It is not well established whether the incident outcomes of the clinical high-risk (CHR) syndrome for psychosis are diagnostically specific for psychosis or whether CHR patients also are at elevated risk for a variety of nonpsychotic disorders. We collected 2 samples (NAPLS-1, PREDICT) that contained CHR patients and a control group who responded to CHR recruitment efforts but did not meet CHR criteria on interview (help-seeking comparison patients [HSC]). Incident diagnostic outcomes were defined as the occurrence of a SIPS-defined psychosis or a structured interview diagnosis from 1 of 3 nonpsychotic Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) groups (anxiety, bipolar, or nonbipolar mood disorder), when no diagnosis in that group was present at baseline. Logistic regression revealed that the CHR vs HSC effect did not vary significantly across study for any emergent diagnostic outcome; data from the 2 studies were therefore combined. CHR (n = 271) vs HSC (n = 171) emergent outcomes were: psychosis 19.6% vs 1.8%, bipolar disorders 1.1% vs 1.2%, nonbipolar mood disorders 4.4% vs 5.3%, and anxiety disorders 5.2% vs 5.3%. The main effect of CHR vs HSC was statistically significant (OR = 13.8, 95% CI 4.2-45.0, df = 1, P < .001) for emergent psychosis but not for any emergent nonpsychotic disorder. Sensitivity analyses confirmed these findings. Within the CHR group emergent psychosis was significantly more likely than each nonpsychotic DSM-IV emergent disorder, and within the HSC group emergent psychosis was significantly less likely than most emergent nonpsychotic disorders. The CHR syndrome is specific as a marker for research on predictors and mechanisms of developing psychosis.

Sensors based on analyte-dependent changes in the conduction of transmembrane protein pores are an interesting prospect. Stochastic sensing, that is, the detection of individual analyte molecules by single pores, has several potential advantages and a variety of sensor elements based on engineered forms of staphylococcal a-hemolysin (aHL) has been tested. [1] In one manifestation of this approach, organic molecules have been detected by using molecular adapters, such as cyclodextrins, which continue to engage in dynamic host-guest interactions after they have become lodged within the lumen of the aHL pore.[2] Here, we show that small organic molecules can also be detected by a scheme in which a host, cucurbit[6]uril (CB6), [3] acts as a carrier rather than an adapter. In this case, the rate of exchange of the guest between the host·guest complex and bulk solvent is slower [4] than the rate of exchange of the host between the solvent and its binding site within the aHL pore. Besides providing a useful means for sensing organic molecules, the carrier system allows the determination of dissociation constants and, independently, association and dissociation rate constants for CB6·guest pairs.CB6 ( Figure 1) contains a hydrophobic cavity, % 5.5 in diameter, which can host small neutral organic molecules.[3] Six carbonyl groups are located at each of the two 4--diameter entrances to the cavity. CB6 is sparingly soluble in water, but its solubility increases in the presence of alkali-metal salts because the carbonyl groups coordinate to the metal cations to form positively charged complexes. [5,6] An X-ray structure of CB6, which was crystallized from an aqueous solution containing Na + ions, shows two sodium ions and their coordinated water molecules at each entrance. [5,6] By contrast, when CB6 is crystallized in the presence of Cs + , only one cesium ion is associated with each entrance.[6] The dimensions of CB6 (maximum external diameter % 14.4 ) suggested that it might become lodged in the lumen of the aHL pore (Figure 1), similar to b-cyclodextrin (diameter % 15.5 ), and mediate the detection of analytes through host-guest interactions.The interaction of CB6 with the aHL pore was first examined in the absence of analyte by monitoring the current through a single pore in a planar bilayer apparatus, as described previously. [7] At + 100 mV in 1.0 m CsCl/10 mm K phosphate buffer (pH 7.4), the current measured through a fully open aHL pore (level L1) was 93.3 AE 1.2 pA (n = 7), and the current with CB6 bound from the trans side (level L2, aHL·CB6) was 41.7 AE 1.5 pA (n = 7) (Figure 2). Binding events were not detected when CB6 was applied to the cis side of the bilayer. The mean interevent intervals (t on ) and the mean durations of the binding events (t off ) were determined from dwell-time histograms.[8]The value of 1/t on increased linearly with [CB6], where [CB6] is the concentration of the cucurbituril, which suggests a simple bimolecular interaction (Scheme 1).[8] The rate constants for association and dissociat...

Background-Missense mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. The mechanistic basis for the phenotypic variability of these allelic disorders of muscle excitability remains unknown. An atypical phenotype with cold-induced hypokalemic paralysis and myotonia at warm temperatures was reported to segregate with the P1158S mutation.

No abstract

In response to sustained depolarization or prolonged bursts of activity in spiking cells, sodium channels enter long-lived non-conducting states from which recovery at hyperpolarized potentials occurs over hundreds of milliseconds to seconds. The molecular basis for this slow inactivation remains unknown, although many functional domains of the channel have been implicated. Expression studies in Xenopus oocytes and mammalian cell lines have suggested a role for the accessory β1 subunit in slow inactivation, but the effects have been variable. We examined the effects of the β1 subunit on slow inactivation of skeletal muscle (Nav1.4) sodium channels expressed in HEK cells. Co-expression of the β1 subunit impeded slow inactivation elicited by a 30 sec depolarization, such that the voltage dependence was right shifted (depolarized) and recovery was hastened. Mutational studies showed this effect was dependent upon the extracellular Ig-like domain, but was independent of the intracellular C-terminal tail. Furthermore, the β1 effect on slow inactivation was shown to be independent of the negative coupling between fast and slow inactivation.