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Based on initially identified needs for further telemedicine (TM) and chronic wound management research, the objective of this article is twofold: to conduct a systematic review of existing knowledge on TM interventions in chronic wound management—including barriers and opportunities—across the specialist and primary care sectors, and to incorporate the review findings into a system framework that can be further developed and validated through empirical data. We conclude that there is a pressing need for broader and more comprehensive empirical explorations into quality improvement and integration of TM in chronic wound management, including using system frameworks that can capture cross-sector system perspectives and associated implications. Of practical consideration, we suggest that the design and execution of TM improvement interventions and associated research projects should be conducted in close cooperation with managers and practitioners knowledgeable about barriers and opportunities that can influence the implementation of important interventions within chronic wound management. publishedVersion

Successful prevention of pressure ulcers is the end product of a complex series of care processes including, but not limited to, the assessment of vulnerability to pressure damage; skin assessment and care; nutritional support; repositioning; and the use of beds, mattresses, and cushions to manage mechanical loads on the skin and soft tissues. The purpose of this review was to examine where and how Statistical Process Control (SPC) measures have been used to assess the success of quality improvement initiatives intended to improve pressure ulcer prevention. A search of 7 electronic bibliographic databases was performed on May 17th, 2017, for studies that met the inclusion criteria. SPC methods have been reported in 9 publications since 2010 to interpret changes in the incidence of pressure ulcers over time. While these methods offer rapid interpretation of changes in incidence than is gained from a comparison of 2 arbitrarily selected time points pre- and post-implementation of change, more work is required to ensure that the clinical and scientific communities adopt the most appropriate SPC methods.

This study examined the morphologic features of the parietal peritoneal membranes of 130 patients undergoing peritoneal dialysis (PD) and compared them with the features of the peritoneal membranes of normal individuals, uremic predialysis patients, and patients undergoing hemodialysis. The median thickness of the submesothelial compact collagenous zone was 50 microm for normal subjects, 140 microm for uremic patients, 150 microm for patients undergoing hemodialysis, and 270 microm for patients undergoing PD (P0.001 for all versus normal subjects). Compact zone thickness increased significantly with the duration of PD therapy [0 to 24 mo, 180 microm (n = 58); 25 to 48 mo, 240 microm (n = 24); 49 to 72 mo, 300 microm (n = 13); 73 to 96 mo, 750 microm (n = 16);97 mo, 700 microm (n = 19)]. Vascular changes included progressive subendothelial hyalinization, with luminal narrowing or obliteration. These changes were absent in samples from normal subjects but were present in 28% of samples from uremic patients and 56% of biopsies from patients undergoing PD. In the PD group, the prevalence of vasculopathy increased significantly with therapy duration (P = 0.0001). The density of blood vessels per unit length of peritoneum was significantly higher for patients with membrane failure and was correlated with the degree of fibrosis (P = 0.01). For the first time, a comprehensive cross-sectional analysis of the morphologic changes in the peritoneal membranes of patients undergoing PD is provided. The infrequency of fibrosis in the absence of vasculopathy suggests that vasculopathy may predispose patients to the development of fibrosis. This study provides a sufficiently large cohort of samples to allow structure-function relationships to be established, as well as providing a repository of tissue for further studies.

The professional and research literature in education show overwhelming supportfor experiential learning such as that typified by the Supervised Agricultural Experience (SAE) program. The agricultural education literature advocates SAE as an integral component of our total program. At the same time, some authors have suggested changes to SAE while others have questioned the appropriateness of some aspects of the program as it is currently conceptualized. The authors of this paper conducted a Delphi study using agricultural teacher educators, agricultural education teachers, state agricultural education supervisory staff members, and professional from the industry of agriculture to examine the efficacy of and structure of SAE as we move into the next century. They conclude that SAE remains a viable component of a comprehensive program of agricultural education but that its definition needs to be broadened and that its structure needs substantial expansion to accommodate the realities facing agricultural educators today.

In the cochlea, outer hair cells (OHCs) generate the active cochlear mechanics whereas the supporting cells, such as Deiters' cells and Hensen's cells, may play a role in both the active and passive cochlear mechanics. The presence of receptors for adenosine triphosphate (ATP) on OHCs, Deiters' cells and Hensen's cells indicates that endogenous ATP may have a role in cochlear mechanics. To explore this possibility, the effects of the ATP antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), were studied in guinea pig both in vitro on isolated OHCs, Deiters' cells, Hensen's cells and pillar cells using the whole-cell configuration of the patch-clamp technique, and in vivo on sound evoked cochlear potentials (cochlear microphonic, CM; summating potential, SP; compound action potential, CAP) and distortion product otoacoustic emissions (DPOAEs) using cochlear perilymphatic perfusion. Results show that PPADS (100 microM) reduced the inward current evoked by 5-10 microM ATP in OHCs, Deiters' cells, Hensen's cells and pillar cells. This effect of PPADS was slow in onset and was slowly reversed to a varying degree in the different cell types. In vivo application of PPADS in increasing concentrations reduced the sound evoked CAP, SP and increased N1 latency starting at about 0.33 mM (SP) and 1 mM (CAP and N1 latency). PPADS (0.33-1 mM) reversibly suppressed the initial value of the quadratic DPOAE and reversed the 'slow decline' in the quadratic DPOAE that occurs during continuous stimulation with moderate level primaries. These results, together with the similar effects of the ATP antagonist suramin reported previously (Skellett et al., 1997), may be evidence that endogenous ATP acting on cells in the organ of Corti alters cochlear mechanics.

The purpose of this study was to test the hypothesis that differences exist in the amount of protection provided by prior sound conditioning with continuous vs. interrupted, moderate-level noise. Differences were determined by monitoring the changes that occurred in cubic (2 f 1 - f 2 ) distortion product otoacoustic emission (DPOAE) amplitude growth functions subsequent to a traumatizing noise exposure (105 dB SPL, 1.0–2.0 kHz octave band noise presented 24 h per day for 3 days) in guinea pigs which had been conditioned with either continuous (89 dB SPL, 1.0–2.0 kHz octave band noise presented 24 h per day for 11 days) or interrupted noise (95 dB SPL, 1.0–2.0 kHz octave band noise presented on a 6-h `on'/18-h `off' schedule for 11 days) of equal acoustic energy. Results suggest that there are significant differences in the degree of protection provided by prior sound conditioning with the continuous and interrupted schedules of moderate-level noise used in this study. Specifically, the interrupted conditioning protocol afforded some degree of protection against the damaging effects of the traumatizing noise exposure, limited to frequencies above the noise exposure band. Conversely, there was a lack of any consistent and sizable protective effect found across the entire test frequency range for the continuous sound conditioning protocol.

In the cochlea, outer hair cells (OHCs) and Deiters' cells most likely contribute to the generation of active cochlear mechanics. The presence of ATP receptors on these cells indicates that endogenous ATP may have a role in cochlear mechanics. To explore this possibility, the effects of ATP antagonists were studied both in vivo on distortion product otoacoustic emissions (DPOAEs) using cochlear perfusion and in vitro on isolated OHCs and Deiters' cells using the whole-cell configuration of the patch-clamp technique. Results show that extracellular application of 5-10 microM ATP to OHCs and Deiters' cells induced an inward current that was reduced by both suramin (100 microM) and cibacron (100 microM). Cibacron reduced the voltage gated currents in Deiters' cells and increased them in OHCs, while suramin had no effect. In addition, cibacron induced a hyperpolarizing shift of the half activation voltage of the whole cell currents in Deiters' cells. Suramin (0.1-1 mM) reversibly suppressed the 'slow decline' in the quadratic DPOAE that occurs during continuous stimulation with moderate level primaries. This effect of suramin may be evidence that endogenous ATP alters active cochlear mechanics.

End-stage renal disease is a chronic condition which reduces the life-span of its victims. At present there is no cure. Renal transplantation, currently the treatment of choice for many patients, is potentially associated with a number of drawbacks: constant risk of rejection, especially during the first six months, the need to comply with a complex regime of medication capable of producing pronounced side-effects and need for ongoing medical supervision. Despite these problems, little research has been undertake with patients following renal transplantation. The aim of the small-scale, exploratory study reported here was to explore patients' perceptions of stress and quality of life at different stages following a first, functioning renal graft: within six months, between one and five years and over five years later (n = 10 in each group). From the results it became apparent that patients had a number of concerns, of which fear of rejection was the most frequently mentioned, followed by stress generated through altered body image (a product of immunosuppressive therapy). Nevertheless, all reported a significant increase in quality of life after transplantation, although improvement was least marked in patients in the intermediate group (1-5 years after surgery) who also experienced most stress. A larger scale study is recommended to increase the validity of findings which clinicians could then use to design patient interventions to enhance quality of care and quality of life.

The distortion product otoacoustic emission (DPOAE) corresponding to the frequency f2–f1 displays stereotyped, time-varying amplitude alterations during continuous primary tone stimulation. The origin of these alterations is unknown; however, evidence that efferent neurons contribute little to the changes has been presented (Kujawa et al., 1994a, 1995; Lowe and Robertson, 1995). The present investigation examines the hypothesis that these alterations in f2–f1 amplitude are a reflection of local, Ca2+-dependent mechanisms involving the outer hair cell (OHC) response to sustained stimulation. Experiments were performed using urethane-anesthetized guinea pigs with sectioned middle ear muscles. Intracochlear perfusion was employed to reversibly lower perilymph Ca2+ levels and to introduce antagonists and agonists of L-type Ca2+ channels. Manipulations that lowered available Ca2+ (zero Ca2+ artificial perilymph; zero Ca2+ with BAPTA) or that blocked its entry into the cell via L-type Ca2+ channels (nimodipine) reduced, prevented or reversed the perstimulatory changes in f2–f1 DPOAE amplitude. These perilymph manipulations also reduced the overall amplitude of this distortion component while perfusion of an L-type Ca2+ channel agonist (Bay K 8644) increased its amplitude. Mg2+ did not substitute for Ca2+, suggesting that these are not merely divalent cation effects. Results are consistent with the hypothesis that continuous stimulation-related changes in f2–f1 DPOAE amplitude are sensitive to perilymph Ca2+ levels and to the function of L-type Ca2+ channels. However, nimodipine also reduced the endocochlear potential (EP) and Bay K 8644 increased the EP. The sensitivity of both the perstimulatory changes in f2–f1 DPOAE amplitude and the EP to the latter drugs leaves their site(s) of action unresolved.

The application of caffeine to the bathing medium of isolated cochlear outer hair cells (OHCs) induces shortening of the cells (Slepecky et al., 1988). This study was designed to test the hypothesis that a 'smooth muscle-like' mechanism was responsible for the caffeine-induced shortening of OHCs as suggested by Slepecky et al. OHCs were isolated from guinea pig cochleae and length measurements were taken during various drug perfusions. Antagonists of the ryanodine receptor/Ca(2+)-induced Ca2+ release (CICR; tetracaine, ruthenium red, and ryanodine) failed to block the caffeine-induced shortening of the OHCs. Application of the Ca2+ ionophore A23187 caused cell length to increase. These results did not support this hypothesis and therefore, an osmotic mechanism was proposed.

The f2-f1 distortion product otoacoustic emission (DPOAE) can be observed to undergo gradual alterations in amplitude during continuous ipsilateral stimulation with primary tones. In the present experiments, we characterized the dependence of these amplitude alterations on several stimulus variables (intensity, duration, frequency) and on DPOAE type (quadratic vs cubic) and tested the hypothesis that such alterations are mediated by the olivocochlear (OC) efferents. Responses were recorded in urethane-anesthetized guinea pigs with sectioned middle ear muscles before and after intracochlear application of antagonists (curare, 1 microM; bicuculline, 10 microM; tetrodotoxin, 1 microM) or before and after OC efferent section at the midline of the floor of the IVth ventricle. We confirm previous reports of continuous stimulation-related alterations in the amplitude of the quadratic distortion product, f2-f1, and report a novel, suppressive 'off-effect' apparent in f2-f1 amplitude following a short rest from such stimulation. Response alterations were sensitive to primary intensity and to duration of rest from continuous stimulation, but were not clearly frequency-dependent over the ranges tested. Corresponding alterations in the amplitude of the cubic nonlinearity, 2f1-f2 were very small or absent. Amplitude alterations in f2-f1 were reduced but not blocked by OC efferent antagonists (curare, bicuculline) and were largely unaffected by TTX or by midline brainstem section. All of these manipulations, however prevented completely the known efferent-mediated contralateral sound suppression of both f2-f1 and 2f1-f2 DPOAEs. Taken together, these results do not provide support for efferent control of the f2-f1 amplitude alterations observed during continuous ipsilateral stimulation.

The P2-purinergic receptor antagonists suramin, cibacron blue and basilen blue, the latter two being isomers of reactive blue 2, were studied for their effects on sound-evoked responses from the cochlea (cochlear microphonic, CM; summating potential, SP; distortion product otoacoustic emissions, DPOAE) and auditory nerve (compound action potential, CAP). Local application of these compounds (10-1000 microM) into the cochlear perilymph was associated with concentration-dependent response alterations. Effects of suramin on cochlear responses were minimal: High-intensity SP was reduced slightly at concentrationsor = 330 microM without significant alterations in CM or DPOAEs. The amplitude of the auditory nerve CAP was suppressed and its latency increased at drug concentrationsor = 100 microM. Cibacron blue and basilen blue were of greater potency in their effects on cochlear and auditory nerve responses. DPOAEs were generally reduced, low-intensity SP was reduced and high-intensity SP was increased and CM was little affected at drug concentrations 100-1000 microM. The CAP was suppressed and its latency increased at concentrationsor = 33 microM. Effects of suramin were largely reversible; those associated with cibacron blue and basilen blue generally were not. To the extent that these drugs acted selectively as antagonists of ATP receptor-mediated activity, results support the hypothesis that endogenous ATP exerts profound actions at the level of the cochlea and the auditory nerve.

Several lines of evidence implicate a neurotransmitter/modulator role for ATP in the cochlea. Most of the work supporting such a notion has been accomplished using in vitro preparations of sensory hair cells or other cochlear tissues. Little is known regarding the functional consequences of ATP receptor activation in vivo. In the present experiments, we tested ATP and related agonist analogs for their effects on sound-evoked responses of the cochlea (cochlear microphonic, CM; summating potential, SP; distortion product otoacoustic emissions, DPOAE) and auditory nerve (compound action potential, CAP) in vivo and on outer hair cell (OHC) currents and cell length in vitro. In vivo, local application of these compounds was associated with concentration- and intensity-dependent response alterations. The slowly-hydrolyzable P2y agonist, ATP-gamma-S, was clearly of greatest in vivo potency: At low to moderate stimulus intensities, micromolar concentrations of this drug reduced all responses, in particular CAP and DPOAEs, which fell to the level of the noise floor. At high intensities, response suppression was smaller and SP was increased. In vivo effects of ATP, ATP-alpha-S and 2-Me-S-ATP were qualitatively similar to, but smaller in magnitude and requiring higher concentrations than those observed for ATP-gamma-S. Adenosine was without significant effect on responses of the cochlea and auditory nerve. In vitro, effects of ATP-gamma-S and ATP were similar: both induced inward currents in OHCs held at -60 mV without producing observable (0.3 micron) changes in OHC length. Results suggest that endogenous ATP influences cochlear function through receptors at several sites in the cochlea. Results suggest further that these response alterations are mediated, at least in part, by receptors of the P2y subtype.

Many cells placed in a hypotonie medium initially swell and then rapidly undergo a regulatory volume decrease (RVD) to return towards original volume. Re-exposure to the isotonic solution results in the cells shrinking followed by a regulatory volume increase (RVI). Previous studies have shown that isolated outer hair cells (OHCs) placed in a hypotonie medium swell and maintain this shape until returned to the original medium. We re-examined this apparent lack of cell volume regulation in OHCs. OHCs were isolated from guinea pig cochleae, mechanically dissociated and dispersed, and placed in a Hank's balanced salt solution (HBS). In the cells studied, switching the perfusate to a hypotonie HBS (290-280 mmol/kg) for 15 min resulted in an immediate shortening of the OHCs (i.e., volume increase). In 26% of the cells, this increase was followed by a return to original length during the time the cell was perfused with the hypotonie medium, a RVD. Twelve percent of the cells demonstrating a RVD also displayed a RVI. Omitting collagenase and increasing Ca2+ concentration did not increase the percentage of cells displaying a RVD, while gadolinium (Gd3+, 10 μM) decreased the percentage to zero. This is the first report of isolated OHCs undergoing cell volume regulation.

Salicylate is well-known to produce reversible hearing loss and tinnitus. The site and mechanism of salicylate's ototoxic actions, however, remain unresolved. Recent experiments demonstrating primarily low-intensity effects on cochlear afferent outflow and effects on otoacoustic emissions (OAEs) suggest that salicylate acts to compromise active, energy-enhancing processes within the cochlea (i.e., the active process). We tested this hypothesis by examining the effect of salicylate on distortion product emissions. Distortion product responses to two-tone stimulation were monitored in the guinea pig before, during, and after intracochlear administration of increasing concentrations of salicylate (0.6-5 mM). These responses were recorded as acoustic signals in the ear canal spectrum (ADP), and as present in the cochlear microphonic (CM) recorded from a wire in basal turn scala vestibuli (CMDP). We also recorded the CM response to a single tone. Cochlear perfusion of salicylate resulted in a dose-responsive reduction in ADPs that was greater for low intensities of stimulation. CMDPs also demonstrated a concentration-dependent reduction at low intensities, but were increased slightly, though not significantly, by salicylate when elicited by high intensity primaries. CM was essentially unchanged by intracochlear salicylate. These results are consistent with an action of salicylate that involves the outer hair cells (OHCs) and are in harmony with the hypothesis that salicylate may selectively compromise the active process.

The hypothesis tested was that intense sound increases the levels of a substance such as glutamate, a putative neurotransmitter and neurotoxic substance, in the perilymph compartment of the cochlea. Artificial perilymph was perfused through the perilymphatic compartment of the guinea pig cochlea and the effluent collected during successive 10-min periods. The effects of perfusing an artificial perilymph containing normal levels of Na+ (NARP) were compared to the effects of perfusing an artificial perilymph containing very low concentrations of Na+ (VLNa). The effluent was collected during ambient noise and during increasing intensities of broad-band noise (10 min at 106, 112, 118 and 124 dB SPL). Levels of amines in the effluent were measured by HPLC utilizing precolumn o-phthalaldehyde (OPA) derivatization and fluorescence detection. VLNa increased the levels of glutamate and several other amines in effluent from the cochlea compared to levels obtained in NARP. Compared with its level during ambient room noise, the concentration of an unidentified amine labeled Unk 2.5 increased during intense noise (124 dB SPL). Intense noise induced no detectable changes in the concentrations of glutamate and fifteen other amines. The chemical identity and role of Unk 2.5 remain to be determined.

Transduction by the inner hair cells is hypothesized to be modulated through a change in the length of the outer hair cells (OHC). It has been suggested that the slow change occurring in OHC length is mediated by an actin-myosin system requiring Ca2+ and ATP. This study was designed to systematically examine the effects of lowering extracellular Ca2+ on OHC length. OHCs were isolated from guinea pig cochleae, mechanically dissociated and dispersed, and placed in a Hank's balanced salt solution (HBS). Exposing the cells to a Ca2+-free HBS and Ca2+-free HBS supplemented with 200 μm EDTA produced a shortening in OHC length with a concomitant increase in cell width. The shortening was reversed successfully by bathing the cells in 8 mM Ca2+. We speculate that the decrease in length due to lowering extracellular Ca2+ may be caused by a relaxation of a circumferential contractile mechanism which is thought to cause elongation of intact OHCs (Slepecky, 1989; Dulon et al., 1990).

Nimodipine, an L-type Ca2+ channel antagonist, was tested using sound-evoked cochlear potentials in guinea pigs to investigate whether these channels are involved in cochlear function. Perilymph spaces of guinea pig cochleae were perfused with artificial perilymph solutions containing 0.1-10 microM nimodipine at a rate of 2.5 microliters/min for 10 min. The cochlear potentials evoked by 10 kHz tone bursts of varying intensities were recorded from the basal turn of the scala vestibuli. Cochlear perfusion of nimodipine resulted in reversible, dose-related suppression of the compound action potential of the auditory nerve (CAP; N1-P1), a prolongation of N1 latency at suprathreshold levels, an elevated CAP threshold, a decrease in N1 latency at a constant amplitude measured at CAP threshold, a reduction in cochlear microphonics (CM), and a reduction of the negative summating potential (SP) to a point where it became positive (i.e., a reversal of SP). The endocochlear potential (EP) was not affected. These results support the hypothesis that L-type Ca2+ channels are directly involved in the operation of the organ of Corti. We speculate that L-type Ca2+ channels are integrally involved in generation of a negative summating potential and the dc motion of the cochlear partition described by others.

Publisher Summary This chapter discusses the origins and philosophy of body-centered psychotherapy (BCP), focusing specifically on the Hakomi method BCP refers to clinical psychotherapeutic work that uses the body as a resource in the therapeutic process. Within BCP it is assumed that deeply held beliefs, guiding images and significant early memories, behavior, body structure, and all levels of physiology, from cellular metabolism and the strength of the immune system, to blood flow and the distribution of heat and muscle tone in the body, to the expression of these beliefs in posture, movement, gesture, and facial expression. Body-centered psychotherapy is a diverse and powerful force in therapy that is enjoying many successes in resolving negative emotions and trauma. It can also be practiced in a very complementary fashion with traditional health care treatment provided there is good communication between practitioners. BCP do not necessarily need to adopt the current manner of labeling and diagnosing. However, they must demonstrate in qualitative, scientific method that these therapies are successful. Only then can body-centered psychotherapies influence the traditional institutions toward a more holistic approach to healing.

• Kidney transplantation is the preferred treatment for patients with end-stage chronic renal disease. • There appears to be no recent and extensive review of the literature on psychosocial recovery from adult kidney transplantation. • This comprehensive review considers literature on six aspects of patient recovery and rehabilitation: psychiatric sequelae, functional recovery, stress and coping, the psychological impact of failed kidney transplants, quality of life (QOL), and adherence with medications. • We conclude that although studies have become both more ambitious and rigorous, there is a pressing need to move away from descriptive research toward carefully designed multidisciplinary psychological intervention studies with kidney transplant patients.

A growing body of evidence indicates that extracellular adenosine triphosphate (ATP) may have a major role in cochlear function. Antagonists of ionotropic ATP receptors (P2X2) have significant effects on cochlear potentials and distortion product otoacoustic emissions (DPOAEs). We tested whether antisense oligodeoxynucleotides (ODNs) would mimic the functional deficiencies induced by the ATP antagonists through binding to P2X2 ATP receptor mRNA and thereby reduce the number of ATP receptors expressed in the membrane of the cells. Both a phosphorothioate ODN (S-ODN) antisense and a phosphodiester ODN (P-ODN) antisense to the P2X2 sequence and random sense ODNs containing 21 nucleotides were administered chronically (7 days) to the guinea pig cochlea via the perilymph compartment. Sound evoked cochlear potentials (cochlear microphonic; summating potential; compound action potential of the auditory nerve, CAP; latency of the first negative peak in the CAP, N1 latency) and DPOAEs were monitored to assess the effects of the ODNs. Results indicate that the phosphorothioate derivatives of both the antisense and random sense ODNs suppressed the CAP and prolonged the N1 latency with no significant effect on the other parameters. The P-ODNs had no effect. Since both the antisense and random sense S-ODNs had the same effect, we conclude that the S-ODNs affected neuronal function in a manner that did not involve binding to the ATP receptor mRNA.

•End stage renal disease (ESRD) inevitably reduces the life-span of its victims. The treatment of choice for many patients is transplantation but this does not effect a cure. Its aim is to improve renal function and thus to enhance the patient's ability to enjoy as full a life as possible. However, surprisingly little research has been concerned with quality of life after transplantation. •A small-scale, exploratory study employing a qualitative design was undertaken to compare stress and quality of life between five patients with ESRD awaiting transplantation and five patients who had received a graft within the previous 6 months. •The desire to undergo transplantation was fuelled by patients' perceived need to `get off dialysis' and to `lead a normal life'. •All patients had received abundant technical information about renal transplantation and pre-operative preparation but information concerning the negative effects of transplantation, including the side-effects of medication appeared lacking. It was not possible to determine whether this information had not been supplied or had been offered but forgotten or denied. •For pre-transplantation patients the main sources of stress were the need to undergo dialysis, awaiting the summons to hospital and the social isolation imposed by having a chronic condition such as constant fatigue. Post-transplantation patients were remarkably free of anxiety considering the impositions placed upon them by frequent clinic attendance to monitor their condition. •Quality of life improved dramatically after transplantation despite the persistence of renal symptoms and patients felt privileged to have been offered this treatment option.

Evidence is accumulating to indicate that extracellular adenosine 5′-triphosphate (ATP) may function as a neurotransmitter, neuromodulator, cytotoxin and mitogen. Many of the cells in the cochlea have ATP receptors, however, their function is unknown. The purpose of the present study was to test whether ATP may act as a cytotoxin in the cochlea. ATP was applied to acutely isolated outer hair cells (OHCs) and their shape changes monitored. In addition, ATP was applied into the cochlea by perfusion of the perilymph compartment for 2 h and the animals allowed to survive 3–4 weeks post drug application. At this time, sound-evoked cochlear potentials and distortion product otoacoustic emissions (DPOAEs) were monitored and the cochleas evaluated histologically. Results indicate that when applied to isolated OHCs, ATP (3–30 mM) induced a bleb formation in the infracuticular region of the cell that burst within a few minutes. Short OHCs were more sensitive to this effect of ATP than long OHCs. 3–4 weeks after the perilymph perfusion of ATP (60 mM; 2 h) cochlear potentials and DPOAEs were abolished, and histologically, cells in the organ of Corti and the stria vascularis were found to have been destroyed. In addition, there was loss of spiral ganglion cells and proliferating connective tissue filled varying proportions of the scala tympani and vestibuli. Application of sodium gluconate, a control, at the same concentrations had no effect either on the isolated OHCs or when applied in vivo. Results suggest that extracellular ATP or a metabolic product may act as a cytotoxin to some epithelial and neural elements in the cochlea and possibly as a mitogen to mesenchymal cells or fibrocytes.

Biochemical and pharmacological evidence support a role for nitric oxide (NO) and glutathione (GSH) in the cochlea. GSH combines with NO in tissue to form nitrosoglutathione (GSNO) that can act as a storage form for GSH and NO. Therefore, we tested GSNO on sound-evoked responses of the cochlea (cochlear microphonic, CM; summating potential, SP; compound action potential, CAP; cubic distortion product otoacoustic emission, DPOAE), on the endocochlear potential (EP), on isolated outer hair cell (OHC) currents and voltage-dependent capacitance, and on Deiters' cell currents. In vivo application of GSNO in increasing concentrations reversibly reduced low-intensity sound-evoked CAP, SP and DPOAEs starting at about 1 mM (CAP) and 3.3 mM (SP, DPOAE). However, even at 10 mM, GSNO had little effect on the EP. In vitro, salicylate (10 mM) but not GSNO (3 and 10 mM) suppressed the early capacitative transients of OHCs. GSNO (3 and 10 mM) had no effect on the whole cell currents of OHCs or Deiters' cells. Results show that GSNO suppresses cochlear function. This suppression may be due to an effect of GSNO on the cochlear amplifier. The actions of GSNO were different from those of other NO donors; therefore, the effects of GSNO may not be mediated by NO. The mechanisms underlying GSNO effects seem to be different from those of salicylate.

Chen et al. (1995) recently reported an altered response to the application of ATP in outer hair cells WHO isolated from guinea pigs continuously exposed for 10 or 11 days to a 65 dB SPL (A-scale) narrow-band noise (1.1–2.0 kHz). The primary goal of the present study was to test the hypothesis that the continuous low-level noise used by Chen et al. (1995) alters cochlear function. Cubic (2f 1 -f 1 ) and quadratic (f 2 -f 1 ) DPOAEs, as well as, the amount of contralateral suppression of DPOAE amplitudes were chosen for study. Responses were recorded in urethane-anesthetized guinea pigs with sectioned middle ear muscles. The animals had either been exposed to the low-level noise for 3 or 11 days or not exposed at all ( n = 13 animals per group). Results demonstrate that this noise induces frequency-dependent and very localized reductions in 2f 1 -f 2 DPOAE input/output (1/O) functions. However, the f 2 -f 1 DPOAE I/O functions appear to be insensitive to the noise exposure. No noise-related changes were found in the amount of contralateral suppression between the different exposure groups, with the exception of one unexplainable data point (f 2 -f 1 DPOAE = 0.5 kHz; day 3) where it was reduced. The 2f 1 -f 2 DPOAE amplitude alterations lend support to the conclusions of Chen et al. (1995) that chronic low-level noise exposure induces molecular changes in the OHCs which may, in turn, alter cochlear function.

Biochemical and pharmacological evidence supports a role for nitric oxide (NO) in the cochlea. In the present experiments, we tested sodium nitroprusside (SNP), an NO donor, applied by intracochlear perfusions on sound-evoked responses of the cochlea (CM, cochlear microphonic; SP, summating potential; EP, endocochlear potential; CAP, compound action potential) and in vitro on outer hair cell (OHC) voltage-induced length changes and current responses. In vivo application of SNP in increasing concentrations (10, 33, 100, 330 and 1000 microM) reduced all sound-evoked responses starting at about 300 microM. The responses continued to decline after a postdrug wash. At 1 mM SNP decreased EP slowly (approximately 80 min) whereas at 10 mM it reduced EP more rapidly (approximately 20 min). Ferricyanide (1 mM) and S-nitroso-N-acetylpenicillamine (SNAP; 1 mM) had no effect on sound-evoked cochlear potentials. Ferricyanide (1 mM and 10 mM) and ferrocyanide (10 mM) had no effect on EP. In vitro, SNP (10 mM) significantly reduced both OHC voltage-induced length changes and whole-cell outward currents. Results suggest that SNP, possibly acting by released NO, influences cochlear function through effects at the stria vascularis and at the OHCs.

The purpose of this investigation was to provide in vivo pharmacologic characterization of a cholinergic receptor mediating the suppressive effects of medial olivocochlear (MOC) efferent activation. MOC neurons were activated by contralateral sound and the resulting suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) was monitored before and after intracochlear perfusions of cholinergic antagonists. Results revealed a dose-dependent blockade of contralateral suppression of DPOAEs by a wide variety of nicotinic and muscarinic cholinergic receptor antagonists, as well as by non-traditional antagonists of cholinergic activity. The nicotinic antagonists, alpha-bungarotoxin, curare and kappa-bungarotoxin, and the glycine antagonist, strychnine, blocked contralateral suppression at nanomolar concentrations and demonstrated similar potencies. IC50 values were 2.38 x 10(-7), 2.79 x 10(-7), 3.81 x 10(-7) and 2.96 x 10(-7) M, respectively. These agents were followed in potency by the nicotinic antagonist, trimethaphan (1.75 x 10(-6) M), the M3 muscarinic antagonist, 4-DAMP (1.88 x 10(-6) M) and the GABAA antagonist, bicuculline (2.39 x 10(-6) M). Increasingly greater concentrations of the muscarinic antagonists, atropine (9.52 x 10(-6) M), AF-DX 116 (2.72 x 10(-5) M) and pirenzepine (8.24 x 10(-4) M) were necessary to block contralateral suppression of DPOAEs. The in vivo pharmacology of this putative outer hair cell cholinergic receptor suggests that it may be a member of the nicotinic family of receptors.

Presentation of an acoustic signal to one ear can suppress sound-evoked activity recorded at the opposite ear. The suppression appears to be mediated by medial olivocochlear (MOC) efferent neurons synapsing with outer hair cells (OHCs) and acting through the MOC neurotransmitter, acetylcholine (ACh). The purpose of the present investigation was to study the suppression of distortion product otoacoustic emissions (DPOAEs) by contralateral sound and to examine whether the suppression could be blocked by known antagonists of olivocochlear (OC) efferent activity. Urethane-anesthetized guinea pigs were used. Perilymph spaces of ipsilateral cochleae were alternately perfused with artificial perilymph and drugs at 2.5 microliters/min for 10 min. After each period of perfusion, DPOAEs were measured before, during and after contralateral wideband noise (WBN) stimulation. Pre-perfusion, contralateral WBN attenuated the ipsilateral DPOAEs between 1-3 dB. This suppression was blocked reversibly by strychnine (10 microM), curare (10 microM) and atropine (20 microM), known antagonists of OC efferent activity. These results confirm the findings of Puel and Rebillard (1990) that contralateral WBN can suppress DPOAEs in anesthetized guinea pigs. Furthermore, results suggest that this efferent control of the cochlear mechanical response can either be mediated by both nicotinic and muscarinic cholinergic receptors, or that a single receptor with as yet undescribed structure and pharmacology mediates effects seen.

Activation of olivocochlear (OC) efferent fibers has been suggested to alter micromechanical events occurring within the cochlear partition, possibly through an effect of the efferent neurotransmitter (acetylcholine; ACh) on outer hair cells (OHCs). Based on the widely-accepted assumption that otoacoustic emissions reflect OHC activity, we investigated the in vivo influence of ACh on OHCs by studying alterations in emission amplitude with local ACh application. Distortion product otoacoustic emissions (DPOAEs) were measured in anesthetized guinea pigs before, during, and after intracochlear application of ACh (250 microM) with the cholinesterase inhibitor, eserine (20 microM). Perfusion of ACh/eserine was associated with a desensitizing reduction in DPOAE amplitude of approximately 4.4 dB. This reduction was intensity-dependent, with greater and more consistent reductions observed for DPOAEs elicited by low- than by moderate-intensity primaries. The response reduction was not seen during consecutive ACh perfusions performed without an intervening artificial perilymph wash, and was effectively blocked in the presence of pharmacologic antagonists of OC efferent activity (curare, 50 microM; strychnine, 50 microM). Finally, a similar alteration in DPOAE amplitude was never seen during perfusion of the control (artificial perilymph) solution alone. It is argued that these results support the hypothesis that OC efferent activation can alter sound-induced cochlear mechanical events.

Previous results demonstrated that nimodipine, an l -type of Ca 2+ channel antagonist, abolished the negative summating potential (SP) recorded from anesthetized guinea pigs (Bobbin et al., 1990), suggesting that Ca 2+ is involved in generation of the negative SP. Therefore we examined the effect of changing concentrations of perilymph Ca 2+ on this cochlear potential. Perilymph spaces of guinea pig cochleae were perfused with artificial perilymph solutions containing zero mM Ca 2+ , zero mM Ca 2+ with 2 mM EGTA, 30 mM Mg 2+ and increasing levels of Ca 2+ (2, 4, 8, 16 mM) at a rate of 2.5 μl/min for 10 min. Immediately after each period of perfusion the compound action potential of the auditory nerve (CAP), cochlear microphonics (CM) and the negative SP evoked by 10 kHz tone bursts of varying intensities were recorded from a wire inserted in the basal turn scala vestibuli. Decreasing the level of Ca 2+ decreased the magnitude of the negative SP, whereas increasing the level of Ca 2+ progressively increased the magnitude of the negative SP. Mg 2+ (30 mM) suppressed the CAP to the same extent as zero mM Ca 2+ with 2 mM EGTA, but only slightly increased the magnitude of the negative SP. These results support the hypothesis that Ca 2+ and l -type Ca 2+ channels are involved in the function of the hair cells and the generation of the negative SP. Mg 2+ appears to be a selective antagonist of the Ca 2+ channel involved in transmitter release.

We examined the effects of changes in cation levels (increased Mg 2+ concentration combined with low Ca 2+ concentration, and two low concentrations of Na + ) on the perilymph levels of gamma-aminobutyric acid (GABA), glutamate (Glu), aspartate (Asp) and other substances. Artificial perilymph solutions containing normal (5 mM) and high (50 mM) levels of K + were perfused through the perilymphatic compartment of the guinea pig cochlea to examine basal release (5 mM K + ) and depolarization-induced release (50 mM K + ). Each of the two K + concentrations were contained in four different solutions: [I] normal artificial perilymph (NARP; Nacl, 137 mM; CaCl 2 , 2 mM; MgCl 2 , 1 mM;); [II] high Mg 2+ (20 mM)/low Ca 2+ (0.1 mM) (HMgLCa); [III] low Na + (117 mM; LNa), and [IV] very low Na + (NaCl, 0 mM; VLNa). The effluent was collected and assayed for eighteen primary amines by HPLC. Compared with NARP, the HMgLCa group had an increase in the high K + -induced release of Asp and Glu with no change in GABA. VLNa increased the normal K + levels of Asp, Glu and GABA up to those observed with high K + in NARP. VLNa increased the high K + levels of Asp and Glu over fivefold compared with the high K + levels in NARP, but decreased GABA. We ascribe the results to an interference with either a Na + -dependent uptake processes or a Na + /Ca 2+ exchange carrier.

Others have shown that in animals born with immature cochleae the basal turn undergoes changes in function during the early days of postnatal life. We examined whether similar changes could be detected in the guinea pig, an animal born with a functionally mature cochlea. Our results indicate that no changes occur in the function of the basal turn of the guinea pig cochlea immediately after birth.

Gamma-aminobutyric acid (GABA) has been proposed as a neurotransmitter of a subset of efferent nerve fibers in the mammalian cochlea. We tested this hypothesis by examining if GABA was released by high concentrations of K+ from the guinea pig cochlea. Artificial perilymph solutions containing either normal K+ (5 mM) or high K+ (50 mM) were perfused through the perilymphatic compartment of the guinea pig cochlea while collecting the effluent. Nineteen primary amines including GABA were quantified in the effluent by HPLC. This was carried out in normal animals and in animals pretreated with ethacrynic acid and kanamycin to destroy the organ of Corti. Significantly greater levels of GABA, taurine, glutamate, aspartate, glycine and three unidentified substances appeared in effluent collected during exposure of the cochlea to solutions containing higher K+ than normal K+. Compared to normal animals, destruction of the organ of Corti significantly decreased the K(+)-induced release of GABA, taurine, glutamate, aspartate, glycine and one of the unidentified substances; although significant release of glutamate and taurine still occurred in the destroyed ears. The release of GABA is consistent with it being a neurotransmitter in the cochlea. In addition the results: confirm the release of glutamate and taurine from the organ of Corti; suggest that additional substances may be released; and demonstrate the release of glutamate and taurine from tissue other than the organ of Corti.

The perilymphatic spaces of guinea pig cochleae were perfused with artificial perilymph, with and without drug, at a rate of 2.5 microliters/minute for 10 minutes. The compound action potential of the auditory nerve, cochlear microphonics, and the summating potential evoked by 10 kHz tone bursts of varying intensities were recorded from a wire inserted in the basal turn scala vestibuli. The endocochlear potential was recorded from the scala media. Sodium salicylate (1.25 to 10 mmol/L) reduced the magnitude of the compound action potential evoked by low-sound intensities without affecting the compound action potential evoked by high-sound intensities. Sodium salicylate also reduced cochlear microphonics and had no effect on summating potential. Cochlear perfusions of prostaglandin synthesis inhibitors, mefenamate (200 mumol/L), and meclofenamate (200 mumol/L), had no effect on the cochlear potentials. Quinine (10 to 100 mumol/L) reduced the compound action potential input-output function in a parallel fashion rather than selectively affecting the low-intensity compound action potential. Quinine (100 mumol/L) reduced cochlear microphonics and summating potential. Neither quinine (100 mumol/L) nor salicylate (5 mmol/L) affected endocochlear potential. These results suggest that salicylate-induced hearing loss is not caused by either antagonism of the hair cell transmitter or cyclooxygenase inhibition, nor is it caused by the same mechanism that causes quinine-induced hearing loss.

Following a short period of amplitude enhancement, the f2−f1 DPOAE can be suppressed during continuous ipsilateral stimulation with primary tones. Evidence for and against efferent control of such response alterations has been presented. Here, an exacerbation of f2−f1 suppression, apparent following a short rest from continuous stimulation, is described and the hypothesis that it is efferent‐mediated is tested. The f2−f1 DPOAE to intermittent or continuous primaries ( f1=6.25 kHz; f2=7.5 kHz; L1=L2=60 dB SPL) was recorded in urethane‐anesthetized guinea pigs with sectioned middle ear muscles before, during, and after perfusion of the cochlear perilymph compartment with antagonists of olivocochlear efferent activity (curare, 1 μM; bicuculline, 10 μM) or of action potentials in general (tetrodotoxin, TTX; 1 μM). Results confirmed an initial f2−f1 amplitude enhancement and gradual suppression during continued stimulation. Following a 1‐min rest, however, the DPOAE was further suppressed from its pre‐rest lev...

1-(p-Bromobenzoyl)-piperazine-2,3-dicarboxylic acid (pBB-PzDA; 0.03-5 mM), an excitatory amino acid antagonist, was perfused through the guinea pig cochlea while monitoring various cochlear potentials. pBB-PzDA (1-5 mM) reversibly suppressed the amplitude of the compound action potential of the auditory nerve (CAP) and increased the latency of N1 (the first negative wave of the CAP) at all sound intensities. pBB-PzDA had no detectable effect on N1 latency at CAP threshold or presynaptic potentials such as the cochlear microphonics and the summating potential. At the single-cell level pBB-PzDA (5 mM) reversibly suppressed the firing of single auditory nerve ganglion cells. pBB-PzDA appeared to have the same potency in the cochlea as kynurenic acid. We conclude that the mechanism of action of pBB-PzDA is consistent with an antagonism of the hair-cell transmitter at the afferent auditory nerve.

1. Salicylate actions on afferent nerve activity in the Xenopus lateral line and on cochlear potentials in guinea pig were investigated. 2. In the lateral line, salicylate (0.3-2.5 mM) suppressed spontaneous activity, water motion evoked excitation and responses to L-glutamate (1-2 mM) and kainate (10-20 microM). 3. In the guinea pig, salicylate (0.6-10 mM) suppressed the compound action potential (CAP) and increased N1 latency at low but not high sound intensities. 4. In the lateral line salicylate action may involve an antagonism of the hair-cell transmitter on the afferent nerve. 5. In the cochlea salicylate may suppress the active process or cochlear amplifier.

We tested 6,7-dinitroquinoxaline-2,3-dione (DNQX); 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); 6,7-dichloro-3-hydroxy-2-quinoxalinecarboxylic acid (DHQC); and 3-hydroxy-2-quinoxalinecarboxylic acid (3HQC), new kainate and quisqualate receptor antagonists, upon cochlear potentials in guinea pig. Perilymph spaces of guinea pig cochleae were perfused with artificial perilymph solutions containing up to 1000 microM concentrations of DHQC and 3HQC, and 500 microM concentrations of DNQX and CNQX, at a rate of 2.5 microliters/min for 10 min. Cochlear potentials evoked by 10 kHz tone bursts of varying intensity were recorded from the basal turn scala vestibuli. Cochlear perfusion of the four drugs resulted in a dose-related suppression of the compound action potential of the auditory nerve (CAP; N1-P1), a prolongation of N1 latency at suprathreshold levels, an elevated CAP threshold, and a decreased N1 latency at CAP threshold. None of the drugs had significant effects on cochlear microphonics (CM) or the summating potential (SP). EC50 values (concentrations causing a 50% reduction in CAP amplitude at 68 dB SPL) were 8 microM for DNQX, 30 microM for DHQC, 35 microM for CNQX, and 1 mM for 3HQC. Results support the hypothesis that kainate and quisqualate receptors are involved in neurotransmission between the hair cell and afferent nerve.

Evidence exists to suggest that intense sound releases excess neurotransmitter from the inner hair cells. However, it has been previously reported that intense sound affects the cochlear micromechanics by altering the stereocilia. Therefore, we tested the hypothesis that intense sound affects structures involved in transduction before it affects the nerve endings. In order to test this hypothesis, we examined the interaction of intense sound with kynurenate which blocks the action of the neurotransmitter on the afferent nerve endings. Intracochlear perfusion of artificial perilymph containing 5 mM kynurenate did not reduce the effect of intense sound when we compare the results with a control group perfused with artificial perilymph alone. These results show that blockade of afferent transmitter receptors did not reduce the effect of acoustic trauma, and the acoustic trauma used herein affected structures involved in transduction before it affected the postsynaptic structures. We speculate that the active process is affected first during acoustic trauma. This interpretation is consistent with the notion that stereocilia are structures that make up part of the active process.

One suggested physiological function of the efferent nerve fibers innervating the cochlea is that they protect the cochlea against the effects of intense sound exposure. In order to test this hypothesis, we studied the effects of intense sound in the presence and in the absence of strychnine which blocks the efferent nerve fibers. The results show that in presence of strychnine an ipsilateral intense sound has a greater effect on the cochlea than in the absence of strychnine. We conclude that the ipsilateral cochlear efferents may act as protectors against intense sound exposure.

The chemical 2-amino-4-phosphonobutyric acid (APB, AP4), an excitatory amino acid antagonist, was perfused through the guinea-pig cochlea while monitoring various cochlear potentials. The drug (0.6–10 mM) had no effect on the magnitude of the compound action potential of the cochlear nerve, N1 latency, cochlear microphonics, or the summating potential (SP). The results are consistent with the hypothesis that the APB receptor is not involved in neurotransmission between cochlear hair cells and afferent nerve fibers.