Prenatal maternal cortisol, stress and anxiety, and childhood obesity at 5 years: a nested case-control study.

BACKGROUND: Paediatric obesity is a global public health issue. Prenatal maternal mental health is potentially implicated in the development of childhood obesity. This study examined associations between prenatal maternal cortisol, self-reported stress, anxiety and depression in the second trimester, and childhood overweight and obesity at 5 years of age. METHODS: A nested case-control study was conducted using data from the Irish prospective longitudinal birth cohort SCOPE BASELINE. Cases were children with overweight or obesity, operationalised as having a BMI z-score above +2 standard deviations. Controls were children with a BMI z-score between -0.5 and 0.5 standard deviations at 5 years of age. Two to one matching by sex was conducted. Thirty-eight cases and 83 sex-matched controls were included. Maternal serum cortisol concentration and self-reported stress, anxiety and depression were measured at 15 ± 1 and 20 ± 1 weeks gestation. Conditional logistic regression analyses were conducted to examine associations between prenatal maternal cortisol and self-reported stress, anxiety and depression, and childhood overweight and obesity. RESULTS: Despite some evidence for associations between anxiety and depression, and child BMI z-scores in univariate analyses, adjusted models indicated no associations between prenatal maternal stress (OR: 1.02, 95% CI: 0.94-1.12), anxiety (OR: 1.03, 95% CI: 0.97-1.09), depression (OR: 1.04, 95% CI: 0.91-1.19), or cortisol concentration (OR: 0.99, 95% CI: 0.99-1.00) and child BMI z-score. CONCLUSION: Our findings do not provide support for associations between foetal exposure during the second trimester of pregnancy and maternal cortisol, stress and anxiety, and childhood overweight or obesity at 5 years of age.

Improving alignment in total knee arthroplasty: a cadaveric assessment of a surgical navigation tool with computed tomography imaging.

PURPOSE: To investigate the accuracy of an imageless, optical surgical navigation tool to assist with femoral and tibial bone cuts performed during TKA. PATIENTS AND METHODS: Six board-certified orthopedic surgeons participated in a laboratory cadaver investigation, performing femoral and tibial bone cuts with the assistance of a computer navigation tool. Femoral and tibial varus/valgus, tibial slope, femoral flexion, and both femoral and tibial rotation measurements from the device were compared with angular measurements calculated from computed tomography (CT) images of the knees. RESULTS: Measurements with the navigation tool were highly correlated with those obtained from CT scans in all three axes. For the distal femoral cut, the absolute mean difference in varus/valgus was 0.83° (SD 0.46°, r = 0.76), femoral flexion was 1.91° (SD 1.16°, r = 0.85), and femoral rotation was 1.29° (SD 1.01°, r = 0.88) relative to Whiteside's line and 0.97° (SD 0.56°, r = 0.81) relative to the posterior condylar axis. For the tibia, the absolute mean difference in varus/valgus was 1.08° (SD 0.64°, r = 0.85), posterior slope was 2.78° (SD 1.40°, r = 0.60), and rotation relative to the anteroposterior axis (posterior cruciate ligament to the medial third of the tibial tuberosity) was 2.98° (SD 2.54°, r = 0.79). CONCLUSION: Utilization of an imageless navigation tool may aid surgeons in accurately performing and monitoring femoral and tibial bone cuts, and implant rotation in TKA and thus, more accurately align TKA components.

Radiographic measurement of leg-length change in the nonoperative leg during total hip arthroplasty: a potential indicator of imaging error?

BACKGROUND: Anteroposterior (AP) pelvic radiographs are subject to errors that may cause measurement inaccuracy in total hip arthroplasty (THA). Such errors may be detected by measuring pre- to postoperative leg-length changes in the nonoperative leg, which experiences no physical changes during THA. METHODS: From AP pelvic radiographs, we measured pre- to postoperative leg-length changes (LLC) in the nonoperative legs of 67 patients who underwent primary THA using the trans-ischial line method. RESULTS: An LLC of 0 mm was observed in the nonoperative leg in only 14 cases (21%). A LLC ⩾ 2 mm was observed in 27% (18/67) of cases, including 13% (9/67) with LLC ⩾ 3 mm and 6% (4/67) with LLC ⩾ 4 mm. A post-hoc analysis used a validated method to measure change in pelvic tilt between pre- and postoperative images and found that changes in pelvic tilt ⩾ 4° in the anterior and posterior directions created apparent lengthening (2.0 ± 1.4 mm, p < 0.001 vs. 0-3° of tilt) and shortening (-2.1 ± 1.6 mm, p < 0.001 vs. 0-3° of tilt) of the nonoperative leg, respectively. CONCLUSIONS: The current study provides evidence of measurement errors in leg length using AP pelvic radiographs following THA. Changes in pelvic tilt may be in part responsible for these errors, with the direction of change in pelvic tilt influencing the apparent lengthening or shortening of the lower limb. Ultimately, these findings may influence the radiographic measurement and interpretation of leg-length changes following THA.

Efficacy of non-surgical treatments for androgenetic alopecia in men and women: a systematic review with network meta-analyses, and an assessment of evidence quality.

BACKGROUND AND OBJECTIVE: Various treatments exist for androgenetic alopecia (AGA); we determined the relative efficacies of non-surgical AGA monotherapies separately for men and women. METHODS: Randomized controlled trials (RCTs) were systematically searched in PubMed, EMBASE, Scopus and clinicaltrials.gov. Separate networks were used for men and women; for each network, a Bayesian network meta-analysis (NMA) of mean change in hair count from baseline (in units of hairs per square centimeter) was performed using a random effects model. RESULTS: The networks for male and female AGA included 30 and 10 RCTs, respectively. We identified the following treatments for male AGA in decreasing rank of efficacy: platelet-rich plasma (PRP), low-level laser therapy (LLLT), 0.5 mg dutasteride, 1 mg finasteride, 5% minoxidil, 2% minoxidil, and bimatoprost. For female AGA the following were identified in decreasing rank of efficacy: LLLT, 5% minoxidil, and 2% minoxidil. The evidence quality of the highest ranked therapies, for male and female AGA, was judged to be low. CONCLUSIONS: While newer treatments like LLLT may be more efficacious than more traditional therapies like 5% minoxidil, the efficacy of the more recent treatment modalities needs to be further validated by future RCTs.

Validation of a Novel Software Measurement Tool for Total Hip Arthroplasty.

Background Preoperative planning and postoperative evaluation of component position in total hip arthroplasty (THA) utilize specialized software that must be able to provide measurements that are both accurate and precise. A new software program for use in THA has recently been developed. We sought to evaluate the accuracy of this new software in comparison with two current, widely used software programs. Methodology Postoperative anteroposterior (AP) pelvic radiographs from 135 THA patients were retrospectively reviewed. Reference values for acetabular anteversion, inclination, and leg length were established using validated software programs (TraumaCad® as the primary reference value [PRV] and OsiriX LiteTM as the secondary reference value [SRV]). Measurements from the new software program (Intellijoint VIEWTM) were compared with reference values using Student's t-test and chi-square test. Results For anteversion, mean values for the PRV (27.34° ± 7.27°) and the new software (27.29° ± 7.21°) were not significantly different (p = 0.49). The new software differed from the PRV by a mean of 0.05° ± 0.93°. Similar results were noted for inclination, where the new software differed from the PRV and SRV by -0.13° ± 0.65° and 0.25° ± 1.26°, respectively (mean values: PRV: 43.62° ± 6.02°; SRV: 43.99° ± 6.27°; new software: 43.74° ± 6.17°; p = 0.87), and for leg length, where the new software differed from the PRV and SRV by 0.05 mm ± 0.46 mm and 0.22 mm ± 0.52 mm, respectively (mean values: PRV: 10.61 mm ± 11.60 mm; SRV: 10.77 mm ± 11.70 mm; new software: 10.56 mm - ± 11.61 mm; p = 0.98). Measurements were highly correlated across multiple reviewers (intraclass correlation coefficient ≥0.987). Conclusions The new software measurement tool is accurate and precise for assessing the acetabular component position and leg length measurements following THA in AP pelvic radiographs compared to currently used image measurement software.

Examining the non-spatial pretraining effect on a water maze spatial learning task in rats treated with multiple intracerebroventricular (ICV) infusions of propionic acid: Contributions to a rodent model of ASD.

Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.

Continuous terbinafine and pulse itraconazole for the treatment of non-dermatophyte mold toenail onychomycosis.

INTRODUCTION: Although dermatophytes are considered the predominant causative organisms in onychomycosis, non-dermatophyte mold (NDM) infections may be more prevalent than originally thought and may be more difficult to treat. There are limited data of oral antifungal efficacy in treating NDM onychomycosis. METHOD: A retrospective chart review (2009-2016) was conducted in patients receiving continuous oral terbinafine or pulse itraconazole for toenail onychomycosis due to NDMs. Mycology results and percent nail affected were recorded with patient characteristics including demographics and concurrent diseases. Complete, clinical, and mycological cure were tabulated. RESULTS: Data from 176 patients were collected. Mycological and complete cure rates for terbinafine (69.8% and 17%) and itraconazole (67.5% and 22%) were not significantly different from each other. Regardless of oral treatment, age (p = .013), baseline severity (p = .016), and presence of atherosclerosis (p = .040) or hyperlipidemia (p = .033) decreased the likelihood of mycological cure, while age decreased the likelihood of complete cure (p = .001). CONCLUSION: Continuous terbinafine and pulse itraconazole were similar in efficacy for curing NDM onychomycosis. Age was the most consistent prognostic factor affecting likelihood of cure, with factors that may influence drug reaching the site of infection also decreasing likelihood of mycological cure.

Once Weekly Application of Urea 40% and Bifonazole 1% Leads to Earlier Nail Removal in Onychomycosis.

INTRODUCTION: Onychomycosis is a chronic nail fungal infection resulting in nail damage and a decreased quality of life. Chemical avulsion of the nail with urea and bifonazole -removes fungally infected debris, increasing antifungal treatment efficacy and penetration. Previous clinical ob-servations describe patients who applied their urea and -bifonazole ointment less frequently, achieving earlier nail removal. In this study, we analyzed the relationship between duration of urea and bifonazole application and time to nail avulsion. METHODS: χ2 tests, multiple regression analysis, and ANOVA were performed to analyze the similarities between treatment regimens (daily, every 3 days, or once a week), association of regimens or patient characteristics to nail removal, and compare time to nail removal between each regimen, respectively. RESULTS: Daily application of ointment and sealing resulted in an average length of time (±SD) to nail removal of 18.7 days (±6.8 days); once every 3 days resulted in nail removal at 12.7 days (±6.2 days) and once per week at 11 days (±4.46 days) (p < 0.001). Age was the only patient factor that affected duration to nail removal. CONCLUSION: Once weekly application of ointment with sealing for a 1-week duration is associated with a decrease in time to complete chemical avulsion of the nail by approximately 1 week.

Topical and device-based treatments for fungal infections of the toenails.

BACKGROUND: Onychomycosis refers to fungal infections of the nail apparatus that may cause pain, discomfort, and disfigurement. This is an update of a Cochrane Review published in 2007; a substantial amount of new research warrants a review exclusively on toenails. OBJECTIVES: To assess the clinical and mycological effects of topical drugs and device-based therapies for toenail onychomycosis. SEARCH METHODS: We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials. SELECTION CRITERIA: Randomised controlled trials of topical and device-based therapies for onychomycosis in participants with toenail onychomycosis, confirmed by positive cultures, direct microscopy, or histological nail examination. Eligible comparators were placebo, vehicle, no treatment, or an active topical or device-based treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were complete cure rate (normal-looking nail plus fungus elimination, determined with laboratory methods) and number of participants reporting treatment-related adverse events. MAIN RESULTS: We included 56 studies (12,501 participants, average age: 27 to 68 years), with mainly mild-to-moderate onychomycosis without matrix involvement (where reported). Participants had more than one toenail affected. Most studies lasted 48 to 52 weeks; 23% reported disease duration (variable). Thirty-five studies specifically examined dermatophyte-caused onychomycosis. Forty-three studies were carried out in outpatient settings. Most studies assessed topical treatments, 9% devices, and 11% both. We rated three studies at low risk of bias across all domains. The most common high-risk domain was performance bias. We present results for key comparisons, where treatment duration was 36 or 48 weeks, and clinical outcomes were measured at 40 to 52 weeks. Based on two studies (460 participants), compared with vehicle, ciclopirox 8% lacquer may be more effective in achieving complete cure (risk ratio (RR) 9.29, 95% confidence interval (CI) 1.72 to 50.14; low-quality evidence) and is probably more effective in achieving mycological cure (RR 3.15, 95% CI 1.93 to 5.12; moderate-quality evidence). Ciclopirox lacquer may lead to increased adverse events, commonly application reactions, rashes, and nail alteration (e.g. colour, shape). However, the 95% CI indicates that ciclopirox lacquer may actually make little or no difference (RR 1.61, 95% CI 0.89 to 2.92; low-quality evidence). Efinaconazole 10% solution is more effective than vehicle in achieving complete cure (RR 3.54, 95% CI 2.24 to 5.60; 3 studies, 1716 participants) and clinical cure (RR 3.07, 95% CI 2.08 to 4.53; 2 studies, 1655 participants) (both high-quality evidence) and is probably more effective in achieving mycological cure (RR 2.31, 95% CI 1.08 to 4.94; 3 studies, 1716 participants; moderate-quality evidence). Risk of adverse events (such as dermatitis and vesicles) was slightly higher with efinaconazole (RR 1.10, 95% CI 1.01 to 1.20; 3 studies, 1701 participants; high-quality evidence). No other key comparison measured clinical cure. Based on two studies, compared with vehicle, tavaborole 5% solution is probably more effective in achieving complete cure (RR 7.40, 95% CI 2.71 to 20.24; 1198 participants), but probably has a higher risk of adverse events (application site reactions were most commonly reported) (RR 3.82, 95% CI 1.65 to 8.85; 1186 participants (both moderate-quality evidence)). Tavaborole improves mycological cure (RR 3.40, 95% CI 2.34 to 4.93; 1198 participants; high-quality evidence). Moderate-quality evidence from two studies (490 participants) indicates that P-3051 (ciclopirox 8% hydrolacquer) is probably more effective than the comparators ciclopirox 8% lacquer or amorolfine 5% in achieving complete cure (RR 2.43, 95% CI 1.32 to 4.48), but there is probably little or no difference between the treatments in achieving mycological cure (RR 1.08, 95% CI 0.85 to 1.37). We found no difference in the risk of adverse events (RR 0.60, 95% CI 0.19 to 1.92; 2 studies, 487 participants; low-quality evidence). The most common events were erythema, rash, and burning. Three studies (112 participants) compared 1064-nm Nd:YAG laser to no treatment or sham treatment. We are uncertain if there is a difference in adverse events (very low-quality evidence) (two studies; 85 participants). There may be little or no difference in mycological cure at 52 weeks (RR 1.04, 95% CI 0.59 to 1.85; 2 studies, 85 participants; low-quality evidence). Complete cure was not measured. One study (293 participants) compared luliconazole 5% solution to vehicle. We are uncertain whether luliconazole leads to higher rates of complete cure (very low-quality evidence). Low-quality evidence indicates there may be little or no difference in adverse events (RR 1.02, 95% CI 0.90 to 1.16) and there may be increased mycological cure with luliconazole; however, the 95% CI indicates that luliconazole may make little or no difference to mycological cure (RR 1.39, 95% CI 0.98 to 1.97). Commonly-reported adverse events were dry skin, paronychia, eczema, and hyperkeratosis, which improved or resolved post-treatment. AUTHORS' CONCLUSIONS: Assessing complete cure, high-quality evidence supports the effectiveness of efinaconazole, moderate-quality evidence supports P-3051 (ciclopirox 8% hydrolacquer) and tavaborole, and low-quality evidence supports ciclopirox 8% lacquer. We are uncertain whether luliconazole 5% solution leads to complete cure (very low-quality evidence); this outcome was not measured by the 1064-nm Nd:YAG laser comparison. Although evidence supports topical treatments, complete cure rates with topical treatments are relatively low. We are uncertain if 1064-nm Nd:YAG laser increases adverse events compared with no treatment or sham treatment (very low-quality evidence). Low-quality evidence indicates that there is no difference in adverse events between P-3051 (ciclopirox hydrolacquer), luliconazole 5% solution, and their comparators. Ciclopirox 8% lacquer may increase adverse events (low-quality evidence). High- to moderate-quality evidence suggests increased adverse events with efinaconazole 10% solution or tavaborole 5% solution. We downgraded evidence for heterogeneity, lack of blinding, and small sample sizes. There is uncertainty about the effectiveness of device-based treatments, which were under-represented; 80% of studies assessed topical treatments, but we were unable to evaluate all of the currently relevant topical treatments. Future studies of topical and device-based therapies should be blinded, with patient-centred outcomes and an adequate sample size. They should specify the causative organism and directly compare treatments.

Propionic acid induced behavioural effects of relevance to autism spectrum disorder evaluated in the hole board test with rats.

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by abnormal social interactions, impaired language, and stereotypic and repetitive behaviours. Among genetically susceptible subpopulations, gut and dietary influences may play a role in etiology. Propionic acid (PPA), produced by enteric gut bacteria, crosses both the gut-blood and the blood-brain barrier. Previous research has demonstrated that repeated intracerebroventricular (ICV) infusions of PPA in adult rats produce behavioural and neuropathological changes similar to those seen in ASD patients, including hyperactivity, stereotypy, and repetitive movements. The current study examined dose and time related changes of exploratory and repetitive behaviours with the use of the hole-board task. Adult male Long-Evans rats received ICV infusions twice a day, 4 h apart, of either buffered PPA (low dose 0.052 M or high dose 0.26 M, pH 7.5, 4 µL/infusion) or phosphate buffered saline (PBS, 0.1 M) for 7 consecutive days. Locomotor activity and hole-poke behaviour were recorded daily in an automated open field apparatus (Versamax), equipped with 16 open wells, for 30 min immediately after the second infusion. In a dose dependent manner PPA infused rats displayed significantly more locomotor activity, stereotypic behaviour and nose-pokes than PBS infused rats. Low-dose PPA animals showed locomotor activity levels similar to those of PBS animals at the start of the infusion schedule, but gradually increased to levels comparable to those of high-dose PPA animals by the end of the infusion schedule, demonstrating a dose and time dependent effect of the PPA treatments.

Monotherapy for Alopecia Areata: A Systematic Review and Network Meta-Analysis.

BACKGROUND: There are many treatments available for alopecia areata; however, none are approved by the US Food and Drug Administration. Thus, there is clinician benefit in efficacy comparison. METHODS: A network meta-analysis was used to create direct and indirect comparisons of alopecia areata studies in addition to an inconsistency analysis, risk of bias, and quality of evidence assessment. RESULTS: For mild disease, intralesional corticosteroids were ranked the most likely to produce a response at 78.9% according to SUCRA (surface under the cumulative ranking curve) followed by topical corticosteroids (67.9%), prostaglandin analogs (67.1%), diphenylcyclopropenone (DPCP, 63.4%), topical minoxidil (61.2%), and squaric acid dibutylester (SADBE, 35.0%). In contrast, for moderate to severe disease (>50% scalp hair loss), DPCP was the top-ranked treatment (87.9%), followed by laser (77.9%), topical minoxidil (55.5%), topical corticosteroids (50.1%), SADBE (49.7%), and topical tofacitinib (47.6%). There were insufficient eligible trials to include oral tofacitinib in the network. CONCLUSION: Statistically significant evidence is presented for the use of intralesional and topical corticosteroids for treatment of mild disease and DPCP, laser, SADBE, topical minoxidil and topical corticosteroids for moderate to severe disease. Further controlled trials are required to analyze the relative efficacy of oral tofacitinib.

Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies.

BACKGROUND: Immune checkpoint inhibitors are not effective for pancreatic ductal adenocarcinoma (PDAC) as single agents. Vaccine therapy may sensitize PDACs to checkpoint inhibitor treatments. Annexin A2 (ANXA2) is a pro-metastasis protein, previously identified as a relevant PDAC antigen that is expressed by a GM-CSF-secreting allogenic whole pancreatic tumor cell vaccine (GVAX) to induce an anti-ANXA2 antibody response in patients with PDAC. We hypothesized that an ANXA2-targeting vaccine approach not only provokes an immune response but also mounts anti-tumor effects. METHODS: We developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC. RESULTS: We show that Lm-ANXA2 prolonged the survival in a transplant model of mouse PDACs. More importantly, priming with the Lm-ANXA2 treatment prior to administration of anti-PD-1 antibodies increased cure rates in the implanted PDAC model and resulted in objective tumor responses and prolonged survival in the genetically engineered spontaneous PDAC model. In tumors treated with Lm-ANXA2 followed by anti-PD-1 antibody, the T cells specific to ANXA2 had significantly increased INFγ expression. CONCLUSIONS: For the first time, a listeria vaccine-based immunotherapy was shown to be able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a "cold" tumor such as PDAC and sensitize the tumor to checkpoint inhibitor therapy. Moreover, this combination immunotherapy led to objective tumor responses and survival benefit in the mice with spontaneously developed PDAC tumors. Therefore, our study supports developing Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.

Impaired Spatial Cognition in Adult Rats Treated with Multiple Intracerebroventricular (ICV) Infusions of the Enteric Bacterial Metabolite, Propionic Acid, and Return to Baseline After 1 Week of No Treatment: Contribution to a Rodent Model of ASD.

Propionic acid (PPA) is a dietary short chain fatty acid and an enteric bacterial metabolite. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes similar to those seen in autism spectrum disorders (ASD), including perseveration. The effects of ICV infusions of PPA on spatial cognition were examined by giving rats infusions of either PPA (0.26 M, pH 7.4, 4 µl/infusion) or phosphate-buffered saline (PBS, 0.1 M) twice a day for 7 days. The rats were then tested in the Morris water maze (MWM) for acquisition of spatial learning. After a recovery period of 1 week of no treatment, the rats were then tested for reversal of spatial learning in the MWM. PPA-treated rats showed impaired spatial learning in the maze, relative to controls, as demonstrated by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. After a recovery period of 1 week of no treatment, these animals exhibited normal spatial reversal learning indicating that the behavioral cognitive deficits caused by PPA seem to be reversible.

Systemic treatment with the enteric bacterial metabolic product propionic acid results in reduction of social behavior in juvenile rats: Contribution to a rodent model of autism spectrum disorder.

The role of the gut microbiome and its enteric metabolites, such as short-chain fatty acids (SCFAs), in the etiology of autism spectrum disorders (ASDs) has recently received increased attention. Of particular interest has been the SCFA, propionic acid (PPA). Several different rodent models have been developed using PPA treatment to examine behaviors of relevance to ASD. The effects of systemic (intraperitoneal, i.p.) administration of PPA on social behavior, anxiety-related behavior, and locomotor activity in juvenile male rats (age 35 days) were examined in this study. Rats received seven i.p. injections of buffered PPA (500 mg/kg) or phosphate-buffered saline. Behavior was video-recorded during social interaction in a large open field (first four injections) or assessed in an automated activity system (individual animals, last three injections). PPA treatment significantly reduced social interaction, increased anxiety-related behavior, and produced hypoactivity and increased abnormal motor movements. These findings suggest that PPA alters behaviors of relevance to ASD in juvenile rats. These results contribute to the behavioral validity of the rodent model of ASD with systemic PPA treatment.

Evidence for biofilms in onychomycosis.

Onychomycosis is a difficult to treat fungal infection of the nails. The chronic nature of onychomycosis contributes to high recurrence rates and the difficulty in treating both dermatophyte and non-dermatophyte infections. It has been hypothesized that the formation of biofilms, sessile, multicellular communities of fungi surrounded by a protective extracellular matrix, allow for fungi to evade current antifungal therapies and contribute to observed antifungal resistance. This review presents the experimental evidence that has accumulated in recent years implicating biofilms in the pathogenesis of onychomycosis. Dermatophytes, non-dermatophyte molds, and yeasts form biofilms in vitro and a model using ex vivo healthy nail fragments has demonstrated biofilm formation on nails for dermatophyte, Candida, and Fusarium species. Implications for disease management are discussed with further research required to incorporate biofilm formation into future drug/device evaluation and treatment protocols.

In vitro efficacy of tavaborole topical solution, 5% after penetration through nail polish on ex vivo human fingernails.

BACKGROUND: Topical antifungal treatments for onychomycosis are applied to clean, unpolished nails for 48 weeks or longer. Patients often wish to mask their infection with nail polish yet there is no evidence to suggest antifungal efficacy in the presence of nail polish. OBJECTIVE: To determine if tavaborole retains the ability to penetrate the nail plate and inhibit fungal growth in the presence of nail polish. METHOD: Tavaborole was applied to human fingernails painted with 2 or 4 coats of nail polish, and unpainted nails in an ex vivo model. Nails were mounted on TurChub® chambers seeded with Trichophyton rubrum and allowed to incubate for 7 days. Antifungal activity was assessed by measuring zones of inhibition. RESULTS AND CONCLUSION: Tavaborole exhibited antifungal activity in all experimental groups. The zones of inhibition of T. rubrum for all experimental groups (2 or 4 coats of polish, unpolished) were greater than infected controls (polished and unpolished), ps < .001. Tavaborole penetrates polished nails and kills T. rubrum in this ex vivo model.

Topical antifungal treatment prevents recurrence of toenail onychomycosis following cure.

Recurrence rates are high for onychomycosis, with prophylactic topical antifungal use proposed to counter recurrence. Although this is a reasonable action for many clinicians, few studies have been conducted on the efficacy of topical prophylaxis. A retrospective chart review (2010-2015) was conducted in patients receiving oral terbinafine or itraconazole for toenail onychomycosis. Following complete cure, a topical antifungal (amorolfine, bifonazole, ciclopirox olamine, or terbinafine spray) was used weekly as prophylaxis. Recurrence was recorded along with patient characteristics including demographics and concomitant medical conditions. Data from 320 patients were collected. Recurrence was significantly lower in patients receiving topical antifungal prophylaxis than in no prophylactic treatment following oral terbinafine (p < .001), but not itraconazole (p = .185). Regardless of oral treatment, the use of topical antifungals as prophylaxis (p < .001) decreased, and the number of affected toenails (p = .048) and family history of fungal infections (p < .001) increased the likelihood that recurrence would occur. This study supports the use of topical antifungal medications as prophylactic treatment to help prevent recurrence of toenail onychomycosis and suggests that those with a family history of fungal infections should be closely monitored.

Hedgehog signaling stimulates Tenascin C to promote invasion of pancreatic ductal adenocarcinoma cells through Annexin A2.

Pancreatic adenocarcinoma (PDA) is characterized by a dense desmoplastic reaction that comprises 60-90% of the tumor, while only 10-40% of the tumor is composed of malignant epithelial cells. This desmoplastic reaction is composed of stromal fibroblast cells, extracellular matrix proteins, and immune cells. Accumulating evidence has suggested that the stromal and epithelial cell compartments interact during the pathogenesis of this disease. Therefore, it is important to identify the signaling pathways responsible for this interaction to better understand the mechanisms by which PDA invades and metastasizes. Here, we show that secreted stromal factors induce invasion of PDA cells. Specifically, hedgehog signaling from the tumor cells induces tenascin C (TnC) secretion from the stromal cells that acts back upon the tumor cells in a paracrine fashion to induce the invasion of PDA cells through its' receptor annexin A2 (AnxA2). Therefore, blocking the interaction between TnC and AnxA2 has the potential to prevent liver metastasis in PDA.

Stromal Annexin A2 expression is predictive of decreased survival in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is renowned for high rates of metastasis and poor survival. Its notoriously dense fibrotic stroma contributes to chemoresistance. Stromal signaling in PDA is recognized for its multiple roles in regulating tumor invasion and metastasis. However, no stromal biomarker which can predict survival in PDA exists. Annexin A2 (AnxA2) was formerly identified as a metastasis-associated protein in PDA and tumoral overexpression is associated with poor survival. In this study, we examined AnxA2 expression in the tumor microenvironment in a preclinical model of PDA which suggests its role in tumor colonization. We injected wild-type (KPC) and AnxA2 knockout (KPCA) pancreatic cells into C57BL/GJ (B6) and AnxA2 knockout (KO) mice using the hemi-spleen model and observed their survival. We performed quantitative immunohistochemistry examining stromal AnxA2 expression in 56 patients who had surgically resected PDA and correlated expression with clinical outcomes. B6 mice injected with KPC cells demonstrated decreased median survival compared to those injected with KPCA cells (90 days vs. not reached, p < 0.0001) whereas there was no survival difference in the AnxA2 KO mice (p = 0.63). In patient specimens, we found that high stromal AnxA2 expression (≥80th percentile) was associated with significantly reduced disease-free survival (p = 0.002) and overall survival (p < 0.001). Using multivariate Cox models, there were no significant associations between other clinical covariates apart from high stromal AnxA2 expression. This study highlights the role that stromal AnxA2 expression plays as a prognostic marker in PDA and its potential as a predictive biomarker for survival outcomes in PDA.