve impulse propagation or cardiovascular function.

Anesthetics, Local↗

Comparison of urban and rural general surgeons: motivations for practice location, practice patterns, and education requirements.

BACKGROUND: The purpose of this study is to determine the differences between rural and urban surgeons with regard to practice patterns, factors in choosing a practice location, and educational needs. STUDY DESIGN: A list of surgeons obtained from the American Medical Association was examined using the Office of Management and Budget definition of rural. Seventeen hundred rural surgeons were mailed surveys; 421 responded. One hundred fourteen urban surgeons were contacted by telephone. Questions were designed to measure job and community satisfaction, factors influencing their decision to practice in their current location, spectrum and volume of cases, and their perceived educational needs. RESULTS: Age distribution did not differ markedly between urban and rural surgeons. Motivation to practice in their current location varied considerably between urban and rural surgeons. Both groups equally rated quality of life as the leading factor influencing their current practice location. Urban surgeons rated other factors, such as income, practice growth, hospital facilities, and proximity to family, higher than rural surgeons. Practice patterns and educational needs also varied between the two groups. Rural surgeons performed more procedures per year with more variety in procedure type. Both groups felt that additional training in advanced laparoscopic techniques would be helpful, and rural surgeons felt that additional training in the surgical subspecialty areas was important. CONCLUSIONS: Although rural and urban surgeons do not differ in age or the importance of lifestyle in deciding career location, different factors do impact their choice of location. Practice pattern and educational needs varied markedly between rural and urban general surgeons.

Attitude of Health Personnel↗

Inflammation alters sodium currents and excitability of temporomandibular joint afferents.

Inflammation-induced changes in voltage-gated sodium currents (I(Na)) in primary afferent neurons may contribute to hyperexcitability and pain. The present study was designed to test the hypothesis that persistent inflammation of the temporomandibular joint (TMJ) increases I(Na) in TMJ afferents. Acutely dissociated retrogradely labeled TMJ afferents were studied using whole-cell patch clamp techniques three days following Complete Freund's Adjuvant-induced inflammation of the TMJ. Inflammation was associated with a decrease in tetrodotoxin (TTX)-sensitive Na+ conductance and no significant change in slowly inactivating TTX-resistant Na+ conductance. However, inflammation increased the excitability of TMJ afferents. These results suggest that changes in ion channels other than those underlying TTX-sensitive and the slowly inactivating TTX-resistant Na+ conductance are likely to account for the inflammation-induced increase in the excitability of TMJ afferents.

Action Potentials↗

Atopic disease in childhood.

A child with atopy produces IgE antibodies after exposure to common environmental allergens. The atopic diseases (eczema, asthma and rhinoconjunctivitis) are clinical syndromes each defined by a group of symptoms and signs. Not all children with atopy will have atopic disease or develop symptoms after exposure to an allergen. Both genetic and environmental factors determine the development of atopic disease. The presence of specific IgE antibodies to environmental allergens is determined with skin prick or radioallergosorbent testing in children with atopy. Test results should be interpreted in the context of the clinical history and further investigations (eg, allergen avoidance or challenge). Management of atopic disease is frequently symptomatic, but it is important to avoid identified allergen triggers. Immunotherapy may be considered in selected school-age children with severe rhinoconjunctivitis. Preventing atopic disease in high-risk infants and hindering progression of disease in children with established disease are the areas of active research.

Allergens↗

Inflammation-mediated hyperexcitability of sensory neurons.

One of the most prominent signs of tissue injury and inflammation is pain and pain continues to be the primary reason people seek medical attention. Inflammatory pain reflects, at least in part, an increase in the excitability, or sensitization, of subpopulations of primary afferent neurons. While the sensitization of high threshold afferents was observed almost 40 years ago, the basis for this phenomenon continues to be an active and fertile area of research today. This review will summarize recent advances in our mechanistic understanding of sensitization, focusing on four general areas where re search has been most active or productive. These include: (1) the characterization of second messenger pathways underlying inflammation-induced changes in afferent excitability; (2) the impact of previous injury on the afferent response to subsequent inflammation; (3) the impact of target of innervation on the specific afferent response to inflammation, and (4) the impact of sex hormones on the sensitization of high threshold afferents. Work in these areas highlights how much has been learned about this process as well as how much there is yet to learn.

Afferent Pathways↗

Estrogen and inflammation increase the excitability of rat temporomandibular joint afferent neurons.

Several painful conditions, including temporomandibular disorders (TMD), are more prevalent and more severe in women than in men. Although the physiological basis for this sex difference remains to be determined, it is likely that estrogen is an underlying factor. The present study was performed to test the hypotheses that estrogen increases the excitability of rat temporomandibular joint (TMJ) afferents and exacerbates the inflammation-induced sensitization of these sensory neurons. Retrogradely labeled TMJ neurons from ovariectomized rats and ovariectomized rats receiving chronic estrogen replacement were studied using whole cell patch-clamp techniques three days after injecting the TMJ with either saline or Complete Freund's Adjuvant to induce inflammation. Excitability was assessed with depolarizing current injection to determine action potential threshold, rheobase, and the response to suprathreshold stimuli. Spontaneous activity was also assessed. Both inflammation and estrogen increased the excitability of TMJ neurons as reflected by decreases in action potential threshold and rheobase and increases in the incidence of spontaneous activity. The effects were additive with neurons from rats receiving both estrogen and inflammation being the most excitable. The increases in excitability were associated with changes in passive properties and action potential waveform, suggesting that estrogen and inflammation affect the expression and/or properties of ion channels in TMJ neurons. Importantly, the influence of estrogen on both baseline and inflammation-induced changes in TMJ neuronal excitability may help explain the profound sex difference observed in TMD as well as suggest a novel target for the treatment of this pain condition.

Action Potentials↗

Cutaneous and colonic rat DRG neurons differ with respect to both baseline and PGE2-induced changes in passive and active electrophysiological properties.

This study was designed to test the hypotheses that pain syndromes associated with specific body regions reflect unique properties of sensory neurons innervating these regions and/or unique responses of these afferents to tissue damage. Acutely dissociated adult rat dorsal root ganglia (DRG) neurons retrogradely labeled from either the colon or the glabrous skin of the hindpaw were studied by whole cell patch-clamp recording in current-clamp mode. Two populations of colonic afferent neurons were studied: pelvic afferents (arising from L(6), S(1), and S(2) DRG = LS DRG) and hypogastric/lumbar colonic afferents (arising from T(13), L(1), and L(2) DRG = TL DRG). Passive and active electrophysiological properties were studied before and after application prostaglandin E(2) (PGE(2)). We observed marked differences between cutaneous and colonic sensory neurons with respect to baseline passive and active electrophysiological properties as well as both the magnitude and pattern of PGE(2)-induced changes in excitability, passive, and active properties. There were also significant differences between TL and LS neurons with respect to baseline and PGE(2)-induced changes in several passive and active electrophysiological properties. Our results suggest that differences between cutaneous and colonic neurons reflect differences in pattern and/or density of ionic currents present in the plasma membrane. More interestingly, the ionic currents underlying the PGE(2)-induced sensitization of cutaneous neurons appeared to differ from those underlying the sensitization of colonic neurons. The implication of this observation is that it may be possible, in fact necessary, to treat pain arising from specific body regions with unique therapeutic interventions.

Action Potentials↗

Absence of an association between axotomy-induced changes in sodium currents and excitability in DRG neurons from the adult rat.

It is generally believed that nerve injury results in neuronal hyperexcitability that reflects in part a change in Na+ currents. However, there are conflicting data on the nature of Na+ current changes and the association between alterations in Na+ currents and increases in excitability. One potential source of conflicting data is that injured and spared neurons may respond differently to nerve injury; these subpopulations of neurons have not been distinguished in previous studies with the axotomy model of nerve injury (complete transection of the sciatic nerve). The present study was performed to determine the relationship between changes in Na+ channels and changes in neuronal excitability in identified injured dorsal root ganglion neurons post-axotomy. Small (< 45 pF) neurons labeled with a DiI injection into the sciatic nerve were studied 10 days and 4 weeks post-axotomy. Ten days post-axotomy, tetrodotoxin-resistant (TTX-R) Na+ current (INa) was decreased and TTX-sensitive (TTX-S) INa was increased, however, excitability was unchanged. Four weeks post-axotomy, neurons had become hyperexcitable while TTX-R INa remained reduced and TTX-S INa had returned to control levels. Thus, axotomy-induced changes in Na+ currents were not correlated with an axotomy-induced change in excitability. Additional analysis of axotomized neurons suggested that concomitant changes in other ionic currents occurred. These results suggest that neuronal excitability following axotomy is dependent on the sum of changes in ionic currents, and the overall effect on excitability may not always correspond to that predicted by a change in a single class of voltage-gated ion channel.

Action Potentials↗

Voltage-gated sodium channels and hyperalgesia.

Physiological and pharmacological evidence both have demonstrated a critical role for voltage-gated sodium channels (VGSCs) in many types of chronic pain syndromes because these channels play a fundamental role in the excitability of neurons in the central and peripheral nervous systems. Alterations in function of these channels appear to be intimately linked to hyperexcitability of neurons. Many types of pain appear to reflect neuronal hyperexcitability, and importantly, use-dependent sodium channel blockers are effective in the treatment of many types of chronic pain. This review focuses on the role of VGSCs in the hyperexcitability of sensory primary afferent neurons and their contribution to the inflammatory or neuropathic pain states. The discrete localization of the tetrodotoxin (TTX)-resistant channels, in particular NaV1.8, in the peripheral nerves may provide a novel opportunity for the development of a drug targeted at these channels to achieve efficacious pain relief with an acceptable safety profile.

Analgesics↗

Local reactions after the fourth dose of acellular pertussis vaccine in South Australia.

OBJECTIVE: To assess the reported rate of local reactions after administration of acellular pertussis vaccine (DTPa) according to dose number and type of pertussis vaccine (whole-cell or acellular) used for the primary course, and to document the severity and outcome of fourth-dose local reactions. DESIGN AND SETTING: Retrospective review. Reports of adverse events after vaccination in South Australia between 1 January 1997 and 31 December 2000 were reviewed, and a questionnaire administered to all parents who reported a local reaction after the fourth dose of DTPa. MAIN OUTCOME MEASURES: The number, and rate per 100 000 administered doses, of local reactions following the primary and booster doses of DTPa, and of local reactions after the fourth-dose in cohorts of children whose primary vaccinations were with either DTPw or DTPa. Redness and/or swelling at the injection site as reported by parents. RESULTS: Of 581 reported adverse events after vaccination, 138 were local reactions after a pertussis-containing vaccine. Primary vaccinations with DTPa was a significant risk factor for a fourth-dose local reaction (relative risk, 6.7; 95% CI, 2.4-18.5). Parental questionnaires were completed for 45 of the 71 children (63%) with reported local reactions after the fourth dose of DTPa; extensive limb swelling was reported in 8 children (18%) and all except one child had recovered by the time of review. CONCLUSIONS: Parents should be informed that children receiving booster doses of DTPa vaccine, after primary doses with DTPa, are at increased risk of local reactions (which tend to resolve spontaneously) but not of systemic effects. Studies should be initiated to investigate the pathogenesis and the risk of recurrence of local reactions to further improve vaccination schedules.

Adverse Drug Reaction Reporting Systems↗