A High-Speed Adaptively-Biased Current-to-Current Front-End for SSPM Arrays

AbstractSolid-state photomultiplier (SSPM) arrays are an interesting technology for use in PET detector modules due to their low cost, high compactness, insensitivity to magnetic fields, and sub-nanosecond timing resolution. However, the large intrinsic capacitance of SSPM arrays results in RC time constants that can severely degrade the response time, which leads to a trade-off between array size and speed. Instead, we propose a front-end that utilizes an adaptively biased current-to-current converter that minimizes the resistance seen by the SSPM array, thus preserving the timing resolution for both large and small arrays. This enables the use of large SSPM arrays with resistive networks, which creates position information and minimizes the number of outputs for compatibility with general PET multiplexing schemes. By tuning the bias of the feedback amplifier, the chip allows for precise control of the close-loop gain, ensuring stability and fast operation from loads as small as 50pF to loads as large as 1nF. The chip has 16 input channels, and 4 outputs capable of driving 100 n loads. The power consumption is 12mW per channel and 360mW for the entire chip. The chip has been designed and fabricated in an AMS 0.35um high-voltage technology, and demonstrates a fast rise-time response and low noise performances

Modification of Unit Discharges in the Medial Geniculate Nucleus by Click-Shock Pairing

The present experiment was concerned with some discharge properties of single neurons in the medial geniculate body of the locally anesthetized paralyzed cat. The effect of pairing clicks with paw shock upon discharge rate and pattern was of particular concern. Twelve neurons obtained from 11 cats were studied exhaustively for periods up to 4 hr. Under control conditions, rate stationarity for both spontaneous and click-evoked activity was found in only 3/12 of the units. Click-shock pairing produced rate changes in lo/12 of the cells; an increase in rate predominated. The pattern of discharges was altered in 9/E of the cells as a consequence of click-shock pairing. Specifically, the initial short-latency discharge was modified; there was a reduction in the proportion of spikes in the first peak to the total number of spikes in the poststimulus time histogram. This reduction was not merely a consequence of increases in over-all rate of discharge. In the case of one cell which was inhibited rather than excited by click stimulation, the click-shock pairing resulted in a reduction in the duration of inhibition. Control findings indicated that the pattern modifications were not due to a change in stimulus intensity, the unconditioned effects of the shock itself, or to an increase in arousal level

Randomized Trials to Optimize Treatment of Multidrug-Resistant Tuberculosis: The time for action is now

The time is now right for randomized trials of MDR-TB, say the authors, as the expansion of MDR-TB programs provides the setting in which trials can be implemented

ACTIVATION OF MUSCARINIC CHOLINERGIC RECEPTORS STIMULATES INOSITOL PHOSPHATES SYNTHESIS IN THE DEVELOPING AVIAN COCHLEAR DUCT

International audienceWe previously reported that the inositol phosphates (IPs) synthesis is induced by muscarinic agonists in the rat cochlea and that this stimulation is maximal at postnatal day 12. This peak response is concomitant with the onset of the efferent synaptogenesis at the outer hair cell level. Whether the correlation between this neuronal plasticity and the enhanced IPs formation is unique to the rat or a general feature of the developing vertebrate cochlea is not known. To examine this question, we measured, in the presence of LiCI, the accumulation of (3H)-IPs induced by carbachol, in the developing chick cochlear duct during a period ranging from embryonic day (E) 8 to post-hatching day (P) 20. Carbachol (1 mM) causes a significant increase of IPs formation relative to basal values at all ages. This IPs accumulation is maximal at E8 (1854% of the basal level), then, rapidly decreases until P13 when it reaches a steady-state level of 294% of the basal level. Strikingly, this gradual decline in IPs formation is interrupted between El5 and El9, by a transient increase in IPs synthesis. This rise peaks at El6 with a stimulation value of 757% of the control level. This maximal stimulation is inhibited by atropine in a dose-dependent manner, as is the case at E9, suggesting the involvement of muscarinic receptors. Interestingly, the occurrence of the peak response is concomitant with the plastic events associated with the maturation of the efferent innervation of the cochlear duct. Thus, these results suggest that there may be a correlation between cochlear plasticity and enhanced IPs synthesis, which is not species-specific. The possible significance of the overall decrease in IPs formation, occurring during embryonic development , is discussed. The degradation of membrane phosphatidylinositol 4,5 biphosphate, by the enzyme phospholi-pase C, leads to the formation of diacylglycerol and inositol phosphates (IPs). Among these metabolites, diacylglycerol and inositol 1,4,5-trisphosphate are considered as second messengers. 4 The former directly activates the protein kinase C enzymes; the latter elicits a massive release of calcium from intracellular stores. This transduction system has been found to be driven by specific agonist-activated receptors such as muscarinic cholinergic receptors. 7 We previously reported that this transduction system is stimulated, in the rat cochlea, by muscarinic cholinergic agonists probably, via the activation of a M3 muscarinic receptor, s During the postnatal development of the mammalian cochlea, the muscarinic agonist-induced IPs formation is characterized by a peak around postnatal day 12. 3 This peak coincides with a time period during which plastic events lead to the setting up of the mature efferent innervation of the outer hair cells of the organ of Corti. I1 These efferent terminals are thought to be cholinergic. 6 Thus, it is conceivable that the IPs metabolism may play a role in cochlear neural plasticity. Whether this concomitance, between the increased IPs synthesis and the efferent synaptogenesis, is an overall developmental process in the vertebrate inner ear or is a specific feature of the rat cochlea remains to be investigated. To address this question, we studied the pattern of the phosphoinositide breakdown during the development of the chick basiler papilla. Although phylogenetically remote, the avian basilar papilla and the mammalian organ of Corti share some morphological homologies. They both possess, for instance, two types of hair cells lying on a basilar membrane and covered by a tector-ial membrane. The sensory hair cells are innervated, in both classes, by four different types of fibres, two of them belonging to the efferent systems and the other two to the efferent systems. II'16'23'25 Finally, physiological evidence, supporting the possibility of the presence of muscarinic receptors in the chick auditory organ, as this is the case in the rat cochlea, 3,8 i

The Medial Nucleus of the Trapezoid Body in the Gerbil Is More Than a Relay: Comparison of Pre- and Postsynaptic Activity

The medial nucleus of the trapezoid body (MNTB) plays an important role in the processing of interaural intensity differences, a feature that is critical for the localization of sound sources. It is generally believed that the MNTB functions primarily as a passive relay in converting excitatory input originating from the contralateral cochlear nucleus (CN) into an inhibitory input to the ipsilateral lateral superior olive. However, studies showing that the MNTB itself is also the target of inhibitory input suggest that the MNTB may serve more than a sign-converting function. To examine the fidelity of signal transmission at the CN–MNTB synapse, presynaptic calyceal potentials ("prepotentials"), reflecting the excitatory input to the MNTB neuron, and postsynaptic action potentials were simultaneously monitored with the same electrode during in vivo extracellular recordings from the gerbil's MNTB. Presynaptic activity differed from postsynaptic activity in several respects: (1) Spontaneous and sound-evoked discharge rates were greater presynaptically than postsynaptically. (2) Frequency tuning was sharper postsynaptically than presynaptically. (3) Calyceal terminals and MNTB neurons both showed phasic–tonic response patterns to tonal stimulation, but the duration of the onset response and the level of the tonic component were reduced postsynaptically. (4) Phase-locking to sound frequencies up to 1 kHz was greater postsynaptically than presynaptically. (5) The rate-intensity characteristics of pre- and postsynaptic activities differed significantly from each other in half of the MNTB neurons. To test the hypothesis that acoustically evoked inhibition of MNTB neurons contributed to the relatively lower levels of postsynaptic discharge, two-tone stimulation was applied, wherein the response to one tone-burst, set at the neuron's characteristic frequency, can be reduced by addition of a second "inhibitory" tone. The inhibitory tone caused a much larger reduction in post- than in presynaptic activity, indicating an acoustically evoked inhibitory influence directly on MNTB units. These findings show that transmission at the CN–MNTB synapse does not occur in a fixed one-to-one manner and that the response of MNTB neurons reflects the integration of their excitatory and inhibitory inputs

Decreased Temporal Precision of Auditory Signaling in Kcna1-Null Mice: An Electrophysiological Study In Vivo

The voltage-gated potassium (Kv) channel subunit Kv1.1, encoded by the Kcna1 gene, is expressed strongly in the ventral cochlear nucleus (VCN) and the medial nucleus of the trapezoid body (MNTB) of the auditory pathway. To examine the contribution of the Kv1.1 subunit to the processing of auditory information, in vivo single-unit recordings were made from VCN neurons (bushy cells), axonal endings of bushy cells at MNTB cells (calyces of Held), and MNTB neurons of Kcna1-null (-/-) mice and littermate control (+/+) mice. Thresholds and spontaneous firing rates of VCN and MNTB neurons were not different between genotypes. At higher sound intensities, however, evoked firing rates of VCN and MNTB neurons were significantly lower in -/- mice than +/+ mice. The SD of the first-spike latency (jitter) was increased in VCN neurons, calyces, and MNTB neurons of -/- mice compared with +/+ controls. Comparison along the ascending pathway suggests that the increased jitter found in -/- MNTB responses arises mostly in the axons of VCN bushy cells and/or their calyceal terminals rather than in the MNTB neurons themselves. At high rates of sinusoidal amplitude modulations, -/- MNTB neurons maintained high vector strength values but discharged on significantly fewer cycles of the amplitude-modulated stimulus than +/+ MNTB neurons. These results indicate that in Kcna1-null mice the absence of the Kv1.1 subunit results in a loss of temporal fidelity (increased jitter) and the failure to follow high-frequency amplitude-modulated sound stimulation in vivo

Effect of upadacitinib on reducing pain in patients with active psoriatic arthritis or ankylosing spondylitis: post hoc analysis of three randomised clinical trials

Objective: Evaluate the effect of upadacitinib on pain outcomes in patients with active psoriatic arthritis (PsA) or ankylosing spondylitis (AS) across 3 randomised trials (SELECT-PsA 1 and 2 for PsA; SELECT-AXIS 1 for AS). Methods: Patients were randomised to upadacitinib 15 mg once daily or placebo (all 3 studies), or adalimumab 40 mg every other week (SELECT-PsA 1 only). Pain outcomes included proportion of patients achieving ≥30%, ≥50% and ≥70% reduction from baseline in patient global assessment of pain and other end points. Results: A higher proportion of patients receiving upadacitinib versus placebo achieved ≥30%, ≥50% and ≥70% reduction in pain end points as early as week 2; these improvements with upadacitinib were generally sustained or increased through year 1 (PsA 1/2 studies: 64%/48%, 58%/42% and 38%/22%, respectively; SELECT-AXIS 1 study: 76%, 72% and 54%). Results were similar with adalimumab in PsA 1 (59%, 49% and 32%). Patients who switched from placebo to upadacitinib 15 mg were able to reach a similar level of improvement as the continuous upadacitinib groups by year 1 (PsA 1/2 studies: 46%–60%, 35%–49% and 15%–34%; AS study: 83%, 72% and 46%). Results were similar with other pain end points. Conclusion: Rapid and sustained improvements in pain outcomes across several end points were consistently shown with upadacitinib over 1 year in patients with active PsA or AS who had either inadequate response to prior non-biologic or biologic disease-modifying antirheumatic drugs (PsA studies) or were biologic-naïve with inadequate response to non-steroidal anti-inflammatory drugs (AS study)