Efficacy and tolerability of vildagliptin-based versus comparative dual therapy in type 2 diabetes : Results of the Austrian subpopulation of the EDGE study.

BACKGROUND: The aim of this post hoc analysis of data from the Austrian subpopulation of the EDGE study was the evaluation of the effectiveness and tolerability of vildagliptin as an add-on to an existing oral antidiabetic (OAD) monotherapy versus a combination therapy with two OADs without vildagliptin in patients with inadequately controlled type 2 diabetes. PATIENTS AND METHODS: In Austria, 422 patients were included. In the framework of regular visits (at baseline, about once per quarter, and at the study end, after 12 months), adverse events (AEs), courses, and changes of therapy were recorded. In addition to the primary end point defined in the primary study, i.e., a reduction of HbA1c by > 0.3 % without hypoglycemia, weight gain ≥ 5 %, peripheral edema, or discontinuation due to gastrointestinal events, the most clinically relevant secondary end point, i.e., HbA1c reduction < 7 % without hypoglycemia or ≥ 3 % increase in body weight after 12 months was used for the analysis of the Austrian data. RESULTS: The initial HbA1c of all enrolled patients was 8.3 ± 1.4 %. The mean reduction of HbA1c was - 1.1 % in the vildagliptin cohort and - 1.0 % in the comparator cohort. In the vildagliptin cohort, 56.4 % of patients, and in the comparator cohort, 45.9 % of patients, reached the primary end point (odds ratio: 1.53, p = 0.04). In the vildagliptin cohort, 18.7 % of patients, and in the comparator cohort, 16.9 % of patients, reached the secondary end point (odds ratio: 1.13, p = 0.68). The incidence of hypoglycemic events (two in each cohort), AEs (approximately 15 % in each cohort), and serious AEs (approximately 2 % in each cohort) was comparable between the two groups. CONCLUSION: In a "real-life" setting, the effectiveness of vildagliptin as second-line treatment is superior to comparator OADs with regard to a reduction in HbA1c of greater than 0.3 % from baseline without well-recognized side effects in patients with inadequately controlled type 2 diabetes (mean baseline HbA1c: 8.5 % (vildagliptin cohort) vs. 8.1 % (comparator cohort)).

Multiple targets of µ-opioid receptor-mediated presynaptic inhibition at primary afferent Aδ- and C-fibers.

Agonists at µ-opioid receptors (MORs) represent the gold standard for the treatment of severe pain. A key element of opioid analgesia is the depression of nociceptive information at the first synaptic relay in spinal pain pathways. The underlying mechanisms are, however, largely unknown. In spinal cord slices with dorsal roots attached prepared from young rats, we determined the inhibitory effect of the selective MOR agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on monosynaptic Aδ- and C-fiber-evoked EPSCs in lamina I neurons. DAMGO depressed presynaptically Aδ- and C-fiber-mediated responses, indicating that MORs are expressed on central terminals of both fiber types. We next addressed the mechanisms of presynaptic inhibition. The effect of DAMGO at both Aδ- and C-fiber terminals was mainly mediated by an inhibition of N-type voltage-dependent Ca(2+) channels (VDCCs), and to a lesser extent of P/Q-type VDCCs. Inhibition by DAMGO was not reduced by K(+) channel blockers. The rate of miniature EPSCs was reduced by DAMGO in a dose-dependent manner. The opioid also reduced Ca(2+)-dependent, ionomycin-induced EPSCs downstream of VDCCs. DAMGO had no effect on the kinetics of vesicle exocytosis in C-fiber terminals, but decreased the rate of unloading of Aδ-fiber boutons moderately, as revealed by two-photon imaging of styryl dye destaining. Together, these results suggest that binding of opioids to MORs reduces nociceptive signal transmission at central Aδ- and C-fiber synapses mainly by inhibition of presynaptic N-type VDCCs. P/Q-type VDCCs and the transmitter release machinery are targets of opioid action as well.

Mammalian Pumilio 2 regulates dendrite morphogenesis and synaptic function.

In Drosophila, Pumilio (Pum) is important for neuronal homeostasis as well as learning and memory. We have recently characterized a mammalian homolog of Pum, Pum2, which is found in discrete RNA-containing particles in the somatodendritic compartment of polarized neurons. In this study, we investigated the role of Pum2 in developing and mature neurons by RNA interference. In immature neurons, loss of Pum2 led to enhanced dendritic outgrowth and arborization. In mature neurons, Pum2 down-regulation resulted in a significant reduction in dendritic spines and an increase in elongated dendritic filopodia. Furthermore, we observed an increase in excitatory synapse markers along dendritic shafts. Electrophysiological analysis of synaptic function of neurons lacking Pum2 revealed an increased miniature excitatory postsynaptic current frequency. We then identified two specific mRNAs coding for a known translational regulator, eIF4E, and for a voltage-gated sodium channel, Scn1a, which interacts with Pum2 in immunoprecipitations from brain lysates. Finally, we show that Pum2 regulates translation of the eIF4E mRNA. Taken together, our data reveal a previously undescribed role for Pum2 in dendrite morphogenesis, synapse function, and translational control.

Induction of synaptic long-term potentiation after opioid withdrawal.

mu-Opioid receptor (MOR) agonists represent the gold standard for the treatment of severe pain but may paradoxically also enhance pain sensitivity, that is, lead to opioid-induced hyperalgesia (OIH). We show that abrupt withdrawal from MOR agonists induces long-term potentiation (LTP) at the first synapse in pain pathways. Induction of opioid withdrawal LTP requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-d-aspartate receptors and a rise of postsynaptic calcium concentrations. In contrast, the acute depression by opioids is induced presynaptically at these synapses. Withdrawal LTP can be prevented by tapered withdrawal and shares pharmacology and signal transduction pathways with OIH. These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia.

Adaptation as a mechanism for gain control in an insect thermoreceptor.

Adaptation controls the gain of the input-function of the cockroach's cold cell during slowly oscillating changes in temperature. When the oscillation period is long, the cold cell improves its gain for the rate of temperature change at the expense of its ability to code instantaneous temperature. When the oscillation period is brief, however, the cold cell reduces this gain and improves its sensitivity for instantaneous temperature. This type of gain control has an important function. When the cockroach ventures from under cover and into moving air, the cold cell is confronted constantly with brief changes in temperature. To be of any use, a limit in the gain for the rate of change seems to be essential. Without such a limit, the cold cell will always indicate temperature change. The decrease in gain for the rate of change involves an increase in gain for instantaneous temperature. Therefore the animal receives precise information about the temperature at which the change occurs and can seek an area of different temperature. If the cockroach ventures back under cover, the rate of change will become slow. In this situation, a high gain improves the ability to signal slow temperature changes. The cockroach receives the early warning of slow fluctuations or even creeping changes in temperature. A comparison of the cold cell's responses with the temperature measured inside of small, cylindrical model objects indicates that coding characteristic rather than passive thermal effects of the structures enclosing the cold cell are responsible for the observed behavior.

Intracellular recording from a spider vibration receptor.

The present study introduces a new preparation of a spider vibration receptor that allows intracellular recording of responses to natural mechanical or electrical stimulation of the associated mechanoreceptor cells. The spider vibration receptor is a lyriform slit sense organ made up of 21 cuticular slits located on the distal end of the metatarsus of each walking leg. The organ is stimulated when the tarsus receives substrate vibrations, which it transmits to the organ's cuticular structures, reducing the displacement to about one tenth due to geometrical reasons. Current clamp recording was used to record action potentials generated by electrical or mechanical stimuli. Square pulse stimulation identified two groups of sensory cells, the first being single-spike cells which generated only one or two action potentials and the second being multi-spike cells which produced bursts of action potentials. When the more natural mechanical sinusoidal stimulation was applied, differences in adaptation rate between the two cell types remained. In agreement with prior extracellular recordings, both cell types showed a decrease in the threshold tarsus deflection with increasing stimulus frequency. Off-responses to mechanical stimuli have also been seen in the metatarsal organ for the first time.

Olfactory receptors on the cockroach antenna signal odour ON and odour OFF by excitation.

A morphologically identifiable type of olfactory sensillum on the antenna of the American cockroach contains a pair of ON and OFF cells that responds oppositely to changes in the concentration of fruit odours. The odour of lemon oil was used to study the accuracy with which these cells can discriminate between rapid step-like, ramp-like and oscillating changes in odour concentration. The discharge rates of both cells are not only affected by the actual concentration at particular instants in time (instantaneous concentration) but also by the rate at which concentration changes. The impulse frequency of the fruit odour ON cell is high when odour concentration is high, but higher still when odour concentration is also rising. Conversely, the impulse frequency of the fruit odour OFF cell is high when odour concentration is low and higher still when odour concentration is also falling. Thus, the effect of odour concentration on the responses of both cells is reinforced by the rate of change. Sensitivity to the rate of concentration change becomes greater when the rate is low. Because of the high sensitivity to low rates of change, these cells are optimized to detect fluctuations in fruit odour concentration. Whereas the ON cell signals the arrival and presence of fruit odour, the OFF cell detects its termination and absence. These cells provide excitatory responses for both increase and decrease in fruit odour concentration and may therefore reinforce contrast information.

Sensory representation of temperature in mosquito warm and cold cells.

A pair of antagonistic thermoreceptive cells is associated with each of two peg-in-pit sensilla located on the antennal tip of Aedes aegypti. One, the warm cell, responds to rapid warming with a sudden increase in the rate of discharge. The other, a cold cell, responds to rapid cooling with a sudden increase in the discharge rate. When temperature changes are provided by oscillating changes in the convective heat contained in the stimulating air stream, the oscillating discharge rates of both cell types are in advance of the oscillations in temperature and slightly behind the oscillations in the rate of temperature change. Analysis of these phase relationships shows that both cell types respond not only to the actual temperature at particular instance in time (instantaneous temperature) but also to the rate with which temperature changes. Individual responses are therefore ambiguous and signal tendencies rather than precise instantaneous values. When the temperature oscillations are delivered by changes in radiation power, however, the oscillating discharge rates of the warm and cold cells are in step with the oscillations in temperature. Here, individual responses signal instantaneous values of temperature rather than tendencies. The power of radiant heat required to modulate the discharge rates is relatively high, suggesting that infrared radiation is not a significant cue in distant host location.

Dendritic excitability and localization of GABA-mediated inhibition in spider mechanoreceptor neurons.

GABAergic inhibition of mechanosensory afferent axon terminals is a widespread phenomenon in vertebrates and invertebrates. Spider mechanoreceptor neurons receive efferent innervation on their peripherally located axons, somata and sensory dendrites, and the dendrites have recently been shown to be excitable. Excitability of the spider sensory neurons is inhibited by muscimol and GABA, agonists of ionotropic GABA receptors. Here we asked where in the neurons this inhibition occurs. We found no evidence for inhibition of action potentials in the sensory dendrites, but axonal action potentials were rapidly suppressed by both agonists. Earlier work showed that metabotropic GABA(B) receptors are located on the dendrites and distal somata of the spider sensory neurons, where they modulate voltage-activated conductances and may provide slower, prolonged inhibition. Therefore, GABA released from single peripheral efferents may activate both ionotropic and metabotropic receptor types, providing rapid suppression of axonal activity followed by slower inhibition that eventually prevents action potential initiation in the distal dendrites.

Active signal conduction through the sensory dendrite of a spider mechanoreceptor neuron.

Rapid responses to sensory stimulation are crucial for survival. This must be especially true for mechanical stimuli containing temporal information, such as vibration. Sensory transduction occurs at the tips of relatively long sensory dendrites in many mechanoreceptors of both vertebrates and invertebrates, but little is known about the electrical properties of these crucial links between transduction and action potential generation. The VS-3 slit-sense organ of the spider Cupiennius salei contains bipolar mechanosensory neurons that allow voltage-clamp recording from the somata, whereas mechanotransduction occurs at the tips of 100- to 200-microm-long sensory dendrites. We studied the properties of VS-3 sensory dendrites using three approaches. Voltage-jump experiments measured the spread of voltage outward from the soma by observing total mechanically transduced charge recovered at the soma as a function of time after a voltage jump. Frequency-response measurements between pseudorandom mechanical stimulation and somatic membrane potential estimated the passive cable properties of the dendrite for voltage spread in the opposite direction. Both of these sets of data indicated that the dendritic cable would significantly attenuate and retard a passively propagated receptor potential. Finally, current-clamp observations of receptor potentials and action potentials indicated that action potentials normally start at the distal dendrites and propagate regeneratively to the soma, reducing the temporal delay of passive conduction.