Systemic corticosteroids for subcutaneous panniculitis-like T-cell lymphoma.

BACKGROUND: Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/ß T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. OBJECTIVES: To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. METHODS: This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zürich (Switzerland) and Tübingen (Germany). The repository spanned 13 years. RESULTS: In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. CONCLUSIONS: Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

Fatal case of Weeksella virosa sepsis.

Weeksella virosa is an aerobic Gram-negative rod that has rarely been reported to cause infection. We describe a fatal case of W. virosa sepsis in a young female with end-stage renal disease, report three additional cases of W. virosa infection, and review the literature regarding this infection.

Pneumococcal vaccination during pregnancy for preventing infant infection.

BACKGROUND: Each year at least one million children worldwide die of pneumococcal infections. The development of bacterial resistance to antimicrobials adds to the difficulty of treatment of diseases and emphasizes the need for a preventive approach. Newborn vaccination schedules could substantially reduce the impact of pneumococcal disease in immunized children, but does not have an effect on the morbidity and mortality of infants less than three months of age. Pneumococcal vaccination during pregnancy may be a way of preventing pneumococcal disease during the first months of life before the pneumococcal vaccine administered to the infant starts to produce protection. OBJECTIVES: To assess the effect of pneumococcal vaccination during pregnancy for preventing infant infection. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (June 2004), CENTRAL (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to June 2004), EMBASE (January 1985 to June 2004), and reference lists of articles. SELECTION CRITERIA: Randomized controlled trials in pregnant women comparing pneumococcal vaccine with placebo or doing nothing or with another vaccine to prevent infant infections. DATA COLLECTION AND ANALYSIS: Two authors independently assessed methodological quality and extracted data using a data collection form. Study authors were contacted for additional information. MAIN RESULTS: Three trials (280 participants) were included. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (one trial, 149 pregnancies, relative risk (RR) 0.51; 95% confidence interval (CI) 0.18 to 1.41). Although the data suggest an effect in reducing pneumococcal colonisation in infants by 16 months of age (one trial, 56 pregnancies, RR 0.33; 95% CI 0.11 to 0.98), there was no evidence of this effect in infants at two months of age (RR 0.28; 95% CI 0.02 to 5.11) or by seven months of age (RR 0.32; 95% CI 0.08 to 1.29). AUTHORS' CONCLUSIONS: There is insufficient evidence to support whether pneumococcal vaccination during pregnancy could reduce infant infections.

Acid detection by taste receptor cells.

Sourness is a primary taste quality that evokes an innate rejection response in humans and many other animals. Acidic stimuli are the unique sources of sour taste so a rejection response may serve to discourage ingestion of foods spoiled by acid producing microorganisms. The investigation of mechanisms by which acids excite taste receptor cells (TRCs) is complicated by wide species variability and within a species, apparently different mechanisms for strong and weak acids. The problem is further complicated by the fact that the receptor cells are polarized epithelial cells with different apical and basolateral membrane properties. The cellular mechanisms proposed for acid sensing in taste cells include, the direct blockage of apical K(+) channels by protons, an H(+)-gated Ca(2+) channel, proton conduction through apical amiloride-blockable Na(+) channels, a Cl(-) conductance blocked by NPPB, the activation of the proton-gated channel, BNC-1, a member of the Na(+) channel/degenerin super family, and by stimulus-evoked changes in intracellular pH. Acid-induced intracellular pH changes appear to be similar to those reported in other mammalian acid-sensing cells, such as type-I cells of the carotid body, and neurons found in the ventrolateral medulla, nucleus of the solitary tract, the medullary raphe, and the locus coceuleus. Like type-I carotid body cells and brainstem neurons, isolated TRCs demonstrate a linear relationship between intracellular pH (pH(i)) and extracellular pH (pH(o)) with slope, DeltapH(i)/DeltapH(o) near unity. Acid-sensing cells also appear to regulate pH(i) when intracellular pH changes occur under iso-extracellular pH conditions, but fail to regulate their pH when pH(i) changes are induced by decreasing extracellular pH. We shall discuss the current status of proposed acid-sensing taste mechanisms, emphasizing pH-tracking in receptor cells.

A novel pharmacological probe links the amiloride-insensitive NaCl, KCl, and NH(4)Cl chorda tympani taste responses.

Chorda tympani taste nerve responses to NaCl can be dissected pharmacologically into amiloride-sensitive and -insensitive components. It is now established that the amiloride-sensitive, epithelial sodium channel acts as a sodium-specific ion detector in taste receptor cells (TRCs). Much less is known regarding the cellular origin of the amiloride-insensitive component, but its anion dependence indicates an important role for paracellular shunts in the determination of its magnitude. However, this has not precluded the possibility that undetected apical membrane ion pathways in TRCs may also contribute to its origin. Progress toward making such a determination has suffered from lack of a pharmacological probe for an apical amiloride-insensitive taste pathway. We present data here showing that, depending on the concentration used, cetylpyridinium chloride (CPC) can either enhance or inhibit the amiloride-insensitive response to NaCl. The CPC concentration giving maximal enhancement was 250 microM. At 2 mM, CPC inhibited the entire amiloride-insensitive part of the NaCl response. The NaCl response is, therefore, composed entirely of amiloride- and CPC-sensitive components. The magnitude of the maximally enhanced CPC-sensitive component varied with the NaCl concentration and was half-maximal at [NaCl] = 62 +/- 11 (SE) mM. This was significantly less than the corresponding parameter for the amiloride-sensitive component (268 +/- 71 mM). CPC had similar effects on KCl and NH(4)Cl responses except that in these cases, after inhibition with 2 mM CPC, a significant CPC-insensitive response remained. CPC (2 mM) inhibited intracellular acidification of TRCs due to apically presented NH(4)Cl, suggesting that CPC acts on an apical membrane nonselective cation pathway.

Decrease in rat taste receptor cell intracellular pH is the proximate stimulus in sour taste transduction.

Taste receptor cells (TRCs) respond to acid stimulation, initiating perception of sour taste. Paradoxically, the pH of weak acidic stimuli correlates poorly with the perception of their sourness. A fundamental issue surrounding sour taste reception is the identity of the sour stimulus. We tested the hypothesis that acids induce sour taste perception by penetrating plasma membranes as H(+) ions or as undissociated molecules and decreasing the intracellular pH (pH(i)) of TRCs. Our data suggest that taste nerve responses to weak acids (acetic acid and CO(2)) are independent of stimulus pH but strongly correlate with the intracellular acidification of polarized TRCs. Taste nerve responses to CO(2) were voltage sensitive and were blocked with MK-417, a specific blocker of carbonic anhydrase. Strong acids (HCl) decrease pH(i) in a subset of TRCs that contain a pathway for H(+) entry. Both the apical membrane and the paracellular shunt pathway restrict H(+) entry such that a large decrease in apical pH is translated into a relatively small change in TRC pH(i) within the physiological range. We conclude that a decrease in TRC pH(i) is the proximate stimulus in rat sour taste transduction.

Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy.

PURPOSE: To review reported inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) in persons infected with HIV-1 and to explore the mechanisms leading to these reactions. DATA SOURCES: MEDLINE search of biomedical literature reporting inflammatory reactions after HAART. Bibliographies of retrieved reports were also reviewed. STUDY SELECTION: Articles describing patients infected with HIV-1 who had immunologic and virologic responses to HAART and subsequently developed inflammatory reactions. DATA EXTRACTION: Data on the immune status, clinical characteristics, and therapeutic management of patients who were seropositive for HIV-1 and had inflammatory reactions after HAART. DATA SYNTHESIS: Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts. Clinical presentation was often atypical of that in patients with untreated HIV-1 infection, probably because of restored immunity. Most cases improved despite continuation of HAART, although some patients required anti-inflammatory drugs or specific antimicrobial agents. CONCLUSIONS: Clinicians caring for patients who are infected with HIV-1 and receiving HAART must be aware of this new and diverse clinical syndrome. As more HAART recipients are studied, new presentations will probably be observed.

Development of rat chorda tympani sodium responses: evidence for age-dependent changes in global amiloride-sensitive Na(+) channel kinetics.

In rat, chorda tympani nerve taste responses to Na(+) salts increase between roughly 10 and 45 days of age to reach stable, mature magnitudes. Previous evidence from in vitro preparations and from taste nerve responses using Na(+) channel blockers suggests that the physiological basis for this developmental increase in gustatory Na(+) sensitivity is the progressive addition of functional, Na(+) transduction elements (i.e., amiloride-sensitive Na(+) channels) to the apical membranes of fungiform papilla taste receptor cells. To avoid potential confounding effects of pharmacological interventions and to permit quantification of aggregate Na(+) channel behavior using a kinetic model, we obtained chorda tympani nerve responses to NaCl and sodium gluconate (NaGlu) during receptive field voltage clamp in rats aged from 12-14 to 60 days and older (60+ days). Significant, age-dependent increases in chorda tympani responses to these stimuli occurred as expected. Importantly, apical Na(+) channel density, estimated from an apical Na(+) channel kinetic model, increased monotonically with age. The maximum rate of Na(+) response increase occurred between postnatal days 12-14 and 29-31. In addition, estimated Na(+) channel affinity increased between 12-14 and 19-23 days of age, i.e., on a time course distinct from that of the maximum rate of Na(+) response increase. Finally, estimates of the fraction of clamp voltage dropped across taste receptor apical membranes decreased between 19-23 and 29-31 days of age for NaCl but remained stable for NaGlu. The stimulus dependence of this change is consistent with a developmental increase in taste bud tight junctional Cl(-) ion permeability that lags behind the developmental increase in apical Na(+) channel density. A significant, indirect anion influence on apical Na(+) channel properties was present at all ages tested. This influence was evident in the higher apparent apical Na(+) channel affinities obtained for NaCl relative to NaGlu. This stimulus-dependent modulation of apical Na(+) channel apparent affinity relies on differences in the transepithelial potentials between NaCl and NaGlu. These originate from differences in paracellular anion permeability but act also on the driving force for Na(+) through apical Na(+) channels. Detection of such an influence on taste depends fundamentally on the preservation of taste bud polarity and on a direct measure of sensory function, such as the response of primary afferents.

Sustained bacteremia associated with transjugular intrahepatic portosystemic shunt (TIPS).

Transjugular intrahepatic portosystemic shunt (TIPS) has become a routine procedure in patients with portal hypertension, yet there are few data concerning the incidence of bacteremia associated with this shunt. All patients who underwent TIPS placement at a university hospital from January 1992 through January 1999 were studied. Ninety-nine TIPS were placed, and 10 patients subsequently developed sustained bacteremia; 5 patients had no identifiable source of bacteremia despite rigorous evaluation and were presumed to represent TIPS infections, for an estimated annual incidence of 7 cases/1000 TIPS procedures. Case patients developed bacteremia a median of 100 days after TIPS placement (range, 6-732 days). Bacteremia resolved in all patients after treatment with appropriate intravenous antibiotics (median, 2 weeks of therapy). Although the incidence of TIPS-associated bacteremia appears low, the increasing frequency of this procedure suggests that more information is needed to define this entity and to develop appropriate treatment recommendations.

Effects of osmolarity on taste receptor cell size and function.

Osmotic effects on salt taste were studied by recording from the rat chorda tympani (CT) nerve and by measuring changes in cell volume of isolated rat fungiform taste receptor cells (TRCs). Mannitol, cellobiose, urea, or DMSO did not induce CT responses. However, the steady-state CT responses to 150 mM NaCl were significantly increased when the stimulus solutions also contained 300 mM mannitol or cellobiose, but not 600 mM urea or DMSO. The enhanced CT responses to NaCl were reversed when the saccharides were removed and were completely blocked by addition of 100 microM amiloride to the stimulus solution. Exposure of TRCs to hyperosmotic solutions of mannitol or cellobiose induced a rapid and sustained decrease in cell volume that was completely reversible, whereas exposure to hypertonic urea or DMSO did not induce sustained reductions in cell volume. These data suggest that the osmolyte-induced increase in the CT response to NaCl involves a sustained decrease in TRC volume and the activation of amiloride-sensitive apical Na(+) channels.

Anion size of sodium salts and simple taste reaction times.

Simple taste reaction times (RT) and taste intensities were measured in adult humans for 100-mM aqueous solutions of sodium chloride, acetate, glutamate, ascorbate, and gluconate flowed over the anterodorsal tongue with a closed liquid delivery system. Results from 12 subjects showed a significant increase in RT with molecular weight of the tastant, and a correlation of 0.941 between RT and the square roots of anionic weights. A multiple regression analysis controlling for perceived taste intensity indicated that RT increased linearly with the square root of the anionic weight. These findings support a model that includes both the permeability of ions through the tight junctions between the taste receptor cells of fungiform papillae taste buds and the effects of ions at apical portions of the receptor cells. They also suggest that gustatory transduction of sodium salts in humans normally involves intercellular spaces of taste buds as part of the functional sensory structures, in addition to individual taste receptor cells.

Acid-induced responses in hamster chorda tympani and intracellular pH tracking by taste receptor cells.

HCl- and NaCl-induced hamster chorda tympani nerve responses were recorded during voltage clamp of the lingual receptive field. Voltage perturbations did not influence responses to HCl. In contrast, responses to NaCl were decreased by submucosal-positive and increased by submucosal-negative voltage clamp. Responses to HCl were insensitive to the Na+ channel blockers, amiloride and benzamil, and to methylisobutylamiloride (MIA), an Na+/H+ exchange blocker. Responses to NaCl were unaffected by MIA but were suppressed by benzamil. Microfluorometric and imaging techniques were used to monitor the relationship between external pH (pHo) and the intracellular pH (pHi) of fungiform papilla taste receptor cells (TRCs) following 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein loading. TRC pHi responded rapidly and monotonically to changes in pHo. This response was unaffected by Na+ removal or the presence of amiloride, benzamil, or MIA. The neural records and the data from isolated TRCs suggest that the principal transduction pathway for acid taste in hamster is similar to that in rat. This may involve the monitoring of changes in TRC pHi mediated through amiloride-insensitive H+ transport across TRC membranes. This is an example of cell monitoring of environmental pH through pH tracking, i.e., a linear change in pHi in response to a change in pHo, as has been proposed for carotid bodies. In taste, the H+ transport sites may be concentrated on the basolateral membranes of TRCs and, therefore, are responsive to an attenuated H+ concentration from diffusion of acids across the tight junctions.

Self-inhibition in Ca2+ -evoked taste responses: a novel tool for functional dissection of salt taste transduction mechanisms.

Rat chorda tympani (CT) responses to CaCl2 were obtained during simultaneous current and voltage clamping of the lingual receptive field. Unlike most other salts, CaCl2 induced negatively directed transepithelial potentials and gave CT responses that were auto-inhibitory beyond a critical concentration. CT responses increased in a dose-dependent manner to approximately 0.3 M, whereafter they decreased with increasing concentration. At concentrations where Ca2+ was self-inhibitory, it also inhibited responses to NaCl, KCl, and NH4Cl present in mixtures with CaCl2. Ca2+ completely blocked the amiloride-insensitive component of the NaCl CT response, the entire KCl-evoked CT response, and the high-concentration-domain CT responses of NH4Cl (>/=0.3 M). The overlapping Ca2+-sensitivity between the responses of the three Cl- salts (Na+, K+, and NH+4) suggests a common, Ca2+-sensitive, transduction pathway. Extracellular Ca2+ has been shown to modulate the paracellular pathways in different epithelial cell lines by decreasing the water permeability and cation conductance of tight junctions. Ca2+-induced modulation of tight junctions is associated with Ca2+ binding to fixed negative sites. This results in a conversion of ion selectivity from cationic to anionic, which we also observed in our system through simultaneous monitoring of the transepithelial potential during CT recording. The data indicate the paracellular pathway as the stimulatory and modulatory site of CaCl2 taste responses. In addition, they indicate that important transduction sites for NaCl, KCl, and NH4Cl taste reception are accessible only through the paracellular pathways. More generally, they show that modulation of paracellular transport by Ca2+ in an intact epithelium has functional consequences at a systemic level.

Effects of extracellular pH, PCO2, and HCO3- on intracellular pH in isolated rat taste buds.

We studied the effects of changing external pH (pHo), external bicarbonate concentration ([HCO3-]o), and PCO2 on taste receptor cell (TRC) intracellular pH (pHi) in taste bud fragments (TBFs) isolated from rat circumvallate and fungiform papillae with the pH-sensitive fluoroprobe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) using microfluorometric and imaging techniques. In N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered solutions, TRC pHi responded rapidly and monotonically to changes in pHo between 6.5 and 8.0. The relationship between pHi and pHo was steep, with slopes varying between 0.8 and 1.2. Similarly, varying pHo by changing PCO2 at constant [HCO3-]o or changing [HCO3-]o at constant PCO2 led to rapid, monotonic changes in pHi. The relationship between pHi and pHo was once again steep, with slopes varying between 0.8 and 1.2. However, simultaneous changes in PCO2 and [HCO3-]o at constant pHo did not cause any significant changes in steady-state pHi. In imaging studies, single, isolated TRCs responded to changes in pHo, with parallel changes in pHi in the soma and apical process. In addition, changes in pHo induced parallel changes in pHi throughout TBFs. These data suggest that the steady-state TRC pHi is a function of pHo. Changes in TRC pHi may be involved in acid sensing, and salivary [HCO3-] may play a role in the maintainance of steady-state TRC pHi and in the neutralization of acid-induced changes in pHi.

Chorda tympani responses under lingual voltage clamp: implications for NH4 salt taste transduction.

Rat chorda tympani (CT) responses to NH4Cl, ammonium acetate (NH4Ac), and ammonium hippurate (NH4Hp) were obtained during simultaneous current and voltage clamping of the lingual field potential. Although functional and developmental similarities for gustation have been reported for NH4+ and K+ salts, we report here that significant differences are discernible in the CT responses to both salts. Unlike neural responses to KCl, those to NH4Cl are voltage sensitive, enhanced by submucosa negative and suppressed by positive voltage clamp. In this regard, NH4Cl responses are qualitatively similar to NaCl responses; however, the magnitude of NH4Cl voltage sensitivity is significantly less than that of NaCl. The concentration dependence of the CT response to NH4Cl manifests a biphasic nonlinear relationship not observed with KCl or NaCl. Below 0.3 M, the CT response increases as if to approach a saturation value. However, beyond 0.3 M an inflection appears in the CT-concentration curve because of an abrupt increase in CT responses. This kinetic profile is Cl-dependent and is correlated with an increase in transepithelial conductance that displays similar NH4Cl concentration dependence. The biphasic relation to salt concentration is not observed when acetate or hippurate is substituted for Cl-. As with Na+ and K+ salts, less mobile anions than Cl- (Ac- and Hp-) lower the CT responses. However, like Na+ salts, but in contrast to K+ salts, the onset kinetics of CT responses to NH4Ac or NH4Hp remained rapid, even under positive voltage-clamp conditions. Amiloride (100 microM) partially suppresses CT responses within the concentration range of 0.05-0.3 M (48-20% suppression). Amiloride also suppresses the voltage sensitivity of NH4Cl CT responses, but does not eliminate the sensitivity as it does for Na+ salts. In conclusion, the data suggest that taste transduction for NH4 salts is mediated over two NH+ conduction pathways in the taste bud. This is especially evident with NH4Cl, where the CT-concentration curves show two distinct kinetic regimes. Below 0.3 M the saturation with increasing concentration, clamp voltage response dependence, and amiloride sensitivity suggest an apical membrane transduction conductance. Above 0.3 M, the high anion dependence of the response and its amiloride insensitivity indicate participation of the paracellular pathway in transduction.

New perspectives in a gustatory physiology: transduction, development, and plasticity.

Major advances in the understanding of mammalian gustatory transduction mechanisms have occurred in the past decade. Recent research has revealed that a remarkable diversity of cellular mechanisms are involved in taste stimulus reception. These mechanisms range from G protein-and second messenger-linked receptor systems to stimulus-gated and stimulus-admitting ion channels. Contrary to widely held ideas, new data show that some taste stimuli interact with receptive sites that are localized on both the apical and basolateral membranes of taste cells. Studies of taste system development in several species indicate that the transduction pathways for some stimuli are modulated significantly during the early postnatal period. In addition, recent investigations of adult peripheral gustatory system plasticity strongly suggest that the function of the Na+ sensing system can be modulated by circulating hormones, growth factors, or cytokines.

Taste-mixture suppression: functional dissection of cellular and paracellular origins.

1. Chorda tympani (CT) nerve responses were recorded during simultaneous current and voltage clamping of the lingual receptive-field epithelium to examine the role of field potential in taste mixture suppression between sodium gluconate (NaG) and potassium gluconate (KG). 2. Under zero current-clamp conditions, CT responses to 100 mM NaG were suppressed by 63% when presented in mixture with 250 mM KG. At this concentration, KG alone elicited no measurable neural activity, but produced a large submucosal-positive field potential. 3. When CT responses to 100 mM NaG were obtained with voltage clamp at the zero-current clamp field potential of the NaG/KG mixture, they were suppressed by only 30% relative to NaG responses under zero-current clamp. Similarly, CT responses to the mixture of NaG and KG measured while voltage was clamped at the field potential of NaG alone were slightly elevated, but not to the magnitude of zero-current clamp responses to NaG. Therefore field potential-mediated suppression of CT responses to NaG accounts for only a part of the total mixture suppression between NaG and KG. 4. Analysis of the voltage dependence of CT responses to NaG indicated that the moderate field potential increase (8.9 mV) caused by the presence of KG in the mixture equates to a 43% increase in the apparent Km for NaG, from 110 to 157 mM. Use of this effective Km obviated the effect of field potential on CT responses to the NaG/KG mixture and permitted kinetic analysis of K+ blockade of Na+ responses. These analyses suggested that K ions block Na+ movement through apical Na+ channels in a voltage-independent manner with an apparent Ko of 405 mM. Importantly, direct inhibition of Na+ transduction by K+ can account for the part of mixture suppression not mediated by field potential. 5. These experiments reveal that mixture suppression between NaG and KG is derived from two distinct sources. Field potential, triggered largely by the limited mobility of both K+ and Na+ through taste bud tight junctions, globally modulates Na+ transduction. In addition, at the level of the apical Na+ channel, K ions directly block movement of depolarizing Na+ across taste receptor apical membranes.

Chorda tympani taste response of rat to hydrochloric acid subject to voltage-clamped lingual receptive field.

The chorda tympani nerve response of the rat to HCl was obtained with the lingual receptive field under voltage clamp. Unlike NaCl responses, HCl responses were not affected by inside positive voltage perturbations. However, HCl responses under negative voltage clamp were suppressed in contrast to NaCl responses, which were enhanced. Unlike NaCl responses, HCl responses were amiloride insensitive. HCl rinsing from the tongue produced a large off-response. At zero current clamp the off-response coincided with an anomalous increased positive potential. The paracellular resistance was also higher for HCl relative to the same concentration of NaCl. This is evidence that H+ binds to the normally fixed anionic sites of the paracellular pathway rendering it anion selective. It is postulated that release of bound H+ from surface buffer sites is responsible for the second burst of neural activity upon rising HCl. Acids stimulate primarily through the paracellular pathway, which also furnishes buffering sites that regulate H+ concentration, thereby protecting the sensory apparatus from hyperacidic conditions.