Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant.

Epilepsy and neurodevelopmental disorders can arise from pathogenic variants of KCNQ (Kv7) channels. A patient with developmental and epileptic encephalopathy exhibited an in-frame deletion of histidine 260 on Kv7.2. Coexpression of Kv7.2 mutant (mut) subunits with Kv7.3 invoked a decrease in current density, a depolarizing shift in voltage for activation, and a decrease in membrane conductance. Biotinylation revealed an increased level of surface Kv7.2mut compared to Kv7.3 with no change in total membrane protein expression. Super-resolution and FRET imaging confirmed heteromeric channel formation and a higher expression density of Kv7.2mut. Cannabidiol (1 µM) offset the effects of Kv7.2mut by inducing a hyperpolarizing shift in voltage for activation independent of CB1 or CB2 receptors. These data reveal that the ability for cannabidiol to reduce the effects of a pathogenic Kv7.2 variant supports its use as a potential therapeutic to reduce seizure activity.

High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.

Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50 nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density.

Evidence-based optimal fluconazole dosing regimen for onychomycosis treatment.

BACKGROUND: Fluconazole could be an alternative to terbinafine and itraconazole for onychomycosis treatment. However, it is difficult to determine the optimal dosing regimen due to the variability in causative agents, dosing regimens and cure rates in clinical trials. By restricting the data to dermatophyte onychomycosis, we aimed to identify an optimal fluconazole dosing regimen. METHODS: We searched the PubMed, EMBASE and CENTRAL databases and the reference sections of published literature for clinical trials on fluconazole monotherapy for culture-proven dermatophyte onychomycosis. Relationships between fluconazole doses, cure rates and duration of therapy were analyzed. RESULTS: Longer treatments, but not higher weekly fluconazole doses, resulted in better cure rates for toenail, and possibly fingernail, onychomycosis. Consequently, mean mycological and clinical cure rates for treatments lasting 6 months or less and more than 6 months were significantly different for toenail onychomycosis. Clinical studies including participants with nondermatophyte mold, Candida species, or negative culture onychomycosis only used fluconazole therapy for 6 months or less. Thus, the relationship between cure rates and duration of treatment could not be confirmed for all causative agents. CONCLUSION: The lowest dose of 150 mg weekly for more than 6 months is recommended for onychomycosis.

Meta-analysis of randomized, controlled trials comparing particular doses of griseofulvin and terbinafine for the treatment of tinea capitis.

Two oral antifungal agents, griseofulvin and terbinafine, have regulatory approval in the United States, but it is unknown whether one has superior overall efficacy. Genus-specific differences in efficacy are believed to exist for the two agents. It is not clear at what doses and durations of treatment these differences apply. The goals of this meta-analysis were to determine whether a statistically significant difference in efficacy exists between these agents at a given dose and duration of each in tinea capitis infections overall and to determine whether a genus-specific difference in efficacy exists for these two treatments at a given dose and duration of each. We performed a literature search for clinically and methodologically similar randomized controlled trials comparing 8 weeks of griseofulvin (6.25-12.5 mg/kg/day) to 4 weeks of terbinafine (3.125-6.25 mg/kg/day) in the treatment of tinea capitis. A meta-analysis was performed using the Mantel-Haenszel method and random effects model; results were expressed as odds ratios with 95% confidence intervals. Meta-analysis of randomized controlled trials did not show a significant difference in the overall efficacy of the two drugs at the doses specified, but specific efficacy differences were observed based on the infectious species. For tinea capitis caused by Microsporum spp., griseofulvin is superior (p = 0.04), whereas terbinafine is superior for Trichophyton spp. infection (p = 0.04). Our results support species-specific differences in treatment efficacy between griseofulvin and terbinafine and provide a clinical context in which this knowledge may be applied.

Systematic review of nondermatophyte mold onychomycosis: diagnosis, clinical types, epidemiology, and treatment.

Nondermatophyte mold (NDM) onychomycosis is difficult to diagnose given that NDMs are common contaminants of the nails and of the mycology laboratory. Diagnostic criteria and definition of cure are inconsistent between studies, which may affect the quality of published data. We identified 6 major criteria used in the literature: identification of the NDM in the nail by microscopy (using potassium hydroxide preparation), isolation in culture, repeated isolation in culture, inoculum counting, failure to isolate a dermatophyte in culture, and histology. Most studies used 3 or more of these (range = 1-5). We recommend using at least 3 of the criteria to rule out contamination; these should include potassium hydroxide preparation for direct microscopy and isolation of the organism in culture. We review geographic distribution and clinical presentations associated with different NDMs. The treatment with the greatest quantity of data and highest reported cure rates is terbinafine, for the treatment of Scopulariopsis brevicaulis and Aspergillus species infections. Topicals such as ciclopirox nail lacquer may also be effective (data originating from Scopulariopsis brevicaulis and Acremonium species infections), especially when combined with chemical or surgical avulsion of the nail. We recommend that future studies use (and clearly indicate) at least 3 of the main criteria for diagnosis, and report the clinical type of onychomycosis and the isolated organism. When evaluating different treatments, we suggest that authors clearly define their efficacy outcomes.

Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis.

Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type- and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma-/- neurons, but not Bim-/- or Noxa-/- neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and Bim(EL) can bind to the antiapoptotic family member Bcl-X(L), only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.