Neurons possess multiple voltage-dependent conductances specific for their function. To investigate how low-threshold outward currents improve the detection of small signals in a noisy background, we ...recorded from gerbil medial superior olivary (MSO) neurons in vitro. MSO neurons responded phasically, with a single spike to a step current injection. When bathed in dendrotoxin (DTX), most cells switched to tonic firing, suggesting that low-threshold potassium currents (I(KLT)) participated in shaping these phasic responses. Neurons were stimulated with a computer-generated steady barrage of random inputs, mimicking weak synaptic conductance transients (the "noise"), together with a larger but still subthreshold postsynaptic conductance, EPSG (the "signal"). DTX reduced the signal-to-noise ratio (SNR), defined as the ratio of probability to fire in response to the EPSG and the probability to fire spontaneously in response to noise. The reduction was mainly attributable to the increase of spontaneous firing in DTX. The spike-triggered reverse correlation indicated that, for spike generation, the neuron with I(KLT) required faster inward current transients. This narrow temporal integration window contributed to superior phase locking of firing to periodic stimuli before application of DTX. A computer model including Hodgkin-Huxley type conductances for spike generation and for I(KLT) (Rathouz and Trussell, 1998) showed similar response statistics. The dynamic low-threshold outward current increased SNR and the temporal precision of integration of weak subthreshold signals in auditory neurons by suppressing false positives.
Abstract Objective Schizotypal features indicate proneness to psychosis in the general population. It is also possible that they increase transition to psychosis (TTP) among clinical high-risk ...patients (CHR). Our aim was to investigate whether schizotypal features predict TTP in CHR patients. Methods In the EPOS (European Prediction of Psychosis Study) project, 245 young help-seeking CHR patients were prospectively followed for 18 months and their TTP was identified. At baseline, subjects were assessed with the Schizotypal Personality Questionnaire (SPQ). Associations between SPQ items and its subscales with the TTP were analysed in Cox regression analysis. Results The SPQ subscales and items describing ideas of reference and lack of close interpersonal relationships were found to correlate significantly with TTP. The co-occurrence of these features doubled the risk of TTP. Conclusions Presence of ideas of reference and lack of close interpersonal relations increase the risk of full-blown psychosis among CHR patients. This co-occurrence makes the risk of psychosis very high.
Subcutaneous delivery of nicotine was performed using a novel electrically-operated needle-free jet injector, and compared to hypodermic needle delivery in a porcine model. Nicotine was delivered as ...a single, one-milligram dose into the abdominal skin, formulated as a 50 microliter aqueous solution. Plasma levels of nicotine and cotinine, its main metabolite, were then monitored over 2 h, following which the injection site was excised for histological examination. No irritation or tissue damage were found at the injection sites, and the jet-injected nicotine exhibited comparable absorption into the systemic circulation to that injected using a conventional needle and syringe. The needle-free jet injection of nicotine is a promising and well tolerated method. The data presented from this porcine model will support a first in human trial towards a new promising nicotine replacement therapy.
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1 Center for Neural Science, New York University, New York, New York 10003
2 Laboratory of Neurophysiology, Biomedical Research Institute, Kaunas University of Medicine, 3000 Kaunas, Lithuania
3 ...Courant Institute of Mathematical Sciences, New York University, New York, New York 10012
Submitted 28 July 2003;
accepted in final form 5 January 2004
Voltage-dependent membrane conductances support specific neurophysiological properties. To investigate the mechanisms of coincidence detection, we activated gerbil medial superior olivary (MSO) neurons with dynamic current-clamp stimuli in vitro. Spike-triggered reverse-correlation analysis for injected current was used to evaluate the integration of subthreshold noisy signals. Consistent with previous reports, the partial blockade of low-threshold potassium channels ( I KLT ) reduced coincidence detection by slowing the rise of current needed on average to evoke a spike. However, two factors point toward the involvement of a second mechanism. First, the reverse correlation currents revealed that spike generation was associated with a preceding hyperpolarization. Second, rebound action potentials are 45% larger compared to depolarization-evoked spikes in the presence of an I KLT antagonist. These observations suggest that the sodium current ( I Na ) was substantially inactivated at rest. To test this idea, I Na was enhanced by increasing extracellular sodium concentration. This manipulation reduced coincidence detection, as reflected by slower spike-triggering current, and diminished the hyperpolarization phase in the reverse-correlation currents. As expected, a small outward bias current decreased the pre-spike hyperpolarization phase, and TTX blockade of I Na nearly eliminated the hyperpolarization phase in the reverse correlation current. A computer model including Hodgkin-Huxley type conductances for spike generation and for I KLT showed reduction in coincidence detection when I KLT was reduced or when I Na was increased. We hypothesize that desirable synaptic signals first remove some inactivation of I Na and reduce activation of I KLT to create a brief temporal window for coincidence detection of subthreshold noisy signals.
Address for reprint requests: J. Rinzel, Center for Neural Science, 4 Washington Place, Room 809, New York, NY 10003-6621 (E-mail: rinzel{at}cns.nyu.edu ).
The monitoring and controlling of pH is important when preparing solutions for ophthalmic administration. In the case of povidone-iodine, dilution in an appropriate buffer is needed to improve its ...ophthalmic safety.
Povidone-iodine is a broad-spectrum antiseptic agent that is commonly used in ophthalmic applications due to its cost-effectiveness and accessibility. However, native povidone-iodine has a pH of about 4.0 and is known to irritate the ocular surface. This study assessed whether adjusting povidone-iodine formulation pH would influence its
ophthalmic safety, alongside its impact on antibacterial efficacy and storage stability.
One per cent w/v povidone-iodine was diluted in normal saline, or 0.1-mol/l citrate or phosphate buffers to yield solutions with a pH ranging from 4.0 to 7.0. Ocular irritancy was evaluated using the bovine cornea opacity and permeability assay. Antibacterial efficacy was assessed by evaluating povidone-iodine minimum inhibitory concentration and minimum bactericidal concentration at varied pH. Storage stability of the preparations was determined over 30-days at room temperature (20-25°C).
Combining povidone-iodine with phosphate buffer notably decreased ocular irritancy of the antiseptic. Surprisingly, combining povidone-iodine with citrate buffer potentiated irritant effects of the preparation. Antibacterial efficacy of povidone-iodine was reduced when formulation pH was increased from 4.0 to 7.0, although its general activity was retained. Finally, povidone-iodine remained stable in both normal saline and phosphate buffer over 30-days.
Ophthalmic application of povidone-iodine can be optimised by adjusting the pH of the formulation to 7.0 using phosphate buffer, reducing irritancy while maintaining adequate antibacterial efficacy and storage stability.
This paper reports a simple fabrication strategy towards 3-dimensionally ordered macroporous (3DOM) poly(3,4-ethylenedioxythiophene) (PEDOT) thin films via vapor phase polymerization (VPP) coupled ...with colloidal crystal templating. PEDOT was synthesized by VPP over a colloidal crystal thin film composed of monodisperse polystyrene colloids functionalized with a Fe(III) tosylate catalyst, after which the polystyrene template was selectively removed. The resulting 3DOM PEDOT films comprised a face-centered cubic array of 280–290 nm spherical macropores in a PEDOT matrix, around 5–6 μm thick. Cyclic voltammetry (CV) was used to probe electrochemistry and highlighted the merits of the fabrication strategy introduced here; the 3DOM PEDOT films exhibit a 2.9-fold increase in electrochemically available surface area compared to the non-templated PEDOT films. As a demonstration of functionality, ion-exchange of the dopant tosylate for the anionic drug dexamethasone phosphate (dexPˉ) was explored. Loading by passive ion exchange was three-fold higher for 3DOM PEDOT compared with non-templated PEDOT. Notably, CV-driven ion exchange was more efficient to load drug into the polymer than passive ion exchange, and occurred to similar extents for both non-templated PEDOT and 3DOM PEDOT structures. Following loading, minimal dexPˉ release was observed in the absence of an electrical stimulus, while dexPˉ release was triggered upon application of a suitable electrical stimulus. 3DOM PEDOT prepared by VPP thus represents a promising material for use as an ion exchange resin with drug loading achieved subsequent to polymerization and electrically triggered drug release demonstrated.
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•Highly ordered macroporous PEDOT synthesized via vapor phase polymerization.•Macropores impart a near 3 fold increase in electrochemically accessible surface area over non-templated PEDOT.•CV-driven ion exchange can be used to enhance drug loading into PEDOT.•Dexamethasone release was triggered upon application of an electrical stimulus.
Abstract Purpose In patients with schizophrenia, premorbid psychosocial adjustment is an important predictor of functional outcome. We studied functional outcome in young clinical high-risk (CHR) ...patients and how this was predicted by their childhood to adolescence premorbid adjustment. Methods In all, 245 young help-seeking CHR patients were assessed with the Premorbid Adjustment Scale, the Structured Interview for Prodromal Syndromes (SIPS) and the Schizophrenia Proneness Instrument (SPI-A). The SIPS assesses positive, negative, disorganised, general symptoms, and the Global Assessment of Functioning (GAF), the SPI-A self-experienced basic symptoms; they were carried out at baseline, at 9-month and 18-month follow-up. Transitions to psychosis were identified. In the hierarchical linear model, associations between premorbid adjustment, background data, symptoms, transitions to psychosis and GAF scores were analysed. Results During the 18-month follow-up, GAF scores improved significantly, and the proportion of patients with poor functioning decreased from 74% to 37%. Poor premorbid adjustment, single marital status, poor work status, and symptoms were associated with low baseline GAF scores. Low GAF scores were predicted by poor premorbid adjustment, negative, positive and basic symptoms, and poor baseline work status. The association between premorbid adjustment and follow-up GAF scores remained significant, even when baseline GAF and transition to psychosis were included in the model. Conclusion A great majority of help-seeking CHR patients suffer from deficits in their functioning. In CHR patients, premorbid psychosocial adjustment, baseline positive, negative, basic symptoms and poor working/schooling situation predict poor short-term functional outcome. These aspects should be taken into account when acute intervention and long-term rehabilitation for improving outcome in CHR patients are carried out.
Previously, we have found that mildronate 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is ...altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson's disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.
Abstract Background Subjects with psychoses have significantly increased rates of physical illnesses, but the nature of the relationship remains largely unknown. Material and methods The present ...study is part of the European Prediction of Psychosis Study (EPOS). Data were collected from 245 help-seeking individuals from six European centers (age 16–35) who met criteria for ultra-high risk of psychosis criteria. This paper seeks to investigate self-reported physical ill health and its associations with psychiatric symptoms and disorders, risk factors, and onset of psychosis during 48 months of follow-up. Results In multivariate analysis, lifetime panic disorder (OR = 2.43, 95%CI: 1.03–5.73), known complications during pregnancy and delivery (OR = 2.81, 95%CI: 1.10–7.15), female gender (OR = 2.88, 95%CI: 1.16–7.17), family history of psychosis (OR = 3.08, 95%CI: 1.18–8.07), and having a relationship (OR = 3.44, 95%CI: 1.33–8.94) were significantly associated with self-reported physician-diagnosed illness. In the Cox proportional hazard model we found no significant differences between those who had undergone a transition to psychosis and those who had not. Conclusions The physical health of patients defined to be at ultra-high risk of psychosis seems to be commonly impaired and associated with female gender, marital status, complications during pregnancy and birth, lifetime panic disorder, and genetic risk of psychosis.
Abstract Aim Our previous study (Salokangas et al., 2009) suggested that the subjective experience of negative attitude of others (NAO) towards oneself is an early indicator of psychotic development. ...The aim of this prospective follow-up study was to test this hypothesis. Methods A total of 55 young psychiatric outpatients assessed as being at current risk of psychosis (CROP) were followed for up to 60 months and rates of transition to psychosis (TTP) identified. CROP was assessed employing the Bonn Scale for assessment of basic symptoms (Schultze-Lutter and Klosterkötter, 2002) and the Structured Interview for prodromal symptoms (Miller et al., 2002) . TTP was defined by a psychotic episode lasting for more than one week. Associations between NAO at baseline and TTP were analyzed by a Cox regression survival analysis. Results Eight (14.5%) TTP were identified: four (57.1%) within seven NAO patients and four (8.7%) within forty-six non-NAO patients. In the multivariate Cox regression analysis, NAO at baseline significantly ( P = 0.007) predicted TTP. Conclusion The prospective follow-up results support our hypothesis that subjective experience of NAO is an early indicator of psychotic in development.
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