Temporal Effects on Monaural Amplitude-Modulation Sensitivity in Ipsilateral,Contralateral and Bilateral Noise

The amplitude modulations (AMs) in speech signals are useful cues for speech recognition. Several adaptation mechanisms may make the detection of AM in noisy backgrounds easier when the AM carrier is presented later rather than earlier in the noise. The aim of the present study was to characterize temporal adaptation to noise in AM detection. AM detection thresholds were measured for monaural (50 ms, 1.5 kHz) pure-tone carriers presented at the onset (‘early’ condition) and 300 ms after the onset (‘late’ condition) of ipsilateral, contralateral, and bilateral (diotic) broadband noise, as well as in quiet. Thresholds were 2–4 dB better in the late than in the early condition for the three noise lateralities. The temporal effect held for carriers at equal sensation levels, confirming that it was not due to overshoot on carrier audibility. The temporal effect was larger for broadband than for low-band contralateral noises. Many aspects in the results were consistent with the noise activating the medial olivocochlear reflex (MOCR) and enhancing AM depth in the peripheral auditory response. Other aspects, however, indicate that central masking and adaptation unrelated to the MOCR also affect both carrier-tone and AM detection and are involved in the temporal effects.     

Revisión de las terapias biológicas en la enfermedad inmunomediada del oído interno

Introduction and objectivesImmune-mediated inner ear disease (IMIED) is one of the few reversible forms of sensorineural hearing loss. Treatment is based on high-dose corticosteroids, although long-term therapy is associated with serious adverse effects; this has led to the use of other agents or different routes of administration such as transtympanic delivery. This study analyses the role of biological agents in IMIED management.Material and methodsWe searched PUBMED for studies that examined the response to treatment with different biological agents in patients with IMIED. The following data were extracted from the selected studies and entered into a standardised database: exclusion and inclusion criteria, characteristics of the patients studied, treatment, outcome measures and response rates achieved.ResultsThirteen studies were included in this review. A TNF alpha inhibitor (etanercept, infliximab, adalimumab) was used in 8 studies, an IL-1 antagonist (anakinra) was used in 3 studies and rituximab, an antibody directed against the CD20 surface antigen on B lymphocytes, was evaluated in 2 studies. Most studies achieved a hearing improvement or stabilisation in more than 70% of treated patients.ConclusionsBiological agents can play a role in the management of patients with IMIED, at least in those patients who do not respond to conventional therapy or whose hearing is not stabilised. However, specially-designed randomised controlled clinical trials are needed to assess their effectiveness.     

Assembly of the TCR/CD3 complex: CD3ϵ/δ and CD3ϵ/γ dimers associate indistinctly with both TCRα and TCRβ chains. Evidence for a double TCR heterodimer model

The TCR/CD3 complex is composed of six subunits which are expressed on the cell surface in a coordinate fashion after assembly in the endoplasmic reticulum (ER). The TCR/CD3 complex is assembled after a series of pairwise interactions involving the formation of dimers of CD3ϵ with either CD3γ or CD3δ. These dimers assemble with TCRα and TCRβ chains, and finally, the CD3ζ homodimer is added to allow export of the full complex from the ER. A model has been proposed suggesting that during assembly the CD3ϵ/CD3γ dimer interacts exclusively with TCRβ and the CD3ϵ/CD3δ dimer with TCRα to form a complex with a single TCRα/β heterodimer. We show in this study, by immunoprecipitation and two-dimensional gel electrophoresis, that in the human T cell line Jurkat as well as in total human thymocytes, this preferential interaction does not occur and instead, the CD3ϵ/CD3γ and CD3ϵ/CD3δ dimers associate with both TCR chains simultaneously and indistinctly. These data are confirmed by the analysis of the TCRα-negative T cell line MOLT-4 in which TCRβ is found separately associated with CD3ϵ/CD3γ and with CD3ϵ/CD3δ dimers. Indirectly, our results support a model of stoichiometry in which two TCRα/β heterodimers are present in a TCR/CD3 complex. Furthermore, immunoprecipitation with anti-CD3γ and anti-CD3δ antibodies from 1 % NP40 and 1 % Brij96 cell lysates showed that these subunits form independent partial complexes which are cross-linked through the CD3ζ homodimer. This suggests that CD3ζ mediates the interaction between both TCRα/β heterodimers contained in the double TCR complex. Further proof for this hypothesis is obtained after analysis of a Jurkat cell transfectant containing a point mutation in the transmembrane domain of TCRβ that impairs the association of CD3ζ. In this mutant cell line, unlike a control line with wild-type TCRβ, the CD3γ- and CD3δ-containing complexes were found completely independent. Altogether, these results support a model of TCR/CD3 assembly and stoichiometry in which two TCR-α/β heterodimers form two hemicomplexes containing either CD3ϵ/γ or CD3ϵ/δ dimers which become associated via the CD3ζ homodimer.     

Olfactory bulb ensheathing glia: A unique cell type with axonal growth-promoting properties

The olfactory bulb (OB) is a structure of the central nervous system (CNS) in which axonal growth occurs throughout the lifetime of the organism. A major difference between the OB and the remaining CNS is the presence of ensheathing glia in the first two layers of the OB. Ensheathing glia display properties that might be involved in the process of regeneration and they appear to be responsible for the permissibility of the adult OB to axonal growth. In fact, transplants of ensheathing glia can be used as promoters of axonal regeneration within the adult CNS. The axonal growth-promoting properties of ensheathing glia make the study of this cell type interesting for understanding the mechanisms underlying axonal regeneration. Several groups have studied OB ensheathing cells extensively in an attempt to classify them within any of the known glial groups. However, this cell type does not exhibit the phenotypic features of any glial population described thus far. In this article we review the characteristics that differentiate ensheathing glia from other peripheral and central glial populations as well as the properties that involve them in axonal regeneration. The evidence suggests that ensheathing glia are unique, have their own identity, and do not belong to any previously described glial type. © 1995 Wiley-Liss, Inc.     

Characterization and in vitro degradation of salicylate-derived poly(anhydride-ester microspheres)

The aim of this study was to investigate how glass transition temperature (Tg) influenced polymer microsphere formation and degradation of three chemically, similar novel salicylatebased poly(anhydride-esters): poly[1,6-bis(o-carboxyphenoxy)hexanoate] (CPH), Tg = 59 degrees C; poly[1,8-bis(o-carboxyphenoxy)octanoate] (CPO), Tg = 30 degrees C; and poly[1,10-bis(ocarboxyphenoxy) decanoate] (CPD), Tg = 27 degrees C. Microspheres of these polymers were prepared using a modified oil-in-water solvent evaporation method and processed by either resuspension or washed by centrifugation. The morphology of the microspheres determined by scanning electron microscopy (SEM) revealed that an extra washing step appears to increase aggregation as the Tg decreases; whereas only limited aggregation occurred in the polymer with the lowest Tg, CPD, in those not washed by centrifugation. Residual polyvinyl alcohol apparently affected the drug release rates from the microspheres by a stabilization process that produced an 8 h lag time and a 5% decrease in the amount of drug released over a 7 day period compared to microspheres washed free of PVA. These results demonstrate that salicylate-based poly(anhydride-esters) with sufficiently high Tgs, can be processed into microspheres that release salicylate over a time period amenable for drug delivery applications.     

IL-2 increased RANTES production and CD25 expression in cultured PBMCs only from antiretroviral treated HIV-1+ patients with detectable viral loads

In order to better understand the possible beneficial effects of intermittent IL-2 treatment as complement of antiretroviral therapy in HIV-1+ patients, we have measured the levels of RANTES in the supernatants and the CD25 expression in cultured PBMCs obtained from HIV-1+ individuals in presence of IL-2. The results showed a significant increases in RANTES production and in the expression of CD25+ in the cultures with IL-2 of PBMC obtained from HIV-1+ patients with a detectable viral load in comparison with both, HIV-1+ patients with no detectable viral loads and with healthy individuals. These results suggest that therapeutic IL-2 administered in addition to highly active anti-retroviral therapy (HAART) may contribute to increase the effect of this therapy by rising both RANTES production and CD25 expression only in HIV-1+ patients with detectable viral loads.     

Long-term care of paraplegic laboratory mammals

Repair of spinal cord injuries (SCIs) is still a major clinical challenge. Several attempts have been made to find a cure for this condition in experimental animals that could be extrapolated to humans. A key for success seems the availability of optimum animal models for testing different therapies. Complete spinal cord lesion in mammals is considered the most accurate injury model. In addition, long-term survival of animals seems more appropriate, as this increases the efficacy of the repair strategies. However, paraplegic animals require special care and treatment for proper longterm maintenance, and to date, there are no published protocols. This lack of available information has discouraged scientists from working with this injury model. Over the past 7 years, we have tested the repair efficacy of olfactory ensheathing glia in paraplegic rats for survival periods of more than 8 months. To keep these animals healthy for this long time, we adapted and administered treatments used in people with paraplegia. These same protocols (developed for rodents in our group) are being applied to paraplegic monkeys. In this review, we provide an overview of the proper handling and care of paraplegic adult laboratory mammals for long periods. This information might help other groups to optimize the outcome obtained and to better evaluate the prospect of a given experimental repair strategy. In addition, the use of human treatments in paraplegic animals provides a more realistic model for a later transfer to the clinical arena.     

Endometrial resection and preoperative LH-RH agonists: a prospective 5-year trial

OBJECTIVE: To evaluate the benefits of systematic preoperative treatment with LH-RH agonists prior to endometrial resection (ER). STUDY DESIGN: The study population was made up of 98 premenopausal women who underwent resectoscopic treatment for abnormal uterine bleeding (AUB) between January 1996 and December 1997. Only patients with endometrial polyps or dysfunctional bleeding were included. The population was divided into two groups: patients who had (group B) and those who had not (group A) received LH-RH before the surgical intervention. RESULTS: ER was carried out as a single procedure in 66 (67.5%) of the patients. ER plus polypectomy was necessary in 32 (32.5%) patients. There were no differences between the two groups as far as the operating time and total volume of distension medium were concerned. No intraoperative complications were seen in either group. A higher negative balance of distension medium was achieved in group A (320 +/- 23 mL versus 187 +/- 16 mL; P < 0.001), and this difference was not modified when cases with polyps were excluded. The failure rate was similar in both groups both at 12 months [group A 6 (14.8%) versus group B 7 (14.9%) patients] and at 60 months [group A, 11 (21.6%) versus group B 10 (21.2%) patients]. Likewise, the amenorrhea and hypomenorrhea rates at 12 months and at 60 months were also shown to be the same in both groups. When two doses of LH-RH are used and the failure rate is taken into account the cost of an acceptable outcome increases from 843.37 Euro to 1373.49 Euro per patient, while the total cost of a hysterectomy is 1355.42 Euro. CONCLUSIONS: Endometrial suppression with LH-RH agonists did not guarantee better results of ER, but they are strongly recommended during the learning curve to achieve a safer procedure.     

Pharmacological characterization of native α7 nicotinic ACh receptors and their contribution to depolarization-elicited exocytosis in human chromaffin cells

BACKGROUND AND PURPOSE

Expression of α7 nicotinic acetylcholine receptors (nAChRs) and their role in exocytosis have not yet been examined in human chromaffin cells.

EXPERIMENTAL APPROACH

To characterize these receptors and investigate their function, patch-clamp experiments were performed in human chromaffin cells from organ donors.

KEY RESULTS

The nicotinic current provoked by 300 µM ACh in voltage-clamped cells was blocked by the nicotinic receptor antagonists α-bungarotoxin (α-Bgtx; 1 µM; 6 ± 1.7%) or methyllycaconitine (MLA; 10 nM; 7 ± 1.6%), respectively, in an irreversible and reversible manner, without affecting exocytosis. Choline (10 mM) pulses induced a biphasic current with an initial quickly activated (5.5 ± 0.4 ms rise time) and inactivated component (8.5 ± 0.4 ms time constant) (termed α7), which was blocked by α-Bgtx or MLA, followed by a slower component (non-α7). α7 nAChR currents were dissected by blocking the non-α7 nAChR current component of the ACh and choline response with the α6* nAChR blocker α-conotoxin (α-Ctx) MII[S4A, E11A, L15A]. PNU-282987, an α7 nAChR-specific agonist, elicited rapidly activated and rapidly inactivated currents. α7 nAChR-positive allosteric modulators, such as 5-hydroxyindole (1 mM) and PNU-120596 (10 µM), potentiated responses that were blocked by α-Bgtx or MLA. Exocytosis was evoked by depolarization-elicited α7 nAChR currents, using choline in the presence of α-Ctx MII[MS4A, E11A, L15A] or PNU-282987 as agonists.

CONCLUSIONS AND IMPLICATIONS

Our electrophysiological recordings of pure α7 nAChR currents elicited by rapid application of agonists demonstrated that functional α7 nAChRs are expressed and contribute to depolarization-elicited exocytosis in human chromaffin cells.