Flukicidal effects of abietane diterpenoid derived analogues against the food borne pathogen Fasciola hepatica.

Control of liver fluke infections remains a significant challenge in the livestock sector due to widespread distribution of drug resistant parasite populations. In particular, increasing prevalence and economic losses due to infection with Fasciola hepatica is a direct result of drug resistance to the gold standard flukicide, triclabendazole. Sustainable control of this significant zoonotic pathogen, therefore, urgently requires the identification of new anthelmintics. Plants represent a source of molecules with potential flukicidal effects and, amongst their secondary metabolites, the diterpenoid abietic acids can be isolated in large quantities. In this study, nineteen (19) chemically modified abietic acid analogues (MC_X) were first evaluated for their anthelmintic activities against F. hepatica newly excysted juveniles (NEJs, from the laboratory-derived Italian strain); from this, 6 analogues were secondly evaluated for their anthelmintic activities against adult wild strain flukes. One analogue, MC010, was progressed further against 8-week immature- and 12-week mature Italian strain flukes. Here, MC010 demonstrated moderate activity against both of these intra-mammalian fluke stages (with an adult fluke EC50 = 12.97 µM at 72 h post culture). Overt mammalian cell toxicity of MC010 was inferred from the Madin-Darby bovine kidney (MDBK) cell line (CC50 = 17.52 µM at 24 h post culture) and demonstrated that medicinal chemistry improvements are necessary before abietic acid analogues could be considered as potential anthelmintics against liver fluke pathogens.

Altered Decorin Biology in Proliferative Vitreoretinopathy: A Mechanistic and Cohort Study.

Purpose: To determine if vitreous levels of the pro-fibrotic cytokine transforming growth factor beta2 (TGF-ß2) and its opposing regulator decorin predict subsequent proliferative vitreoretinopathy (PVR) development in patients with rhegmatogenous retinal detachment (RRD). Methods: We examined the effect of TGF-ß2 and decorin on epithelial-mesenchymal transition (EMT) and collagen expression in vitro using ARPE-19 cells, and we analyzed extracellular matrix marker expression in PVR membrane and internal limiting membrane patient samples. We performed a prospective noninterventional cohort study, recruiting 125 patients undergoing vitrectomy for RRD and macular hole surgery, measured vitreous levels of TGF-ß2 and decorin by ELISA, and followed them up for 6 months. Patients who did not develop PVR were compared to those who did, in order to determine whether vitreous TGF-ß2 and decorin levels predicted PVR development. Results: In vitro, TGF-ß2 induced EMT and collagen production. Decorin strongly inhibited EMT and collagen production at high levels. PVR membranes expressed high levels of fibrosis-associated proteins, consistent with EMT. Vitreous TGF-ß2 levels were unchanged between patients with macular holes and RRD who did or did not subsequently develop PVR. Average decorin levels were higher in the vitreous of RRD patients who subsequently developed PVR compared to those who did not, but at the measured vitreous concentrations (1-2 µg/mL), decorin did not demonstrate an in vitro inhibitory effect on EMT. Conclusions: In vitro, high concentrations of decorin inhibited EMT and fibrosis. At the levels seen in human vitreous, decorin did not prevent fibrosis or EMT in vitro, and higher initial vitreous decorin levels were associated with the development of postoperative PVR after vitrectomy to treat RRD, but did not reliably predict the outcome.

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms.

PURPOSE: To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801. METHODS: Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a+ RGC survival, GFAP+ reactive gliosis, and GAP43+ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. RESULTS: Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43+ axon regeneration at 400 to 1200 µm beyond the ONC site, and potentiated the reactive GFAP+ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP+ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity. CONCLUSIONS: The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

Peptide aptamers: Novel coatings for orthopaedic implants.

Current processes for coating titanium implants with ceramics involve very high energy techniques with associated high cost and disadvantages such as heterogeneity of the coatings, phase transformations and inability to coat complex structures. In order to address the above problems, we propose a biomimetic hydroxyapatite coating process with the use of peptides that can bind both on titanium surfaces and hydroxyapatite. The peptides enabled homogeneous coating of a titanium surface with hydroxyapatite. The hydroxyapatite-peptide sandwich coating showed no adverse effects on cell number or collagen deposition. This makes the sandwich coated titanium a good candidate for titanium implants used in orthopaedics and dentistry.

Comparing demographic characteristics and adverse event rates at two dermatologic surgery practices.

BACKGROUND: Patient demographics and operative techniques may contribute to adverse events after surgeries. OBJECTIVE: To identify differences in adverse event rates between different dermatologic surgery centers and potential contributing features affecting these rates. METHODS: Data regarding demographics, procedure type, and adverse events were collected at two dermatologic surgery centers. RESULTS: The most common adverse event at both sites was infection: 2.1% at site 1 versus 0.5% at site 2 (p < .001). Using multivariate logistic regression, procedure type (Mohs surgery), geographic location (being at site 1), older age, and anatomic location of surgery were associated with a higher risk of infection. CONCLUSION: Adverse event rate appears to correlate with patient demographics, procedure type, and setting of surgery more than use of prophylactic antibiotics. Identification of differences in adverse event rates and potential contributing variables at different practices may allow for identification of opportunities to prevent adverse events.

Subcutaneous sarcoidosis without systemic involvement.

Subcutaneous sarcoidosis is a rare variant of cutaneous sarcoidosis, which typically presents as single or multiple, indurated, ill-defined plaques, typically on the upper extremities. Granulomas consisting of macrophages with multinucleated giant cells and sparse lymphocytic inflammation are confined to the subcutaneous tissue, rather than to their usual location within the dermis in typical lesions of cutaneous sarcoidosis. An association between subcutaneous sarcoidosis and systemic involvement has been reported, although response to treatment and prognosis remain good. We report a case of a middle-aged woman with subcutaneous sarcoidosis, with negative work-up for systemic involvement of sarcoidosis. Interestingly, family history was significant for a son who died from complications of pulmonary sarcoidosis. The patient was successfully treated with a tapering course of oral prednisone in combination with hydroxychloroquine.

Are topical keratolytic agents needed in the treatment of scalp psoriasis?

BACKGROUND: Topical corticosteroids are the primary treatment for scalp psoriasis. Keratolytic agents are promoted as adjunctive treatments. However, complex treatment regimens may result in poor adherence and outcomes. OBJECTIVE: To evaluate the evidence for the need for use of topical keratolytic agents as opposed to topical corticosteroid monotherapy in the treatment of scalp psoriasis. METHODS: A review of the literature was performed seeking clinical trials using topical keratolytics, topical corticosteroids or the combination for treatment of scalp psoriasis. RESULTS: Complete clearance of scalp psoriasis can be achieved in 10-78% of patients using topical corticosteroids alone, in 3% of patients using topical keratolytics alone, and in up to 84% using a combination of topical keratolytics and topical steroids. Clinical trials comparing the combination of keratolytics and topical corticosteroids versus topical corticosteroids alone found marginally more efficacy using combination regimens. LIMITATIONS: We could not find any long term study evaluating the efficacy of combination therapy in scalp psoriasis and its effect on the patients' adherence. CONCLUSION: High potency topical corticosteroids are usually effective in treating scalp psoriasis in clinical trials. Poor efficacy in clinical practice may be owing to poor adherence to the treatment regimen. Using a keratolytic agent in conjunction with a topical corticosteroid may provide marginal additional benefit in clinical trials, but that benefit is likely outweighed by the downside of complicating treatment and reducing adherence in the clinical setting, unless a single product containing both medications were used.

Measure of atopic dermatitis disease severity using actigraphy.

BACKGROUND: Analyzing adherence to treatment and outcomes in atopic dermatitis is limited by methods to assess continual disease severity. Atopic dermatitis significantly impacts sleep quality, and monitoring sleep through actigraphy may capture disease burden. PURPOSE: To assess if actigraphy monitors provide continuous measures of atopic dermatitis disease severity and to preliminarily evaluate the impact of a short-course, high-potency topical corticosteroid regimen on sleep quality. METHODS: Ten patients with mild to moderate atopic dermatitis applied topical fluocinonide 0.1% cream twice daily for 5 days. Sleep data were captured over 14 days using wrist actigraphy monitors. Investigator Global Assessment (IGA) and secondary measures of disease severity were recorded. Changes in quantity of in-bed time sleep were estimated with random effects models. RESULTS: The mean daily in-bed time, total sleep time, and wake after sleep onset (WASO) were 543.7 minutes (SEM 9.4), 466.0 minutes (SEM 7.7), and 75.0 minutes (SEM 3.4), respectively. WASO, a marker of disrupted sleep, correlated with baseline (ρ  =  .75) and end of treatment IGA (ρ  =  .70). Most patients did not have marked changes in sleep. IGA scores declined by a median change of 1 point at days 7 (p  =  .02) and 14 (p  =  .008). CONCLUSIONS: Using actigraphy, atopic dermatitis disease severity positively correlated with sleep disturbances. Actigraphy monitors were well tolerated by this cohort of atopic dermatitis subjects.

Voice use in professional soccer management.

Vocal load related to heavy voice use in particular professions increases the risk of occupational voice disorders. Research on professional voice use has primarily focused on educators, singers, and call-centre advisors. This paper describes the daily experiences of professional soccer managers' occupational voice use through qualitative methods. Four global themes were identified: 1) voice uses, 2) factors affecting voice change, 3) impact of voice use, and 4) the importance of voice in soccer management. All describe the nature of soccer managers' vocal demands. Risk factors for voice disorders include intense and prolonged voice use in environments with adverse acoustic properties for speakers and poor phonation methods. Research on vocal behaviours and early prevention programmes for this population group is warranted.

Recruiting underserved mothers to medical research: findings from North Carolina.

Representative samples are required for ethical, valid, and useful health research. Yet, recruiting participants, especially from historically underserved communities, can be challenging. This paper presents findings from in-depth interviews with 40 mothers about factors that might influence their willingness to participate or allow their children to participate in medical research. Saliency analysis organizes the findings. Frequent and important salient themes about research participation included concerns that it might cause participants harm, hope that participants might gain a health benefit, and recognition that time and transportation resources could limit participation. Ultimately, we propose that a theoretical model, such as the Theory of Planned Behavior (TPB), will facilitate more systematic evaluation of effective methods for recruitment and retention of participants in medical research. Future research should explore the utility of such a model for development of effective recruitment and retention strategies.

Adherence to a five day treatment course of topical fluocinonide 0.1% cream in atopic dermatitis.

BACKGROUND: Adherence in the treatment of chronic inflammatory skin diseases such as atopic dermatitis is poor. Methods to improve adherence have proven difficult. PURPOSE: To determine whether a short course of treatment with a high-potency corticosteroid will improve adherence compared to longer treatment studies and if improvement in disease and itch continues after treatment. METHODS: 10 patients with mild to moderate atopic dermatitis were instructed to apply fluocinonide 0.1% cream twice daily for 5 days. Adherence was self-reported and electronically monitored. Treatment outcomes were assessed in terms of Visual Analog Scale of Itch (VAS), Eczema Area and Severity Index (EASI), and Investigator Global Assessment (IGA) scores. RESULTS: The median adherence rate was 40% (range of 0-100). The median percent change in VAS from baseline measures on days 7 and 14 were 90% (range -13, 100, p=0.02) and 52% (range 0, 100, p=0.004). On days 7 and 14, 20% and 70% patients achieved an EASI-75 and 40% and 60% an IGA of 0 or 1. LIMITATIONS: Small sample size limited subgroup analyses. CONCLUSIONS: Adherence rates with short-term treatment were similar to previously reported rates in longer term treatment studies. However, even non-adherent patients had significant improvement in itch and disease severity.

Adherence to adalimumab in patients with moderate to severe psoriasis.

Background The chronic and relapsing course of psoriasis is often associated with poor adherence to treatment. Adherence to topical treatment is abysmal. Adherence to systemic treatments also decreases over time, with an overall adherence rate of 67% for injectable biologic medications. Whereas overall trends in poor adherence have been documented, the fine details of adherence in individual patients is not well characterized. Purpose To assess adherence to adalimumab in patients with moderate to severe psoriasis. Methods Data on adherence were obtained from a 1-year open label trial including seven patients with moderate to severe psoriasis who agreed to participate in a randomized trial of standard physician education materials plus extended nurse education versus standard physician education materials alone. Adherence to treatment was recorded with electronic monitoring via Medication Event Monitoring System (MEMS) caps undisclosed to the patients. Patients were also instructed to note the time and date they used treatment in a journal. Results The subjects exhibited a broad range of adherence behaviors. Conclusions Adherence to adalimumab therapy for moderate-to-severe psoriasis is variable and can be very poor. The clinical impact of poor adherence to injectable biologic medications is not yet well characterized.

Quantifying and characterizing adverse events in dermatologic surgery.

BACKGROUND: Although office-based dermatologic procedures are generally considered safe, there is a lack of prospective data on the rate of adverse events (AEs) associated with these procedures. OBJECTIVE: To determine the frequency of AEs after dermatologic surgery and to characterize the most commonly encountered AEs. METHODS: A web-based interface was designed to track AEs with the input of four dermatologic surgeons. Patient demographic and operative data were collected at the time of the dermatologic surgery procedure. AEs occurring at any time during the data collection period were logged according to an a priori categorization scheme. RESULTS: The AE rate was 2.0% in this series of 2,418 subjects undergoing dermatologic surgery from February 1 through December 14, 2010. The most commonly reported AEs were suspicion of infection (64%), postoperative hemorrhage (20%), and wound dehiscence (8%). Suspicion of infection was slightly less frequent in subjects who received prophylactic preoperative antibiotics (0.4%) than in those who did not (1.5%, p = .07). There were no serious AEs and no deaths. CONCLUSION: AEs are uncommon after office-based dermatologic surgery procedures. Preoperative antibiotics may further decrease the infection rate after dermatologic surgery, but the risks and benefits must be weighed given the already low AE rate.

Sleep disturbances in psoriasis.

BACKGROUND: Psoriasis negatively impacts sleep, but the factors that cause this sleep disturbance are not well characterized. PURPOSE: To assess sleep quality in subjects with psoriasis. METHODS: 35 outpatients diagnosed with chronic plaque psoriasis affecting at least 10 percent BSA and 44 controls completed the Pittsburgh Sleep Quality Index, Patient Health Questionnaire, Itch Severity Scale, Insomnia Severity Index, and Epworth Sleepiness Scale. For multiple testing, alpha was set at 0.008. RESULTS: Adjusting for age, BMI, and gender, patients with psoriasis had 4.3 times the odds to score in a higher insomnia category (OR 95% CI: 1.7, 11.2; p=0.01), a trend toward experiencing "poor sleep" (p=0.04), and no difference in odds to be "sleepy" (p=0.83). Patients with psoriasis had greater itch than those without psoriasis (mean ISS 8.5 vs. 2.0; p<0.0001). When adjusting for age, BMI, gender, and depression, those with psoriasis were not more likely to experience poor sleep quality (p=0.25), nor to score in a higher insomnia category (p=0.20) or be more "sleepy" (p=0.53). CONCLUSIONS: Patients with psoriasis suffer from sleep disturbances and pruritus more than those without psoriasis. Although sleep disturbances are more prevalent, this may be secondary to depression rather than related to a direct effect of psoriasis.

Cardiac manifestations of cutaneous disorders.

A number of cutaneous disorders encountered by the dermatologist have overlapping cardiac pathology. In recent years, many genetic linkages common to pathological processes in the cutaneous and cardiovascular systems have been identified. This review will describe primary cutaneous disorders with potential cardiac manifestations, including congenital syndromes, inherited cutaneous disorders associated with later cardiovascular disease, and syndromes associated with early cardiovascular pathology. The dermatologist may be the first to diagnose cutaneous findings associated with underlying cardiovascular disease; therefore, it is of prime importance for the dermatologist to be aware of these associations and to direct the appropriate workup.

Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010.

BACKGROUND: Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs. OBJECTIVES: To characterize the most common skin cancers arising from chronic immunosuppression in OTRs. METHODS: A PubMed search for retrospective single- and multicenter studies reporting skin cancer incidence from 2006 to 2010 was undertaken. Data regarding each study's immunosuppressive regimen, affected skin cancer cohort, and associated risk factors were extracted. RESULTS: Thirty-six articles that met our inclusion criteria reported incidences of nonmelanoma skin cancer (NMSC), Kaposi's sarcoma, melanoma, and Merkel cell carcinoma. NMSC was the most commonly reported cancer of all skin cancers after transplantation. Common risk factors were sex, age, sunlight exposure, and immunosuppressive agent-related (duration, type). CONCLUSION: Sun education programs and frequent screenings in organ transplant clinics have provided the best preventative strategies after transplantation, although the characteristics of the immunosuppressive regimen also play an important role. Thus, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further long-term, randomized controlled studies should assess the effect of using less immunosuppressant medication while preserving graft function.

Comparing the lifetime risks of TNF-alpha inhibitor use to common benchmarks of risk.

OBJECTIVE: The study aims to illustrate the range of lifetime risks of lymphoma, tuberculosis (TB), and demyelinating diseases with TNF-α inhibitors in psoriasis patients. METHODS: Previously published data and online resources were used to determine the risk of the TB, demyelinating disease, and lymphoma with and without TNF-α inhibitor treatment. Lifetime risks for heart disease and stroke were collected using a Medline search. All cancer, trauma, and environmental statistics were obtained from the data published by National Cancer Institute, National Safety Council, and the National Oceanic and Atmospheric Administration, respectively. RESULTS: The lifetime risks of TNF-α-inhibitor-linked conditions and comparators are as follows: TNF-α inhibitor-linked conditions: lymphoma with: without TNF-α inhibitors (0.5-4.8%:2.3%), TB with:without TNF-α inhibitors (0-17.1%:0.3%), and demyelinating disease with:without TNF-α inhibitors (0.1-1.7%:0.15%). Comparators: cancer (40.4%), heart disease (36.2%), stroke (18.4%), accidental death (3.0%), motor vehicle death (1.2%), and lightning strike (0.033%). LIMITATIONS: Much of the data on lifetime risks of disease with TNF-α inhibitor were for patients with rheumatoid arthritis and not psoriasis. CONCLUSIONS: The risks of lymphoma, demyelinating diseases, and tuberculosis with TNF-α inhibitors are lower than risks patients face on a regular basis. Screening reduces the risk of tuberculosis in patients receiving TNF-α inhibitors.

Comparative efficacy of biologics in psoriasis: a review.

BACKGROUND: Psoriasis is a chronic, immune-mediated skin disease that also has systemic manifestations. Safe and effective long-term treatments are needed. Biologic treatments that inhibit the immunopathogenesis of psoriasis have helped meet this need. PURPOSE: The purpose of this study was to compare the efficacy of biologic therapies used for psoriasis. METHODS: A literature search was performed using PubMed and the keywords '(PASI-75 OR efficacy) AND psoriasis AND (adalimumab OR alefacept OR etanercept OR infliximab OR ustekinumab).' Randomized, double-blind, and placebo-controlled studies on US FDA-approved biologics were selected. Studies assessing the proportion of subjects achieving 75% improvement in Psoriasis Area and Severity Index (PASI-75) within a 12-week period were included. Studies on pediatric populations and psoriatic arthritis were excluded. The weighted average of PASI-75 for each reported regimen was calculated to determine the efficacy of biologic agents used for moderate-to-severe psoriasis. Tolerance and secondary efficacy measures were also examined for the selected studies. RESULTS: FDA-approved regimens of adalimumab, infliximab, ustekinumab, and alefacept were effective in treating moderate-to-severe psoriasis. Weighted average PASI-75 scores for infliximab, ustekinumab, adalimumab, etanercept, and alefacept were 78.6%, 72.1%, 70.5%, 48.1%, and 21%, respectively. LIMITATIONS: The comparative efficacy of biologic agents data was limited to 12 weeks, thus generalizing the results to longer treatment periods may not be accurate. CONCLUSIONS: Various biologic agents for psoriasis were effective at 12 weeks in placebo-controlled trials. Available data cannot fully account for situations in clinical practice, in which combination and longer duration of therapy may be required. When choosing the most effective or best agent, multiple factors should be considered including patient preference, cost, tolerance, adverse effects, dosing schedule, and mode of administration.