Gliptin-Induced Bullous Pemphigoid: Canadian Case Series of 10 Patients.

BACKGROUND: Bullous pemphigoid (BP) is a chronic immune-mediated vesiculobullous disorder. Recently, several reports have described dipeptidyl peptidase-4 inhibitors, also known as gliptins, as causative agents for drug-induced BP. OBJECTIVE: To report and describe clinical and histologic characteristics of 10 cases of gliptin-induced BP. RESULTS: We identified 10 patients with gliptin-induced BP. Nine were secondary to linagliptin, and 1 case was attributed to sitagliptin. All patients showed significant improvement after withdrawal of gliptin medications and proper medical treatment. There has been no evidence of relapse after 4 months of follow-up. CONCLUSION: This report supports the proposed association between gliptins and BP. Physicians should be aware of this potential adverse effect, as gliptin-induced BP can be reversible once identified and the responsible medication is stopped. Early withdrawal of the offending drug and proper treatment can lead to rapid improvement and reduced morbidity.

Dentine decalcification and smear layer removal by different ethylenediaminetetraacetic acid and 1-hydroxyethane-1,1-diphosphonic acid species.

AIM: To compare solutions of di- and tetrasodium ethylenediaminetetraacetic acid (EDTA) and 1-hydroxyethane-1,1-diphosphonic acid (HEDP) regarding their ability to solubilize calcium from dentine and remove smear layer. METHODOLOGY: Solutions with a molarity corresponding to that of 17% Na2 EDTA (pH adjusted to 8.5) were prepared by dissolving Na2 and Na4 salts of HEDP (etidronate), or Na4 EDTA in deionized water. Standardized root dentine discs covered by a smear layer were prepared from human third molars. These discs (n = 10 per group) were immersed in test solutions or phosphate-buffered saline for 1 min. The dissolved Ca2+ was determined by atomic absorption spectroscopy, apparently opened dentinal tubules by laser scanning microscopy and automated image analysis. Ca2+ values were compared between groups by parametric, tubular areas by nonparametric methods, α = 0.05. RESULTS: Solutions prepared from the tetrasodium salts were alkaline (pH 11.3-11.4), whilst counterparts made from the disodium salts were acidic. The EDTA solutions dissolved more calcium than the HEDP counterparts (P < 0.05); solutions prepared with the disodium salts dissolved more calcium than those made from the tetrasodium salts (P < 0.05). There was a high correlation between dissolved calcium and the apparently opened tubular areas (Spearman's ρ = 0.81). Differences between groups regarding opened tubules were similar to those observed regarding the Ca2+ values, with a slightly reduced discerning power due to high variance. CONCLUSION: Calcium chelation and thus smear layer removal by EDTA and HEDP are influenced by pH.

Chemical, cytotoxic and genotoxic analysis of etidronate in sodium hypochlorite solution.

AIM: To test whether the incorporation of a chelation powder, etidronate, marketed for root canal irrigation (Dual Rinse HEDP) into a sodium hypochlorite (NaOCl) solution induced additional cytotoxic and genotoxic effects not observed with NaOCl alone. METHODOLOGY: Fresh and 24-h-old mixtures of 0.9 g of etidronate in 10 mL of 2.5% NaOCl were assessed for their basic chemical features including pH and the ability to chelate Ca2+ from hydroxylapatite. Pure NaOCl and phosphate-buffered saline (PBS) with/without etidronate served as control solutions. Cytotoxic and genotoxic effects of diluted solutions (1:10, 1:100, and 1:1000) were assessed on Chinese hamster lung fibroblast (V79) using the MTT, clonogenic and micronucleus assays, respectively. One-way ANOVA and Tukey's HSD test were applied with an alpha-type error of 5% (P < 0.05). RESULTS: In mixtures of NaOCl and etidronate, the free available chlorine was lost completely after 24 h, and the pH dropped by more than 3 units. However, the ability of the etidronate to chelate Ca2+ was maintained. The fresh mixtures of NaOCl and etidronate were not more toxic than NaOCl alone (P > 0.05), whilst the 24-h-old mixtures were less toxic (P < 0.05) and statistically similar to pure etidronate. Etidronate per se showed little cytotoxicity and no genotoxicity at the tested dilutions. CONCLUSIONS: The ability of the used etidronate, Dual Rinse HEDP, to chelate calcium is not affected by NaOCl. Cytotoxicity and genotoxicity of mixed solutions is dictated by the presence of free available chlorine therein.

Short-term storage stability of NaOCl solutions when combined with Dual Rinse HEDP.

AIM: To assess the stability of NaOCl solutions when combined with a novel product for clinical use, Dual Rinse HEDP, which contains etidronate (1-hydroxyethane 1,1-diphosphonate). METHODOLOGY: Mixtures of NaOCl solutions with Dual Rinse HEDP were prepared so that they initially contained 5.0%, 2.5% or 1.0% NaOCl and always 9.0% of dissolved Dual Rinse HEDP powder per total weight. NaOCl solutions alone were used as controls. The stability of these solutions over 8 h was assessed in transparent borosilicate glass bottles at ambient temperature (23 °C). Subsequently, the effects of heating (60 °C) or storing the solutions at 5 °C were studied in polypropylene syringes. NaOCl concentrations were measured by iodometric titration, that is free available chlorine contents. Experiments were performed in triplicate. RESULTS: In the glass bottles at 23 °C, the 5.0% NaOCl/9.0% Dual Rinse HEDP solution lost 20% of the available chlorine after 1 h, whilst the corresponding 2.5% NaOCl and 1.0% NaOCl solutions retained this relative amount of available chlorine for 2 and 4 h, respectively. Results obtained in the glass bottles were similar to those achieved in the syringes. Heating of the NaOCl/Dual Rinse HEDP mixtures had a detrimental effect on available chlorine, with a complete loss after 1 h. In contrast, storing the NaOCl/Dual Rinse HEDP mixtures in a refrigerator at 5 °C kept the available chlorine high for 7 h, with the expected loss after a further hour of storage at 23 °C. CONCLUSIONS: Initial NaOCl concentration and temperature both affected short-term storage stability of combined solutions containing Dual Rinse HEDP.

Gene expression in human adipose-derived stem cells: comparison of 2D films, 3D electrospun meshes or co-cultured scaffolds with two-way paracrine effects.

Finding the appropriate cues to trigger the desired differentiation is a challenge in tissue engineering when stem cells are involved. In this regard, three-dimensional environments are often compared to cells' two-dimensional culture behaviour (plastic culture dish). Here, we compared the gene expression pattern of human adipose-derived stem cells (ASC) seeded in a three-dimensional (3D) electrospun mesh and on a two-dimensional (2D) film - both of exactly the same material. Additionally, we conducted experiments with a scaffold floating above a film to investigate two-way paracrine effects (co-system). Electrospun meshes (3D scaffolds) and films (2D), consisting either of pristine poly-lactic-co-glycolic acid (PLGA) or of PLGA-containing dispersed amorphous calcium phosphate nanoparticles (PLGA/aCaP), were seeded with ASCs and cultured either in Dulbecco Minimum Essential Medium (DMEM) or in osteogenic medium. After two weeks, minimum stem cell criteria markers as well as typical markers for osteogenesis, endothelial cell differentiation, adipogenesis and chondrogenesis were analysed by quantitative real-time PCR. Interestingly, mostly osteogenic genes of cells seeded on 3D meshes were upregulated compared to those on 2D films, while stem cell markers seemed to be only slightly affected. Runx2 and osteocalcin showed an especially strong upregulation under all conditions, while most other factors analysed for 2D/3D changes were highly dependent on the material composition, the culture medium and on paracrine signalling effects. The beneficial 3D environment for stem cells found in many studies has therefore not to be attributed to the third dimension alone and should carefully be compared to 2D films fabricated of the same material. Furthermore, paracrine interactions triggering differentiation are not negligible.

Effect of endodontic irrigants on biofilm matrix polysaccharides.

AIM: To specifically investigate the effect of endodontic irrigants at their clinical concentration on matrix polysaccharides of cultured biofilms. METHODOLOGY: Saccharolytic effects of 3% H2 O2 , 2% chlorhexidine (CHX), 17% EDTA, 5% NaOCl and 0.9% saline (control) were tested using agarose (α 1-3 and ß 1-4 glycosidic bonds) blocks (n = 3) in a weight assay. The irrigants were also applied to three-species biofilms (Streptococcus mutans UAB 159, Streptococcus oralis OMZ 607 and Actinomyces oris OMZ 745) grown anaerobically on hydroxyapatite discs (n = 6). Glycoconjugates in the matrix and total bacterial cell volumes were determined using combined Concanavalin A-/Syto 59-staining and confocal laser-scanning microscopy. Volumes of each scanned area (triplicates/sample) were calculated using Imaris software. Data were compared between groups using one-way anova/Tukey HSD, α = 0.05. RESULTS: The weight assay revealed that NaOCl was the only irrigant under investigation capable of dissolving the agarose blocks. NaOCl eradicated stainable matrix and bacteria in cultured biofilms after 1 min of exposure (P < 0.05 compared to all groups, volumes in means ± standard deviation, 10-3  mm3 per 0.6 mm2 disc; NaOCl matrix: 0.10 ± 0.08, bacteria: 0.03 ± 0.06; saline control matrix: 4.01 ± 1.14, bacteria: 11.56 ± 3.02). EDTA also appeared to have some effect on the biofilm matrix (EDTA matrix: 1.90 ± 0.33, bacteria: 9.26 ± 2.21), whilst H2 O2 and CHX merely reduced bacterial cell volumes. CONCLUSION: Sodium hypochlorite can break glycosidic bonds. It dissolves glycoconjugates in the biofilm matrix. It also lyses bacterial cells.

The Role of IL-17 in the Pathogenesis of Psoriasis and Update on IL-17 Inhibitors for the Treatment of Plaque Psoriasis.

BACKGROUND: Major advances have been made in the understanding of the pathophysiology of psoriasis. OBJECTIVES: The authors review the role of interleukin (IL) 17 in the pathogenesis of psoriasis and provide updates on approved and investigational therapies targeting IL-17 and the IL-17 receptor. METHODS: A PubMed search was performed for relevant literature. CONCLUSION: The IL-23/Th17 signaling pathway (including IL-17) plays a central role in the pathogenesis of psoriasis. Biologic agents that block IL-17 (secukinumab and ixekizumab) or its receptor (brodalumab) are effective and safe for the treatment of psoriasis.

Use of Apremilast in Combination With Other Therapies for Treatment of Chronic Plaque Psoriasis: A Retrospective Study.

BACKGROUND: Apremilast is an oral phosphodiesterase 4 inhibitor that has been approved as monotherapy for the treatment of moderate to severe chronic plaque psoriasis. No data exist on the safety or efficacy of apremilast as a component of combination therapy with either phototherapy or conventional systemic or biological therapies. OBJECTIVE: To evaluate the short term-efficacy and safety of apremilast in combination with at least one form of photo-, systemic, or biologic therapy in the treatment of chronic plaque psoriasis. METHODS: A retrospective chart review was conducted for patients who received apremilast in addition to systemic, biologic, or phototherapy. The primary outcome was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index score (PASI-75). RESULTS: A total of 81 patients with plaque psoriasis were treated with apremilast in combination with at least 1 other therapy (NB-UVB, methotrexate, acitretin, cyclosporin, etanercept, adalimumab, infliximab, or ustekinumab). Fourteen patients (17%) discontinued treatment before completion of 12 weeks of apremilast therapy. Sixty-seven patients continued on drug past 12 weeks. Of these patients, 81% achieved PASI-75 at week 12 after apremilast was added to an existing therapy. Nausea and/or diarrhea were reported in 25% of these patients, and weight loss was observed in 15%. CONCLUSION: Apremilast can be safely and effectively combined with phototherapy, systemic, and/or biological agents in patients with plaque psoriasis not responding adequately to these agents alone. Gastrointestinal side effects were manageable in the majority of patients.

Hobnail Hemangioma (Superficial Hemosiderotic Lymphovascular Malformation) in Children: A Series of 6 Pediatric Cases and Review of the Literature.

BACKGROUND: Hobnail hemangioma is a small benign vascular malformation of the superficial and mid-dermis with variable clinical presentation. OBJECTIVES: To review the clinical characteristics of hobnail hemangioma in pediatric patients. METHODS: A retrospective chart review performed of all histopathologically confirmed cases of hobnail hemangioma from May 2000 to December 2014. Data on demographics, clinical characteristics, and results of immunohistochemical staining were collected. RESULTS: Four male and 2 female patients identified. Congenital lesions were reported in 3 cases. The most common anatomic location was the extremities. Treatment options included observation and surgical excision. CONCLUSIONS: Hobnail hemangioma is an uncommon benign vascular malformation. Due to its benign nature, treatment is not required. If treatment is indicated, complete surgical excision appears to be the most effective option.

Successful treatment of severe psoriasis in an adolescent with ustekinumab.

Psoriasis is a chronic, inflammatory, immune-mediated disease. Approximately 30% of patients have disease onset before age 18 years. Psoriasis in children and adolescents may be difficult to control, with subsequent poor quality of life and psychosocial consequences. We describe the case of a 12-year-old boy with severe, refractory, chronic plaque psoriasis for 6 years. Various therapeutic regimens including different topical corticosteroids, topical vitamin D analogs, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin, and combination therapies showed only partial or transient responses with frequent relapses. Because anti-interleukin-12/23 agents have been successfully used in adults with psoriasis, ustekinumab was initiated and our patient showed a rapid, excellent, sustained response. No recurrence or flares have been observed after 33 months of follow-up. This case illustrates that ustekinumab may be an effective and safe therapeutic option in adolescents with psoriasis.

Radio-opaque nanosized bioactive glass for potential root canal application: evaluation of radiopacity, bioactivity and alkaline capacity.

AIM: To produce novel nanosized bioactive glass particles with radio-opaque properties and high alkaline capacity and to evaluate their performance as a potential bioactive root canal dressing or filling material. METHODOLOGY: Flame spray-derived bioactive glass particles in the nanometre range were produced including bismuth oxide as a radiopacifier. Calcium hydroxide, barium sulphate and bismuth oxide served as controls. Corresponding materials were compressed to obtain dense specimens with increased alkaline capacity. Radiopacity was evaluated, and in vitro bioactivity was monitored using Raman spectroscopy and scanning electron microscopy. Leaching of bismuth was controlled using atomic absorption spectroscopy. RESULTS: Bioactive glass particles with up to 50 wt% bismuth oxide revealed radiopacity with an equivalent of 4.94-mm aluminium. The introduction of bismuth into the bioactive glass altered the alkaline capacity and the in vitro bioactivity only for high bismuth oxide quantities. Bismuth oxide leaching out of the glass matrix was hardly detectable. CONCLUSION: Bioactive glass can be modified with bismuth oxide to become radio-opaque.

Composites made of flame-sprayed bioactive glass 45S5 and polymers: bioactivity and immediate sealing properties.

AIM: To engineer systems using polyisoprene (PI) or polycaprolactone (PCL) and nanometric bioactive glass 45S5 (BG) that could create a hydroxyapatite interface and thus ultimately make the use of an endodontic sealer unnecessary. METHODOLOGY: Different composites using PI or PCL as matrix material were prepared with BG contents of up to 30 wt%. Unfilled PI and PCL, commercially available filled PI (Obtura gutta-percha) and PCL pellets (Resilon) served as control materials. Bioactivity (in vitro precipitate formation in simulated body fluid) was investigated using scanning electron microscopy and X-ray diffraction analysis. To test immediate sealing ability, simulated root canals were filled with heated materials, and dye leakage was assessed. Leakage was statistically compared between groups using Kruskal-Wallis analysis of variance followed by Mann-Whitney U tests and Bonferroni correction. The alpha-type error was set at 0.05. RESULTS: Both composite systems revealed hydroxyapatite formation on their surface. This was not observed on control materials. Incorporating 30 wt% BG into PI and PCL significantly (P < 0.05) improved their immediate sealing ability compared to that of unfilled polymers, so that dye leakage in simulated root canals was prevented completely. CONCLUSION: Polyisoprene and PCL composites with BG showed promising results as single root canal filling materials. Incorporation of BG fillers into the polymers under investigation made the resulting composite materials bioactive and improved their immediate sealing ability.

Ocrelizumab-induced alopecia areata-A series of five patients from Ontario, Canada: A case report.

BACKGROUND: Ocrelizumab is a humanized monoclonal antibody that targets the CD20 antigen found on B-cells. It is indicated in the treatment of both relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. OBJECTIVE: The aim of this study is to report and describe the characteristics of alopecia areata following treatment with ocrelizumab for multiple sclerosis. RESULTS: Five patients were reported, two female and three male. Four of the five patients had alopecia areata of the scalp, one of the five having alopecia to the beard area. All patients responded well to conventional treatment with topical and intralesional corticosteroids and topical minoxidil foam. Ocrelizumab can be associated with the development of alopecia areata. Initiation of proper treatment may lead to quick improvement or resolution of this potentially reversible adverse effect.

Treatment of recalcitrant erosive oral lichen planus and desquamative gingivitis with oral apremilast.

BACKGROUND: Erosive oral lichen planus and desquamative gingivitis are uncommon but severe debilitating variants of oral lichen planus. Treatment of these presentations is difficult and challenging. MAIN OBSERVATION: A 44-year-old woman was referred to the dermatology clinic with chronic painful lichen planus-related gingivitis and buccal erosions. She has failed multiple treatments including topical clobetasol and tacrolimus, intralesional corticosteroids and several systemic and immunosuppressive agents. Following completion of three months of treatment with oral apremilast at a dose of 30 mg twice daily, significant improvement was noted in her disease activity. CONCLUSION: Oral apremilast may be a safe and effective treatment for erosive oral lichen planus.

Effect of extending G-suit coverage on cardiovascular responses to positive pressure breathing.

The purpose of this study was to compare cardiovascular responses of subjects exposed to long-duration positive pressure breathing (PPB) while wearing a standard (Combat Edge; CE) vs. extended coverage (Tactical Life Support System; TLSS) G-suit. Twelve experienced subjects, wearing TLSS and CE, were separately exposed to counterbalanced 60, 70, 80, and 88 mm Hg PPB for up to 10 min continuously. Termination resulted if presyncopal symptoms arose. G-suit inflation was 4 x mask/jerkin pressure. Using TLSS, all subjects completed 10 min of PPB at all levels, vs. 7 and 5 subjects completing 10 min at 80 and 88 mm Hg, respectively, using the CE ensemble (p < 0.001). Heart rate was significantly elevated at all PPB levels using CE (p < 0.0001) vs. TLSS. Stroke and Cardiac Indexes were significantly lower with CE at all levels vs. TLSS (p < 0.0001), and mean arterial blood pressure failed to be maintained at the 80 and 88 PPB mm Hg levels using CE (p < 0.0001). Extended G-suits afford superior protection against PPB-induced cardiovascular dysfunction vs. standard ensembles and consequently permit use of higher levels of PPB. This is due to the larger and more uniform application of pressure in the leg G-suit bladders, augmenting venous return and stroke volume.

Cardiovascular responses with standard and extended bladder coverage G-suits during rapid decompression.

This study compared the cardiovascular responses of subjects exposed to 60,000 ft. rapid decompressions while wearing the Combined Advanced Technology Enhanced Design "G" Ensemble (COMBAT EDGE or CE) and the Tactical Life Support System (TLSS). Eight subjects were rapidly decompressed from 22,500 ft (6,858 m) to 60,000 ft (18,288 m), once wearing the CE ensemble and once wearing the TLSS ensemble. There were significant differences in heart rate, stroke volume, cardiac index, and mean arterial pressure (p < 0.0001), due to garment type, with TLSS providing better cardiovascular support. Oxygen saturation did not decrease to the same degree with CE as with TLSS (p < 0.0001). Both TLSS and CE provided sufficient physiological support to maintain oxygen saturations above 65% during the 3-min exposures to 60,000 ft altitude. Short-term physiological support at higher altitudes with greater PPB levels or longer duration excursions at 60,000 ft may not be possible without the greater G-suit bladder coverage and cardiovascular support provided by TLSS-type garments.

Fine-tuning of bioactive glass for root canal disinfection.

An ideal preparation of 45S5 bioactive glass suspensions/slurries for root canal disinfection should combine high pH induction with capacity for continuing release of alkaline species. The hypothesis of this study was that more material per volume of bioactive glass slurry is obtained with a micrometric material (< 5 microm particle size) or a micrometric/ nanometric hybrid, rather than a solely nanometric counterpart. This should correlate with alkaline capacity and antimicrobial effectiveness. Slurries at the plastic limit were prepared with test and reference materials in physiological saline. Total mass and specific surface area of glass material per volume were determined. Continuous titration with hydrochloric acid was performed, and antimicrobial effectiveness was tested in extracted human premolars mono-infected with E. faecalis ATTC 29212 (N = 12 per material). While the nanometric slurry had a 12-fold higher specific surface area than the micrometric counterpart, the latter had a considerably higher alkaline capacity and disinfected significantly better (Fisher's exact test, P < 0.05). The hybrid slurry behaved similarly to the micrometric preparation.

Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo.

During gastrulation in the mouse, mesoderm is induced and patterned by secreted signaling molecules, giving rise first to primitive erythroblasts and vascular endothelial cells. We have demonstrated previously that development of these lineages requires a signal(s) secreted from the adjacent primitive endoderm. We now show that Indian hedgehog (Ihh) is a primitive endoderm-secreted signal that alone is sufficient to induce formation of hematopoietic and endothelial cells. Strikingly, as seen with primitive endoderm, Ihh can respecify prospective neural ectoderm (anterior epiblast) along hematopoietic and endothelial (posterior) lineages. Downstream targets of the hedgehog signaling pathway (the genes encoding patched, smoothened and Gli1) are upregulated in anterior epiblasts cultured in the presence of Ihh protein, as is Bmp4, which may mediate the effects of Ihh. Blocking Ihh function in primitive endoderm inhibits activation of hematopoiesis and vasculogenesis in the adjacent epiblast, suggesting that Ihh is an endogenous signal that plays a key role in the development of the earliest hemato-vascular system. To our knowledge, these are the earliest functions for a hedgehog protein in post-implantation development in the mouse embryo.

Short inverted-repeat transposable elements in teleost fish and implications for a mechanism of their amplification.

Angel is the first miniature inverted-repeat transposable element (MITE) isolated from fish. Angel elements are imperfect palindromes with the potential to form stem-loop structures in vitro. Despite sequence divergence of elements of up to 55% within and between species, their inverted repeat structures have been maintained, implying functional importance. We estimate that there are about 10(3)-10(4) Angels scattered throughout the zebrafish genome, evidence that this family of transposable elements has been significantly amplified over the course of evolution. Angel elements and Xenopus MITEs carry common sequence motifs at their termini, indicating common origin and/or related mechanisms of transposition. We present a model in which MITEs take advantage of the basic cellular mechanism of DNA replication for their amplification, which is dependent on the characteristic inverted repeat structures of these elements. We propose that MITEs are genomic parasites that transpose via a DNA intermediate, which forms by a folding-back of a single strand of DNA, that borrow all of the necessary factors for their amplification from products encoded in the genomes in which they reside. DNA polymorphisms in different lines of zebrafish were detected by PCR using Angel-specific primers, indicating that such elements, combined with other transposons in vertebrate genomes, will be useful molecular tools for genome mapping and genetic analyses of mutations.