Toynbee Memorial Lecture 1997. Middle ear mechanics in normal, diseased and reconstructed ears

A review of the structure-function relationships in normal, diseased and reconstructed middle ears is presented. Variables used to describe the system are sound pressure, volume velocity and acoustic impedance. We discuss the following: (1) Sound can be transmitted from the ear canal to the cochlea via two mechanisms: the tympanoossicular system (ossicular coupling) and direct acoustic stimulation of the oval and round windows (acoustic coupling). In the normal ear, middle-ear pressure gain, which is the result of ossicular coupling, is frequency-dependent and smaller than generally believed. Acoustic coupling is negligibly small in normal ears, but can play a significant role in some diseased and reconstructed ears. (2) The severity of conductive hearing loss due to middle-ear disease or after tympanoplasty surgery can be predicted by the degree to which ossicular coupling, acoustic coupling, and stapes-cochlear input impedance are compromised. Such analyses are used to explain the air-bone gaps associated with lesions such as ossicular interruption, ossicular fixation and tympanic membrane perforation. (3) With type IV and V tympanoplasty, hearing is determined solely by acoustic coupling. A quantitative analysis of structure-function relationships can both explain the wide range of observed post-operative hearing results and suggest surgical guidelines in order to optimize the post-operative results. (4) In tympanoplasty types I, II and III, the hearing result depends on the efficacy of the reconstructed tympanic membrane, the efficacy of the reconstructed ossicular chain and adequacy of middle-ear aeration. Currently, our knowledge of the mechanics of these three factors is incomplete. The mechanics of mastoidectomy and stapedectomy are also discussed.     

High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis

To determine whether counterregulation by interleukin (IL)-10 plays a role in the generation or maintenance of the antigen-specific hyporesponsiveness seen in asymptomatic microfilaremic (MF) patients, parasite antigen (PAg)- and nonparasite antigen (NPAg)-driven IL-10 production by peripheral blood mononuclear cells (PBMC) was studied in 10 MF patients and in ll patients with chronic lymphatic pathology (CP). PBMC from MF patients spontaneously secreted 10-fold more IL-10 than did PBMC from patients with CP. PAg also induced significantly more IL-10 production by PBMC from CP patients. There was a negative correlation between PAg driven IL-10 production by PBMC and PAg-specific T cell proliferation in the MF group. IL-10 secretion by plastic adherent cells from MF persons was higher in response to PAg than NPAg, whereas IL-6 and tumor necrosis factor-alpha secretion were equivalent for PAg and NPAg, suggesting that PAg preferentially induces IL-10 secretion in these cells. Thus, PAg-induced IL-10 likely plays an important role in down-regulating antigen-specific proliferative responses in MF patients.     

Beta-lactamase inhibitors: agents to overcome bacterial resistance

Parental illness can have a profound impact on family relationships and children's behaviour. The amount and nature of communication between parents and children about the illness can play an important role, both positively and negatively, in mediating the outcomes. When children have a disability, families can be reluctant to communicate with them about family difficulties. They are often concerned about the impact that parental unavailability may have on their child's life. This paper reports on three families in which the mother was diagnosed with breast cancer and one child in the family had a disability. The extent and specific characteristics of their communication about the maternal illness with their children, behavioural changes in the children, explanations of communication strategies and attributions of behavioural changes are described. Family coping strategies are examined with reference to Lazarus's process model of stress and coping and the use of either problem-focused or emotion-focused strategies. Implications for possible clinical interventions are proposed. In particular it is suggested that families be offered consultation about: what children might understand; ways in which to communicate effectively; and strategies for coping with the long-term implications of serious parental illness.     

Ca2+ channel beta3 subunit enhances voltage-dependent relief of G-protein inhibition induced by muscarinic receptor activation and Gbetagamma

The Ca2+ channel beta subunit has been shown to reduce the magnitude of G-protein inhibition of Ca2+ channels. However, neither the specificity of this action to different forms of G-protein inhibition nor the mechanism underlying this reduction in response is known. We have reported previously that coexpression of the Ca2+ channel beta3 subunit causes M2 muscarinic receptor-mediated inhibition of alpha1B Ca2+ currents to become more voltage-dependent. We report here that the beta3 subunit increases the rate of relief of inhibition produced by a depolarizing prepulse and also shifts the voltage dependency of this relief to more hyperpolarized voltages; these effects are likely to be responsible for the reduction of inhibitory response of alpha1B channels to G-protein-mediated inhibition seen after coexpression of the Ca2+ channel beta3 subunit. Additionally, the beta3 subunit alters the rate and voltage dependency of relief of the inhibition produced by coexpressed Gbeta1gamma1, in a manner similar to the changes it produces in relief of M2 receptor-induced inhibition. We conclude that the Ca2+ channel beta3 subunit reduces the magnitude of G-protein inhibition of alpha1B Ca2+ channels by enhancing the rate of dissociation of the G-protein betagamma subunit from the Ca2+ channel alpha1B subunit.     

Determination of the temperature of thermosensitive spots of the human skin]

The ETV6 (TEL) locus at chromosome band 12p 13 is a major site of translocations in acute leukemia, particularly in childhood acute lymphoblastic leukemia (ALL). In cases with translocations involving ETV6, the normal ETV6 allele is often deleted. In addition, loss of heterozygosity of ETV6 is frequently observed in childhood'ALL. Thus, it has been suggested that ETV6 may have an anti-oncogenic role to play, in addition to its oncogenic role. We have described an unusual case of ALL in which ETV6 is found fused to the ABL gene; ABL is normally activated by fusion to the BCR gene in the 9:22 translocation. We expanded the primary cells from this ETV6/ABL rearranged case of ALL in SCID animals and analyzed them for expression of both ETV6/ABL and the normal ETV6 mRNA. We found that both the rearranged and normal ETV6 mRNAs are expressed in the expanded cell population. Furthermore, sequence analysis of the ETV6 PCR product revealed no point mutations which would influence the amino acid sequence. Thus, deletion of the second ETV6 allele is not necessary for the transformation to leukemia by ETV6/ABL.     

Pharmacological correction of lipid peroxidation during hypoxia and possibility to enhance human resistance to high altitude by using preparations of the metabolic type of action

In simulating acute hypoxic hypoxia with the participation of male volunteers, the authors investigated the antihypoxic and antioxidative activity of metabolic drugs (jakton, amtizole succinate, nootropil, probucol, and a mixture which consists of jakton, amtizole succinate, and probucol). The pharmaceuticals were shown to have heterodirectional effects on lipid peroxidative processes. Drugs having a pronounced antioxidative activity (such as probucol and the mixture) promotes oxygen utilization during hypoxia and posthypoxic reoxygenation chiefly by the oxygenase pathway. This rearrangement of oxygen utilization processes caused an increase in human high-altitude resistance. The use of the above drugs is a promising trend in the development of an adaptative response to hypoxia in persons engaged in hazardous jobs.     

Review of liver trauma management in Tasmania: an analysis of risk factors for mortality and morbidity

A review of liver trauma treated by the major trauma care facilities of Tasmania in the 5 year period between 1989 and 1993 is presented. The aim of this retrospective review was to provide an audit of the management of liver trauma in the island of Tasmania and to analyse the risk factors contributing to mortality and major morbidity. Thirty-seven patients were treated with a median Injury Severity Score (ISS) of 14 (range 9-34). The overall mortality rate of this series was 5.8%. Age, mechanism of injury (blunt or penetrating), delay prior to hospital presentation and modality of treatment (operative or non-operative) were not significant risk factors for mortality and morbidity; however, transfusion requirement of over 10 units of blood (P < 0.005), ISS score of over 20 (P < 0.0005), haemodynamic instability at presentation (P < 0.05) and a Hepatic Injury Score (HIS) grade of 3 or more (P < 0.05) were statistically significant risk factors.     

Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue

Peripheral nerve injury may lead to a chronic neuropathic pain state that results from an increase in excitability of central neurons. This central sensitization is mediated via an N-methyl-D-aspartic acid (NMDA) receptor and may involve the production of nitric oxide (NO). As NO is suggested to play a role in nociceptive transmission following nerve injury, we examined for altered NO synthase activity at multiple levels of peripheral and spinal neural tissue in a rat model of neuropathic pain. Peripheral neuropathy was induced in rats (N = 12) by ligation of the left L5 and L6 nerve roots. Six other rats had sham surgery. An ipsilateral decrease in paw withdrawal threshold to mechanical stimuli confirmed the presence of a neuropathic pain state. Samples of the lumbar and thoracic spinal cords, L4, L5, and L6 dorsal root ganglia (DRGs), and the sciatic nerves were obtained from the lesioned and contralateral sides at 2 and 4 weeks after neuropathic surgery (N = 6 per group). In the lumbar spinal cord, a bilateral decrease in nitric oxide synthase (NOS) activity was observed 2 and 4 weeks after neuropathic surgery. NOS activity was increased in the ipsilateral L5 and 6 DRGs 2 weeks following neuropathic surgery. An increase in NOS activity in the DRG may be an early mechanism for inducing more central changes. The bilaterally decreased NOS activity in the lumbar spinal cord may be secondary to a negative feedback mechanism resulting from increased NO production in the spinal dorsal root ganglia. Multiple alterations in expression of NOS activity that occur in both peripheral and central processing may play a role in the pain behavior resulting from peripheral nerve injury. (Preliminary results of these studies have been presented in abstract form at the annual meetings of the Society for Neuroscience, 1994, and the American Society of Anesthesiologists, 1994).     

Alterations of the catalytic activities of drug-metabolizing enzymes in cultures of human liver slices

The pharmacokinetics of deramciclane (CAS 120444-78-8, EGIS-3886) was investigated in rabbits after i.v., p.o. and s.c. administration of 3 mg/kg 14C-phenyl-deramciclane. The plasma, concentration-time curves of total radioactivity, the parent compound (deramciclane) and its N-demethylated metabolite (EGIS-7056) were determined. The radioactivity level was measured by liquid scintillation technique while the concentration of the parent compound and its metabolite was determined by gas chromatography-mass spectrometry detection. The p.o. and i.v. studies were carried out on the same group of animals, while a separate group of rabbits was used for studying s.c. absorption. Deramciclane was readily absorbed after p.o. and s.c. treatment (tmax 1.0 to 1.4 h). The terminal elimination half-life (t1/2 beta) of the parent compound fell between 5.8 to 7.1 h, while that of the total radioactivity ranged from 21.6 and 26.0 h. The absolute bioavailability of deramciclane calculated from the AUC0-infinity values was found to be 43 and 60% after p.o. and s.c. treatment. The apparent volume of distribution (Vd) and the whole body clearance (Cl) of deramciclane after i.v. administration were 25.0 +/- 7.1 l/kg and 2.6 +/- 0.5 l/h/kg, respectively. The AUC0-infinity values of the parent compound varied between 4.6 and 7.9% of that of total radioactivity, suggesting that deramciclane was subjected to intensive metabolic conversion. The AUC0-infinity of N-desmethyl-deramciclane was 5.7%, compared to that of the parent compound after i.v. administration.