This report documents slow changes in cochlear responses produced by electrical stimulation of the olivocochlear bundle (OCB), which provides efferent innervation to the hair cells of the cochlea. These slow changes have time constants of 25–50 sec, three orders of magnitude slower than those reported previously. Such “slow effects” are similar to classically described “fast effects” in that (1) they comprise a suppression of the compound action potential (CAP) of the auditory nerve mirrored by an enhancement of the cochlear microphonic potential (CM) generated largely by the outer hair cells; (2) the magnitude of suppression decreases as the intensity of the acoustic stimulus increases; (3) they share the same dependence on OCB stimulation rate; (4) both are extinguished upon cutting the OCB; and (5) both are blocked with similar concentrations of a variety of cholinergic antagonists as well as with strychnine and bicuculline. These observations suggest that both fast and slow effects are mediated by the same receptor and are produced by conductance changes in outer hair cells. Slow effects differ from fast effects in that (1) fast effects are greatest for acoustic stimulus frequencies between 6 and 10 kHz, whereas slow effects peak for frequencies from 12 to 16 kHz, and (2) fast effects persist over long periods of OCB stimulation, whereas slow effects diminish after 60 sec of stimulation. The time course of the slow effects can be described mathematically by assuming that each shock-burst produces, in addition to a fast effect, a small decrease in CAP amplitude that decays exponentially with a time constant that is long relative to the intershock interval. The long time constant of the slow effect compared to the fast effect suggests that it may arise from a distinct intracellular mechanism, possibly mediated by second- messenger systems.

The cholinergic efferent fibers to the outer hair cells (OHCs) of the mammalian cochlea suppress sound-evoked activity of the auditory nerve on two time scales via one nicotinic receptor. A rapid action (tens of milliseconds) is responsible for modulating auditory nerve responses to acoustic stimulation. A slower action (tens of seconds) may protect the ear from acoustic overstimulation. The rapid action is likely caused by calcium influx through the nicotinic receptor that leads to opening of calcium-activated potassium (KCa) channels, but the mechanism of the slower action has not been explained. To investigate this mechanism, we perfused the cochlea with agents that alter intracellular calcium release and uptake. Both fast and slow effects were enhanced by perfusion of the cochlea with ryanodine, an agonist of calcium-induced calcium release (CICR). Antagonists of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), cyclopiazonic acid, and thapsigargin (1) selectively enhanced the magnitude of slow effects, (2) prevented the diminution of slow effects with continued efferent stimulation, and (3) spread the range of frequencies over which slow effects were observed. We propose that the slow effect is attributable to release of calcium from the subsurface cisterna of the OHC, perhaps triggered by CICR from the synaptic cisterna; the two time scales of efferent action may result from the unique arrangement of the two cisternae in the baso-lateral region of the OHC.

Background: The 2010 guidelines by ASCO-CAP have mandated that breast cancer specimens with ≥1% positively staining cells by immunohistochemistry should be considered Estrogen Receptor (ER) positive. This has led to a subclass of low-ER positive (1-10%) breast cancers. We have examined the biology and clinical behavior of these low ER staining tumors.Methods: We have developed a probabilistic score of the “ER-positivity” by quantitative estimation of ER related gene transcripts from FFPE specimens. Immunohistochemistry for ER was done on 240 surgically excised tumors of primary breast cancer. Relative transcript abundance of 3 house-keeping genes and 6 ER related genes were determined by q-RT PCR. A logistic regression model using 3 ER associated genes provided the best probability function, and a cut-off value was derived by ROC analysis. 144 high ER (>10%), 75 ER negative and 21 low-ER (1-10%) tumors were evaluated using the probability score and the disease specific survival was compared.Results: Half of the low-ER positive tumors were assigned to the ER negative group based on the probability score; in contrast 95% of ER negative and 92% of the high ER positive tumors were assigned to the appropriate ER group (p<0.0001). The survival of the low-ER group was intermediate between that of the high ER positive and ER negative groups (p<0.05).Conclusion: Our results suggest that the newly lowered ASCO-CAP criteria for ER positivity, leads to the false categorization of biologically ER negative tumors as ER positive ones. This may have particular relevance to India, where we have a much higher proportion of ER negative tumors in general.

Background: Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance.