The use of lidocaine spray (Xylocaine) as a topical anaesthetic for minor ear procedures.

BACKGROUND: Injectable anaesthetic agents, topical creams and aqueous solutions have previously been used to anaesthetise the tympanic membrane for minor ear procedures. Topical creams take 20-30 minutes to work and injectable anaesthetics can cause canal swelling. The effectiveness of lidocaine spray has not previously been investigated in patients undergoing minor ear procedures. METHODS: Eighteen participants attending for out-patient grommet insertion or intratympanic steroid injection were prospectively recruited for this study over six months. Post-operatively, they were asked about their perceived level of pain and overall experience. RESULTS: The median level of pain measured on an 11-point visual analogue scale was 2 out of 10. Forty-four per cent reported the overall experience as pleasant, with the remainder selecting slightly unpleasant (66 per cent). All participants stated they would undergo the procedure again. CONCLUSION: Xylocaine spray is simple to administer, rapid-acting and well tolerated by patients for anaesthesia of the tympanic membrane during minor ear procedures in the out-patient setting.

Use of office based transnasal oesophagoscopy in management of Head & Neck conditions during the COVID-19 pandemic at the Royal Albert Edward Infirmary, Wigan, United Kingdom.

OBJECTIVES: To assess the clinical and cost effectiveness of transnasal oesophagoscopy (TNO) in cases of suspected upper aerodigestive tract malignancy and define its role as a safe alternative to panendoscopy. We have also analysed if the implementation of TNO during the COVID-19 pandemic was beneficial in order to provide uninterrupted care to the patients with the limited resources available in these challenging times. METHODS: All patients who underwent TNO guided biopsies or dilatation attempted over a 7 month period during COVID- 19 pandemic were included by searching the hospital and department database at The Royal Albert Edward Infirmary. A comparative group of patients who underwent panendoscopy over 9 months were included for comparison. Demographic data, histological diagnosis, second procedure and cost involved were recorded. RESULTS: During this period, 20 TNO procedures (16 biopsies and 4 dilatations) were attempted which were compared with 20 panendoscopy procedures. The diagnostic accuracy of TNO biopsy for identifying benign and malignant pathology was 81.1%. The sensitivity and specificity for identifying malignancy was 76.9% and 100% respectively. The most common lesion location was laryngeal (43.8%) followed by oropharyngeal (37.5%), more specifically located at the tongue base. The median waiting period between the procedure being listed and TNO being performed was 5.5 days compared to 12 days for panendoscopy. There were 12/16 patients who did not require further interventions for histological diagnosis of the tumor. The TNO procedure was well tolerated with no complications and all were done under local anaesthesia as outpatient procedure without need for admission. TNO resulted in cost saving of £356 per case on a standard NHS tariff. CONCLUSION: TNO is a valuable diagnostic tool for patients with suspected UADT malignancy and dysphagia and has proven to be an asset during the COVID-19 pandemic when we have to make the best use of the limited theatre time and resources. Also, the cost analysis showed that outpatient based TNO can provide significant cost savings for the current standard of care. Furthermore, it has shown better patient tolerability, lesser complications and shortened the time for diagnosis and hence starting timely treatment for these patients.

Cation, magnetic, and charge ordering in MnFe3O5.

The recently-discovered high pressure material MnFe3O5 displays a rich variety of magnetically ordered states on cooling. Fe spins order antiferromagnetically below a Néel transition at 350 K. A second transition at 150 K marks Mn spin order that leads to spin canting of some of the Fe spins and ferrimagnetism. A further transition at 60 K is driven by charge ordering of Fe2+ and Fe3+ over two inequivalent Fe sites, with further canting of all spins. Electrical resistivity measurements reveal semiconducting behaviour in MnFe3O5 with a change in activation energy at 285 K.

How contexts promote and prevent relapse to drug seeking.

The contexts where drugs are self-administered play an important role in regulating persistent drug taking and in relapse to such taking after periods of abstinence. Here, we review the behavioral and brain mechanisms enabling contexts to promote and prevent relapse to drug seeking. We review the key brain structures, their neuropharmacology and their connectivity. We discuss the similarities and differences between the mechanisms for context-induced reinstatement of drug seeking vs. other forms of relapse to drug seeking in animal models and we highlight the numerous deficits in our understanding. We emphasize that current understanding, although significant, defies explanations in terms of models at the level of brain structures and their connectivity. Rather, we show that there is significant functional compartmentalization and segregation within these structures during reinstatement and extinction of drug seeking that parallels their anatomical segregation into circuits and channels. A key challenge is to recognize this complexity, understand how these circuits and channels are organized, as well as understand how different modes of activity of ensembles of neurons within them promote abstinence or relapse to drug seeking.

Renewal of extinguished cocaine-seeking.

Rats were trained to self-administer cocaine in a distinctive context (context A). They were then extinguished in a second context (context B) prior to test for cocaine-seeking in the original training context, context A (group ABA), context B (group ABB) or no test (group AB0). Group ABA showed renewal of extinguished cocaine-seeking associated with c-Fos induction in basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex. Groups ABA and ABB showed test-associated c-Fos induction in prelimbic prefrontal cortex, nucleus accumbens (core, shell, rostral pole), striatum, lateral amygdala, perifornical hypothalamus, and ventral tegmental area. Double immunofluorescence revealed that renewal-associated c-Fos was expressed in orexin-negative lateral hypothalamic neurons whereas test-associated c-Fos was expressed in orexin-positive perifornical hypothalamic neurons. Retrograde tracing from lateral hypothalamus with cholera toxin revealed only sparse dual-labeled neurons in basolateral amygdala and infralimbic prefrontal cortex, suggesting that these regions contribute to renewal of cocaine-seeking independently of their projections to lateral hypothalamus. Retrograde tracing from the ventral tegmental area suggested that hypothalamic contributions to cocaine-seeking are likewise independent of projections to the midbrain. These results suggest that renewal of cocaine-seeking depends critically on basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex. Whereas basolateral amygdala and lateral hypothalamus contributions may be common to renewal of extinguished cocaine-, alcohol-, and sucrose-seeking, infralimbic prefrontal cortex contributions appear unique to renewal of cocaine-seeking and may reflect the habitual nature of relapse to cocaine.

The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking.

We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished alcohol-seeking. Rats were trained to respond for 4% beer in one context (A), extinguished in a different (B) context, and then tested for responding in the original training context (A) or the extinction context (B). ABA renewal was mediated by D1 dopamine receptors because it was prevented by SCH23390. ABA renewal of alcohol-seeking was associated with selective increases in c-Fos protein induction in basolateral amygdala, ventral accumbens shell, and lateral hypothalamus (renewal-associated Fos). By contrast, being tested was associated with increased c-Fos induction in anterior cingulate, prelimbic and infralimbic cortex, rostral agranular insula, dorsomedial accumbens shell, and accumbens core (test-associated Fos). Renewal-associated Fos in ventral accumbens shell and lateral hypothalamus, but not basolateral amygdala, was D1 dopamine receptor dependent. Double immunofluorescence showed that renewal-associated Fos was expressed in orexin-negative lateral hypothalamic neurons. However, c-Fos induction in either lateral hypothalamic orexin-negative or orexin-positive neurons was positively and significantly correlated with alcohol-seeking. Test-associated c-Fos induction was observed in orexin-positive perifornical neurons. In both regions, c-Fos expression was dependent on D1 dopamine receptors. These results suggest that renewal of extinguished alcohol-seeking depends on a distributed neural circuit involving basolateral amygdala, ventral accumbens shell, and lateral hypothalamus that involves D1 dopamine receptors. Comparison with our previous results [Hamlin AS, Blatchford KE, McNally GP (2006) Renewal of an extinguished instrumental response: Neural correlates and the role of D1 dopamine receptors. Neuroscience 143:25-38] permits identification of similarities and differences in the correlates of renewal of extinguished drug- and natural-reward seeking.

Renewal of an extinguished instrumental response: neural correlates and the role of D1 dopamine receptors.

Contexts play an important role in controlling the expression of extinguished behaviors. We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished instrumental responding. Rats were trained to respond for a sucrose reward in one context (A). Responding was then extinguished in the same (A) or different (B) context. Rats were tested for responding in the original training context (A). Return to the original training context after extinction (group ABA) was associated with a return of responding. Three distinct patterns of Fos induction were detected on test: 1) ABA renewal was associated with selective increases in c-Fos protein induction in basolateral amygdala, ventral accumbens shell, and lateral hypothalamus (but not in orexin- or melanin-concentrating hormone (MCH)-hypothalamic neurons); 2) being placed in the same context as extinction training (AAA or ABB) was associated with a selective decrease in c-Fos induction in rostral agranular insular cortex; 3) being placed in any context on test was associated with the up-regulation of c-Fos induction in anterior cingulate, dorsomedial accumbens shell, accumbens core, lateral septum, and substantia nigra. The return of responding in ABA renewal was prevented by pre-treatment with the D1 dopamine receptor antagonist SCH23390 (10 microg/kg; s.c.). SCH23390 also suppressed basal and renewal-associated c-Fos protein induction throughout accumbens, and, selectively suppressed renewal-associated c-Fos induction in lateral hypothalamus. These results suggest that renewal of extinguished responding for a sucrose reward depends on a distributed neural circuit involving basolateral amygdala, ventral accumbens shell, and lateral hypothalamus. D1 dopamine receptors within this circuit are essential for renewal. The results also suggest that rostral agranular insular cortex may play an important role in suppressing reward-seeking after extinction training.

Power Doppler ultrasound assessment of follicular vascularity in the early follicular phase and its relationship with outcome of in vitro fertilization.

OBJECTIVE: To determine whether ovarian perifollicular blood flow (PFBF) in the early follicular phase (EFP) was associated with treatment outcome. DESIGN: Retrospective longitudinal cohort study. SETTING: Tertiary referral centre/university hospital. PATIENTS: Thirty-four women underwent 37 IVF cycles, which resulted in 35 embryo transfers. INTERVENTIONS: Serial transvaginal scans using power Doppler ultrasound during the follicular phase. Ovarian PFBF of follicles > or =5 mm was subjectively assessed using a modified grading system (grades 0-4). MAIN OUTCOME MEASURES: Ovarian PFBF and pregnancy. RESULTS: Treatment cycles were retrospectively divided into two groups: Group 1 (n=20) had cycles with at least one small (5-10 mm) or medium (11-14 mm) size follicle(s) of high grade (2-4) PFBF on cycle day 5 or 6 or 7; and Group 2 (n=17), had cycles that did not. Group 1 had a significantly higher proportion of high grade large follicles in the late follicular phase (35% vs. 21%) (OR 2.0; 95% CI 1.1-3.7) and higher clinical pregnancy rate (47% vs. 12%) (OR 6.3; CI 1.1-35.7) compared to Group 2. CONCLUSION: High grade ovarian PFBF in the EFP during IVF is associated with both high grade PFBF in the late follicular phase and a higher clinical pregnancy rate.

Longitudinal assessment of ovarian perifollicular and endometrial vascularity by power Doppler ultrasound in pregnant and non-pregnant cycles in the IVF setting.

PURPOSE: This longitudinal study aimed to compare ovarian perifollicular and endometrial blood flow (PFBF and EBF, respectively) during the follicular phase in pregnant and non-pregnant IVF cycles. METHODS: Serial transvaginal scans were performed in 15 subjects undergoing IVF treatment. Both PFBF and EBF were subjectively graded (grades 0-4 for PFBF and grades 1-3 for EBF). After confirmation of clinical pregnancy, the treatment cycles were grouped into 'Pregnant' and 'Non-pregnant' cycles. Ovarian PFBF and EBF were retrospectively compared between the two groups. RESULTS: In pregnant cycles, the proportion of large (> or = 15 mm) follicles with high (24) grade PFBF increased with time throughout the follicular phase, and the proportion of large follicles with poor (0-1) grade PFBF decreased. In non-pregnant cycles these trends were reversed. There was no difference in EBF between the two groups. CONCLUSION: The pattern of ovarian PFBF but not EBF may be predictive of treatment outcome.

Role of corticotropin-releasing hormone in the amygdala and bed nucleus of the stria terminalis in the behavioral, pain modulatory, and endocrine consequences of opiate withdrawal.

The extra-hypothalamic actions of corticotropin-releasing hormone (CRH) have been accorded an important role in coordinating responses to stressors and contributing to the consequences of drug abuse. Recent proposals suggest that CRH actions in the bed nucleus of the stria terminalis coordinate responses to tonic/unpredictable stressors whereas these actions in the central nucleus of the amygdala coordinate responses to phasic/predictable stressors. We used in situ hybridization histochemistry and site-specific microinjections of a CRH receptor antagonist to study the role of CRH in opiate withdrawal. Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed significant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal). An increase of CRH mRNA in the paraventricular nucleus of the hypothalamus was specific to rats undergoing withdrawal. Intracerebroventricular microinjection of the CRH receptor antagonist, alpha(h)CRH(9-41), reduced the severity of opiate withdrawal. Microinjections of alpha(h)CRH(9-41) into the central nucleus of the amygdala also reduced the severity of withdrawal whereas bed nucleus of the stria terminalis microinjections of alpha(h)CRH(9-41) were without effect. These experiments provide evidence for a role of amygdala, but not bed nucleus of the stria terminalis, CRH in opiate dependence. We propose a specific role for down-regulation of opiate receptor signaling in increased expression of the CRH gene in the amygdala. Moreover, we suggest that the roles accorded to CRH in the bed nucleus of the stria terminalis versus amygdala in coordinating responses to stressors may need to be reconsidered to distinguish between external and internal/interoceptive stressors.

Effects of contextual or olfactory cues previously paired with morphine withdrawal on behavior and pain sensitivity in the rat.

RATIONALE: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal. OBJECTIVES: To determine whether exposure to a distinctive context or odor paired with morphine withdrawal would provoke a withdrawal syndrome, defensive behaviors (e.g., freezing) and pain modulatory (e.g., hypoalgesia) responses similar to those produced by exposure to stimuli signaling other sources of aversive stimulation (e.g., footshock), or whether both withdrawal and fear-like responses would be provoked. METHODS: Rats were used in four experiments to study the effects on defensive behavior and pain sensitivity of naloxone-precipitated morphine withdrawal or exposure to a distinctive context or odor previously paired with such withdrawal. RESULTS: Injection of 2.5 mg/kg naloxone in morphine-dependent rats precipitated a withdrawal syndrome characterized by whole body shaking, diarrhea, ptosis, and postural abnormalities (experiment 1). Exposure to either a distinctive context (experiment 2) or odor (experiments 3) previously paired with morphine withdrawal provoked the species-typical defense response of freezing but not signs of withdrawal. Exposure to an odor previously paired with morphine withdrawal also provoked hypoalgesia in the formalin test, which was mediated by activity at opioid receptors (experiment 4). CONCLUSIONS: These results show that opiate withdrawal supports the conditioning of defensive and hypoalgesic responses consistent with the arousal of a fear motivational system. The emergence of fear in these experiments, and the relationship between the freezing observed here and the learned avoidance and suppression observed in other withdrawal conditioning preparations, is discussed with reference to dual representation accounts of Pavlovian conditioning.

Acute exposure to saccharin reduces morphine analgesia in the the rat: evidence for involvement of N-methyl-D-aspartate and peripheral opioid receptors.

RATIONALE: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug's peripheral effect, while learned tolerance involves activation of N-methyl-D-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. OBJECTIVES: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. METHODS: Six experiments used the rat's tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the noncompetitive NMDA receptor antagonist MK-801 on this modulation of analgesia. RESULTS: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment la), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. CONCLUSIONS: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.

A peripheral, intracerebral, or intrathecal administration of an opioid receptor antagonist blocks illness-induced hyperalgesia in the rat.

We used the tail-flick response of rats to study the role of opioid receptors in illness-induced hyperalgesia. An intraperitoneal injection of lithium chloride (LiCl) produced hyperalgesia that was blocked in a dose-dependent manner by subcutaneous injection of the opioid antagonist naloxone. Neither hyperalgesia nor its blockade by naloxone were due to variations in tail-skin temperature induced by LiCl. Hyperalgesia was also blocked when opioid receptor antagonism was restricted to (a) the periphery, by intraperitoneal administration of the quaternary opioid receptor antagonist naloxone methiodide; (b) the brain, by intracerebroventricular microinjection of naloxone; or (c) the spinal cord, by intrathecal microinjection of naloxone. These results document a pain facilitatory role of opioid receptors in both the peripheral and central nervous systems and are discussed with reference to their analgesic and motivational functions.

Pain facilitatory circuits in the mammalian central nervous system: their behavioral significance and role in morphine analgesic tolerance.

Sensitivity to noxious stimulation is not invariant; rather, it is modulated by discrete pain inhibitory and facilitatory circuits. This paper reviews the neural circuits for pain facilitation, describes the conditions governing their environmental activation, and examines their role in an animal's behavioral repertoire. Mechanisms for pain facilitation are contrasted at both the neural and behavioral level with mechanisms for pain inhibition. In addition, the involvement of mechanisms for pain facilitation in morphine analgesic tolerance is discussed, and the implications of this involvement for accounts of the role of associative processes in analgesic tolerance are highlighted.

Test type influences the expression of lithium chloride-induced hyperalgesia.

The hyperalgesic properties of the emetic drug lithium chloride (LiCl) were examined in eight experiments. At a dose of 63.6 mg/kg, LiCl produced hyperalgesia in the radiant-heat (Experiment la) and immersion (Experiment 1b) tail-flick tests. At doses of 15.9, 31.8, 63.6, and 127.2 mg/kg, LiCl failed to produce hyperalgesia during the delayed behavioral response in the formalin test (Experiments 2a and 2b), but 63.6 mg/kg LiCl did produce hyperalgesia during the normally quiescent, interphase period of formalin responding (Experiment 2c). At the dose of 63.6 mg/kg, LiCl did not produce hyperalgesia in the hotplate test (Experiments 3a and 3b) and did not exert significant motoric effects in a step-down passive-avoidance task (Experiment 4). The results were discussed with reference to the behavioral effects of LiCl and their implications for demonstrations of associatively mediated morphine analgesic tolerance.

Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms.

A review of the literature and a preliminary study of family compliance in a developmental disabilities clinic.

To investigate the compliance of family members with the treatment recommended for patients, three child and adolescent psychiatrists assessed the charts of all active outpatients in a developmental disabilities clinic in the psychiatric department of a tertiary care municipal hospital utilizing a Family Compliance Checklist, a survey form for chart review, in October, 1993 (n = 40), and in April, 1994 (n = 41). Almost no clients missed appointments over a 6-mo. period. Only one family refused to permit the use of medication. Three families refused to make appointments. The majority of the patients were Hispanic and almost half were Roman Catholic. We conclude that most families of patients in a developmental disabilities clinic comply with recommended treatment plans including scheduled appointments and prescribed medications.

The detection, quantification and partial characterisation of cathepsin B-like activity in human pathological synovial fluids.

In this study, the levels of the cysteine proteinase--cathepsin B were measured in diseased synovial fluids using a steady state fluorometric assay. Cathepsin B-like activity was shown to be present in all the samples analysed, with the rheumatoid arthritic synovial fluids possessing significantly higher concentrations (mean value ca. 416 mg/l) than the osteoarthritic fluids (mean value ca. 142.4 mg/l). In addition, upon treatment with pepsin, all of the rheumatoid arthritis samples were shown to possess additional cathepsin B-like activity, suggesting the presence of a reservoir of latent precursor molecules. By utilising a recently developed biotinylated affinity label for cathepsin B-like proteinases and sheep anti-(human cathepsin B) antibodies, used in combination with SDS-PAGE and Western blotting, the rheumatoid arthritic synovial cathepsin B was shown to exist in two forms with apparent molecular masses of M(r) 29,000 and 42,000. We propose that the former is a functionally active proteinase, whereas the latter is a pepsin activatable proform which, when cleaved by this aspartyl proteinase, is converted into a catalytically competent species of M(r) 20,000.