Atrial fibrillation detected after stroke is related to a low risk of ischemic stroke recurrence.

OBJECTIVE: To compare the risk of 1-year ischemic stroke recurrence between atrial fibrillation (AF) diagnosed after stroke (AFDAS) and sinus rhythm (SR) and investigate whether underlying heart disease is as frequent in AFDAS as it is in AF known before stroke (KAF). METHODS: In this retrospective cohort study, we included all ischemic stroke patients admitted to institutions participating in the Ontario Stroke Registry from July 1, 2003, to March 31, 2013. Based on heart rhythm assessed during admission, we classified patients as AFDAS, KAF, or SR. We modeled the relationship between heart rhythm groups and 1-year ischemic stroke recurrence by using Cox regression adjusted for multiple covariates (e.g., oral anticoagulants). We compared the prevalence of coronary artery disease, myocardial infarction, and heart failure among the 3 groups. RESULTS: Among 23,376 ischemic stroke patients, 15,885 had SR, 587 AFDAS, and 6,904 KAF. At 1 year, 39 (6.6%) patients with AFDAS, 661 (9.6%) with KAF, and 1,269 (8.0%) with SR had recurrent ischemic strokes (p = 0.0001). AFDAS-related ischemic stroke recurrence adjusted risk was not different from that of SR (hazard ratio 0.90 [95% confidence interval 0.63, 1.30]; p = 0.57). Prevalence of coronary artery disease (18.2% vs 34.7%; p < 0.0001), myocardial infarction (11.6% vs 20.5%; p < 0.0001), and heart failure (5.5% vs 16.8%; p < 0.0001) were lower in AFDAS relative to KAF. CONCLUSIONS: The lack of difference in 1-year ischemic stroke recurrence between AFDAS and SR and the lower prevalence of heart disease in AFDAS compared to KAF suggest that the underlying pathophysiology of AFDAS may differ from that of KAF.

Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach.

BACKGROUND: It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart. METHODS: The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator-driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke. CONCLUSIONS: PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke.

Group II metabotropic glutamate receptor interactions with NHERF scaffold proteins: Implications for receptor localization in brain.

The group II metabotropic glutamate receptors mGluR2 and mGluR3 are key modulators of glutamatergic neurotransmission. In order to identify novel Group II metabotropic glutamate receptor (mGluR)-interacting partners, we screened the C-termini of mGluR2 and mGluR3 for interactions with an array of PDZ domains. These screens identified the Na+/H+ exchanger regulatory factors 1 and 2 (NHERF-1 & -2) as candidate interacting partners. Follow-up co-immunoprecipitation studies demonstrated that both mGluR2 and mGluR3 can associate with NHERF-1 and NHERF-2 in a cellular context. Functional studies revealed that disruption of PDZ interactions with mGluR2 enhanced receptor signaling to Akt. However, further studies of mGluR2 and mGluR3 signaling in astrocytes in which NHERF expression was reduced by gene knockout (KO) and/or siRNA knockdown techniques revealed that the observed differences in signaling between WT and mutant mGluR2 were likely not due to disruption of interactions with the NHERF proteins. Electron microscopic analyses revealed that Group II mGluRs were primarily expressed in glia and unmyelinated axons in WT, NHERF-1 and NHERF-2 KO mice, but the relative proportion of labeled axons over glial processes was higher in NHERF-2 KO mice than in controls and NHERF-1 KO mice. Interestingly, our anatomical studies also revealed that loss of either NHERF protein results in ventriculomegaly, which may be related to the high incidence of hydrocephaly that has previously been observed in NHERF-1 KO mice. Together, these studies support a role for NHERF-1 and NHERF-2 in regulating the distribution of Group II mGluRs in the murine brain, while conversely the effects of the mGluR2/3 PDZ-binding motifs on receptor signaling are likely mediated by interactions with other PDZ scaffold proteins beyond the NHERF proteins.

Management of Onychomycosis in Canada in 2014.

BACKGROUND: Onychomycosis has several clinical presentations and is caused by various infectious organisms. OBJECTIVE: To provide guidance for selection of appropriate treatment. METHODS: The literature on onychomycosis management was reviewed to generate an evidence-based decision tree. RESULTS AND CONCLUSION: Several options are available: terbinafine, itraconazole, fluconazole, ciclopirox 8% nail lacquer, efinaconazole 10% nail solution, and laser therapy. Further studies on lasers are needed before use can be recommended. Nondermatophyte molds or mixed infection can be managed with terbinafine or itraconazole with or without topicals. Itraconazole, fluconazole, and efinaconazole can be used for Candida infection. For dermatophytes, topicals can be considered for mild to moderate onychomycosis. For moderate to severe cases, any oral monotherapy can be used; however, we suggest terbinafine if there is a possibility of a drug interaction. These recommendations can be applied for all ages, immune function, or metabolic status, but proper monitoring and contraindications should be taken into consideration.

A retrospective chart review of the clinical efficacy of Nd:YAG 1064-nm laser for toenail onychomycosis.

Cosmetic improvement in nail appearance is a great concern to patients with onychomycosis. Although oral and topical treatments for onychomycosis can potentially eradicate the infection, unsightly nails may remain despite negative mycology. Laser-based devices have been approved for the temporary clearance of nails with onychomycosis, thus providing a means of improving the aesthetic appearance of the nails. A retrospective chart review of patients treated with a Nd:YAG 1064-nm laser and debridement for onychomycosis, and terbinafine 1% cream for associated tinea pedis, between July 2012 and February 2014 was performed to ascertain the proportion of patients who achieved clinical outcomes. A temporary improvement in the appearance of the target nail was observed in 78% of patients and the affected area of the nail plate was reduced by at least 50% from baseline in 46% of patients. It appears that patients whose great toenails are potentially infected with non-dermatophyte molds may particularly benefit from laser therapy. Higher clinical outcome rates were observed with administration of four or more treatments, but additional observations and/or studies are needed to optimize the regimen of laser therapy to improve the cosmetic appearance of infected nails.

Therapies for onychomycosis a systematic review and network meta-analysis of mycological cure.

New therapies for onychomycosis continue to be developed, yet treatments are seldom directly compared in randomized controlled trials. The objective of this study was to compare the rates of mycological cure for oral and topical onychomycosis treatments using network meta-analysis. A systematic review of the literature on onychomycosis treatments published before March 25, 2013, was performed, and data were analyzed using network meta-analysis. Terbinafine, 250 mg, therapy was significantly superior to all treatments except itraconazole, 400 mg, pulse therapy; itraconazole, 200 mg, therapy was significantly superior to fluconazole and the topical treatments; and fluconazole, efinaconazole, ciclopirox, terbinafine nail solution, and amorolfine treatments were significantly superior to only placebo. These results support the superiority of 12-week continuous terbinafine, 250 mg, therapy and itraconazole, 400 mg, pulse therapy (1 week per month for 3 months) while suggesting the equivalence of topical therapies. These results reflect findings from the literature and treatment efficacy observed in clinical practice.

A randomized, double-blind, placebo-controlled clinical trial evaluating Dermytol(®) cream for the treatment of actinic keratoses.

PURPOSE: Actinic keratosis lesions (AKs) have the potential to develop into squamous cell carcinoma (SCC) and thus therapies to prevent SCC development from AKs are warranted. The aim of this study was to assess the effects of a 3 month application of a canola phenolic acid-based cream (CPA) on AK lesions. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled, 12 week clinical study conducted at a single-center in Santo Domingo, Dominican Republic. Forty-five subjects (30 CPA and 15 placebo), aged 45-85 years with 3-10 AKs within a 20 cm(2) treatment area (scalp, forehead, dorsal forearm, neck, or back of hand) were enrolled. The primary outcome was complete or partial lesion clearance and the secondary outcome was safety of CPA. RESULTS: Although complete AK lesion clearance was not seen in this study, a significant reduction in the mean change from baseline in the average lesion area was observed at weeks 3 (P=0.002), 6 (P<0.001), and 12 (P<0.001) in the CPA group, but only at weeks 6 and 12 in the placebo group (P=0.005 and P=0.002, respectively). Furthermore, the proportion of participants with a $10% decrease in average lesion area was significantly higher in the CPA group than the placebo group at weeks 3 (P=0.05) and 6 (P=0.02), and showed a trend at week 12 (P=0.06). A subset analysis of the change in average lesion area based upon the total lesion area at baseline revealed that CPA elicited a greater reduction than placebo (2×) in participants with a baseline total AK lesion area of 100-500 mm(2) than in participants with a total area <100 mm(2) (1.3×). CONCLUSION: The results of this study and previous in vitro studies suggest a potential role for CPA in the treatment of AK lesions and the prevention of SCC development.

Placebo cure rates in the treatment of onychomycosis.

Placebo cure rates vary among randomized clinical trials for onychomycosis, but the factors influencing these cure rates have not been systematically investigated. The PubMed database and reference sections of relevant publications were searched for randomized controlled trials of dermatophyte toenail onychomycosis that included a placebo control and that assessed cure rates. From 21 studies, the pooled mean ± SD placebo cure rates regarding mycological, clinical, and complete cure were 8.7% ± 3.7%, 3.4% ± 2.2%, and 1.2% ± 1.4%, respectively. There was no statistically significant difference between oral and topical treatments. None of the cure rates significantly correlated with any of the participant or study design characteristics analyzed. Placebo cure rates in randomized controlled trials of toenail onychomycosis are relatively low and are independent of the study characteristics.

Efinaconazole 10% nail solution: a new topical treatment with broad antifungal activity for onychomycosis monotherapy.

BACKGROUND: Topical therapies for onychomycosis are associated with less adverse events than systemic therapies, but poor nail penetration limits their efficacy. Consequently, an efinaconazole 10% nail solution was developed. OBJECTIVE: To review the evidence supporting the usefulness of efinaconazole monotherapy in onychomycosis management. METHODS: PubMed and clinicaltrials.gov databases and abstracts from the 2013 annual meeting of the American Academy of Dermatology were searched in April 2013 using the terms "efinaconazole," "IDP-108," and "KP-103." RESULTS: In vitro, efinaconazole possesses a broad antifungal activity similar or superior to that of other antifungals. Its low affinity for keratin results in good nail penetration. Efinaconazole 10% nail solution administered daily for 36 or 48 weeks to treat mild to moderate toenail onychomycosis caused by dermatophytes results in complete and mycologic cure rates of 15 to 25% and 53 to 87%, respectively. No serious skin reaction is associated with its use. CONCLUSION: Efinaconazole 10% nail solution is a promising new treatment for onychomycosis.

Systematic review of systemic treatments for tinea versicolor and evidence-based dosing regimen recommendations.

BACKGROUND: Extensive or recurrent tinea versicolor (TV) can be treated with systemic antifungal therapies, but no dosing regimens have been approved for this indication. OBJECTIVE: To provide evidence-based recommendations for dosing regimens. METHODS: A systematic literature search was performed to identify trials reporting mycologic cure. All trials were included and assessed for quality. Correlation and statistical analyses were used to evaluate the effects of different dosing regimen parameters on efficacy. RESULTS: Fifty-seven trials investigating itraconazole, ketoconazole, fluconazole, and pramiconazole were included. Cumulative dose, treatment duration, and daily/weekly concentrations were shown to significantly influence mycologic cure rates for ketoconazole and pramiconazole but not for itraconazole and fluconazole. CONCLUSION: Based on the efficacy evidence and potential safety concerns, this review supports the following dosing regimens: 200 mg/d for 5 or 7 days of itraconazole, 300 mg/wk for 2 weeks of fluconazole, and 200 mg/d for 2 days of pramiconazole.

Therapies for the treatment of onychomycosis.

Onychomycosis treatments include nail avulsion and debridement by chemical or surgical procedures, topical and oral antifungals, and device-based therapies. The advantages, disadvantages, and limitations of the different types of treatments--including the most commonly prescribed topical (ciclopirox) and oral (terbinafine, itraconazole, and fluconazole) treatments for onychomycosis caused by dermatophytes, non-dermatophyte molds, and yeasts--are reviewed. Safety and efficacy data for the healthy adult population and for special populations such as children and diabetic patients have confirmed the importance of proper mycological diagnosis before the initiation of therapy as well as the evaluation of the risks and benefits of the different treatments.

Improved efficacy in onychomycosis therapy.

The success rate of onychomycosis treatment is limited by several factors, including the access of the therapeutic agent to the fungal mass, the presence of conidia, and the susceptibility of the different infectious agents to the antifungals. Different strategies used to improve efficacy of the currently available antifungal treatments, their rationale, and the published evidence of their beneficial effects are reviewed. An improved efficacy was demonstrated for some of these strategies, such as combined oral and topical antifungal therapies, whereas most of them lack clear and direct evidence of an increase in therapeutic success.

Ingenol mebutate: a promising treatment for actinic keratoses and nonmelanoma skin cancers.

BACKGROUND: A new treatment for actinic keratoses, ingenol mebutate, was recently approved by the US Food and Drug Administration. OBJECTIVE: To review the mechanisms of action, efficacy and safety data, and practical recommendations for ingenol mebutate. METHODS: The PubMed and clinicaltrials.gov databases were searched in March/April 2012 using the terms PEP005, ingenol mebutate, and ingenol 3-angelate. The abstracts from the Annual Scientific Meeting of the Australian College of Dermatologists (2009-2011) and the Annual Meeting of the American Academy of Dermatology (2009-2012) were also searched. RESULTS: Due to its multiple mechanisms of action, ingenol mebutate treatment resulted in short- and long-term efficacy similar to other topical treatments for actinic keratoses in a shorter period of 2 or 3 days. This short therapy would reduce the duration of adverse events. Premarketing trials for treatment of nonmelanoma skin cancers also showed promising results for ingenol mebutate. CONCLUSION: Ingenol mebutate is a convenient, safe, and effective intervention for precancerous and cancerous skin conditions.

Recurrences of dermatophyte toenail onychomycosis during long-term follow-up after successful treatments with mono- and combined therapy of terbinafine and itraconazole.

BACKGROUND: The influence of dosing regimens on the recurrence rates of onychomycosis has not been investigated. OBJECTIVE: To compare recurrence rates for toenail dermatophyte onychomycosis between four dosing regimens. METHODS: A prospective, investigator-blinded, long-term follow-up (1.25 to 7 years postenrolment) study of the following regimens was undertaken with or without booster therapy at week 36: overlapping continuous itraconazole and terbinafine (COMBO), continuous terbinafine (CTERB), intermittent terbinafine (TOT), and pulsed itraconazole (III). RESULTS: One hundred six mycologically and 43 completely cured participants at week 48 were included. Recurrence rates (RR) for mycologically and completely cured participants were respectively termed mycologic recurrence (MRR) and complete cure recurrence (CRR) rates. No statistically significant difference was detected between the four regimens for the two rates. However, lower MRRs were obtained for CTERB (32%) and TOT (36%) compared to III (59%) and COMBO (57%). When participants who received booster therapy were excluded from the analysis, the MRR was lower for CTERB (21%) compared to TOT (39%). CONCLUSIONS: Itraconazole therapy was associated with higher RRs than terbinafine therapy. Combined therapy did not reduce the RRs compared to monotherapies. A difference might exist between continuous and intermittent antifungal regimens, but additional randomized clinical trials are needed for confirmation.

Role of metabotropic glutamate receptor 5 signaling and homer in oxygen glucose deprivation-mediated astrocyte apoptosis.

BACKGROUND: Group I metabotropic glutamate receptors (mGluR) are coupled via Gαq/11 to the activation of phospholipase Cß, which hydrolyzes membrane phospholipids to form inositol 1,4,5 trisphosphate and diacylglycerol. In addition to functioning as neurotransmitter receptors to modulate synaptic activity, pathological mGluR5 signaling has been implicated in a number of disease processes including Fragile X, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and drug addiction. The expression of mGluR5 in astrocytes has been shown to be increased in several acute and chronic neurodegenerative conditions, but little is known about the functional relevance of mGluR5 up-regulation in astrocytes following injury. RESULTS: In the current study, we investigated primary mouse cortical astrocyte cell death in response to oxygen glucose deprivation (OGD) and found that OGD induced both necrotic and apoptotic cell death of astrocytes. OGD resulted in an increase in astrocytic mGluR5 protein expression, inositol phosphate formation and extracellular regulated kinase (ERK1/2) phosphorylation, but only inositol phosphate formation was blocked with the mGluR5 selective antagonist MPEP. Cortical astrocytes derived from mGluR5 knockout mice exhibited resistance to OGD-stimulated apoptosis, but a lack of mGluR5 expression did not confer protection against necrotic cell death. The antagonism of the inositol 1,4,5 trisphosphate receptor also reduced apoptotic cell death in wild-type astrocytes, but did not provide any additional protection to astrocytes derived from mGluR5 null mice. Moreover, the disruption of Homer protein interactions with mGluR5 also reduced astrocyte apoptosis. CONCLUSION: Taken together these observations indicated that mGluR5 up-regulation contributed selectively to the apoptosis of astrocytes via the activation of phospholipase C and the release of calcium from intracellular stores as well as via the association with Homer proteins.

Systemic antifungals to treat onychomycosis in children: a systematic review.

Because of the low prevalence of onychomycosis in children, little is known about the efficacy and safety of systemic antifungals in this population. PubMed and Embase databases and the references of related publications were searched in March 2012 for clinical trials (CTs), retrospective analyses (RAs), and case reports (CRs) on the use of systemic antifungals for onychomycosis in children (<18 years). Twenty-six studies (5 CTs, 3 RAs, and 18 CRs) were published between 1976 and 2011. Most of these studies reported the use of systemic terbinafine and itraconazole for the treatment of onychomycosis in children. Therapy with systemic antifungals alone in children ages 1 to 17 years resulted in a complete cure rate of 70.8% (n = 151), whereas combined systemic and topical antifungal therapy in one infant and 19 children age 8 and older resulted in a complete cure rate of 80.0% (n = 20). The efficacy and safety profiles of terbinafine, itraconazole, griseofulvin, and fluconazole in children were similar to those previously reported for adults. In conclusion, based on the little information available on onychomycosis in children, systemic antifungal therapies in children are safe and cure rates are similar to the rates achieved in adults.

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.

Interventions for actinic keratoses.

BACKGROUND: Actinic keratoses are a skin disease caused by long-term sun exposure, and their lesions have the potential to develop into squamous cell carcinoma. Treatments for actinic keratoses are sought for cosmetic reasons, for the relief of associated symptoms, or for the prevention of skin cancer development. Detectable lesions are often associated with alteration of the surrounding skin (field) where subclinical lesions might be present. The interventions available for the treatment of actinic keratoses include individual lesion-based (e.g. cryotherapy) or field-directed (e.g. topical) treatments. These might vary in terms of efficacy, safety, and cosmetic outcomes. OBJECTIVES: To assess the effects of topical, oral, mechanical, and chemical interventions for actinic keratosis. SEARCH METHODS: We searched the following databases up to March 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also searched trials registers, conference proceedings, and grey literature sources. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the treatment of actinic keratoses with either placebo, vehicle, or another active therapy. DATA COLLECTION AND ANALYSIS: At least two authors independently abstracted data, which included adverse events, and assessed the quality of evidence. We performed meta-analysis to calculate a weighted treatment effect across trials, and we expressed the results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes (e.g. participant complete clearance rates), and mean difference (MD) and 95% CI for continuous outcomes (e.g. mean reduction in lesion counts). MAIN RESULTS: We included 83 RCTs in this review, with a total of 10,036 participants. The RCTs covered 18 topical treatments, 1 oral treatment, 2 mechanical interventions, and 3 chemical interventions, including photodynamic therapy (PDT). Most of the studies lacked descriptions of some methodological details, such as the generation of the randomisation sequence or allocation concealment, and half of the studies had a high risk of reporting bias. Study comparison was difficult because of the multiple parameters used to report efficacy and safety outcomes, as well as statistical limitations. We found no data on the possible reduction of squamous cell carcinoma.The primary outcome 'participant complete clearance' significantly favoured four field-directed treatments compared to vehicle or placebo: 3% diclofenac in 2.5% hyaluronic acid (RR 2.46, 95% CI 1.66 to 3.66; 3 studies with 420 participants), 0.5% 5-fluorouracil (RR 8.86, 95% CI: 3.67 to 21.44; 3 studies with 522 participants), 5% imiquimod (RR 7.70, 95% CI 4.63 to 12.79; 9 studies with1871 participants), and 0.025% to 0.05% ingenol mebutate (RR 4.50, 95% CI 2.61 to 7.74; 2 studies with 456 participants).It also significantly favoured the treatment of individual lesions with photodynamic therapy (PDT) compared to placebo-PDT with the following photosensitisers: aminolevulinic acid (ALA) (blue light: RR 6.22, 95% CI 2.88 to 13.43; 1 study with 243 participants, aminolevulinic acid (ALA) (red light: RR 5.94, 95% CI 3.35 to 10.54; 3 studies with 422 participants), and methyl aminolevulinate (MAL) (red light: RR 4.46, 95% CI 3.17 to 6.28; 5 studies with 482 participants). ALA-PDT was also significantly favoured compared to cryotherapy (RR 1.31, 95% CI 1.05 to 1.64).The corresponding comparative risks in terms of number of participants completely cleared per 1000 were as follows: 313 with 3% diclofenac compared to 127 with 2.5% hyaluronic acid; 136 with 0.5% 5-fluorouracil compared to 15 with placebo; 371 with 5% imiquimod compared to 48 with placebo; 331 with ingenol mebutate compared to 73 with vehicle; 527 to 656 with ALA/MAL-PDT treatment compared to 89 to 147 for placebo-PDT; and 580 with ALA-PDT compared to 443 with cryotherapy.5% 5-fluorouracil efficacy was not compared to placebo, but it was comparable to 5% imiquimod (RR 1.85, 95% Cl 0.41 to 8.33).A significant number of participants withdrew because of adverse events with 144 participants affected out of 1000 taking 3% diclofenac in 2.5% hyaluronic acid, compared to 40 participants affected out of 1000 taking 2.5% hyaluronic acid alone, and 56 participants affected out of 1000 taking 5% imiquimod compared to 21 participants affected out of 1000 taking placebo.Based on investigator and participant evaluation, imiquimod treatment and photodynamic therapy resulted in better cosmetic outcomes than cryotherapy and 5-fluorouracil. AUTHORS' CONCLUSIONS: For individual lesions, photodynamic therapy appears more effective and has a better cosmetic outcome than cryotherapy. For field-directed treatments, diclofenac, 5-fluorouracil, imiquimod, and ingenol mebutate had similar efficacy, but their associated adverse events and cosmetic outcomes are different. More direct comparisons between these treatments are needed to determine the best therapeutic approach.

GLAST stability and activity are enhanced by interaction with the PDZ scaffold NHERF-2.

The astrocytic glutamate transporter GLAST (also known as EAAT1) is a key regulator of extracellular glutamate levels in many regions of vertebrate brains. To identify novel interacting partners that might regulate the localization and function of GLAST in astrocytes, we screened the transporter's C-terminus (GLAST-CT) against a proteomic array of 96 different PDZ domains. The GLAST-CT robustly and specifically interacted with PDZ domains from two related scaffolding proteins, the Na(+)/H(+) exchanger regulatory factors 1 and 2 (NHERF-1 and NHERF-2). Studies on cultured rat cortical astrocytes revealed that these cells are highly enriched in NHERF-2 relative to NHERF-1. Endogenous GLAST and NHERF-2 from cultured astrocytes were found to robustly co-immunoprecipitate, and further co-immunoprecipitation studies on mutant versions of GLAST expressed in transfected cells revealed the GLAST/NHERF-2 interaction to be dependent on the last amino acid of the GLAST-CT. Knockdown of endogenous NHERF-2 in astrocytes via siRNA treatment resulted in a significant reduction in GLAST activity, which corresponded to significantly reduced total expression of GLAST protein and reduced half-life of GLAST, as assessed in pulse-chase metabolic labeling studies. These findings reveal that NHERF-2 can interact with GLAST in astrocytes to enhance GLAST stability and activity.