No abstract available
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Δευτέρα 12 Φεβρουαρίου 2018
Intensive Care Unit Enhanced Recovery Pathway for Patients Undergoing Orthotopic Liver Transplants Recipients: A Prospective, Observational Study
BACKGROUND: Liver transplant recipients continue to have high perioperative resource utilization and prolonged length of stay despite improvements in perioperative care. Enhanced recovery pathways have been shown in other surgical populations to produce reductions in hospital resource utilization. METHODS: A prospective, observational study was performed to examine the effect of an enhanced recovery pathway for postoperative care after liver transplantation. Outcomes from patients undergoing liver transplantation from November 1, 2013, to October 31, 2014, managed by the pathway were compared to transplant recipients from the year before pathway implementation. Multivariable regression analysis was used to assess the association of the clinical pathway on clinical outcomes. RESULTS: The intervention and control groups included 141 and 106 patients, respectively. There were no demographic differences between the control and intervention group including no differences between the length of surgery and cold ischemic time. Median intensive care unit length of stay was reduced from 4.4 to 2.6 days (P
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Congenital Langerhans cell histiocytosis presenting in a 27-week-gestation neonate
Abstract
Langerhans cell histiocytosis is exceedingly rare in premature infants, and the few cases reported suggest a poor prognosis with systemic involvement. We present a case of Langerhans cell histiocytosis limited to a single cutaneous lesion, presenting in a 27-week-gestation infant, which is the youngest gestational age of reported Langerhans cell histiocytosis cases. The lesion showed spontaneous resolution by 41 weeks corrected gestational age, and systemic involvement was absent, demonstrating a mild course of skin-only Langerhans cell histiocytosis in a premature infant.
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Geographic tonguelike presentation in a child with pityriasis rosea: Case report and review of oral manifestations of pityriasis rosea
Abstract
Oral lesions are rarely reported in patients with pityriasis rosea. We report a case of a 3-year-old boy with clinical evidence of generalized pityriasis rosea who developed asymptomatic oral lesions similar in appearance to geographic tongue. The generalized eruption and tongue lesions resolved simultaneously within 4 weeks. We also review the literature on the oral manifestations of Pityriasis rosea.
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Bascule syndrome associated with syncopal episodes
Abstract
Bascule syndrome is a recently described benign vasomotor dermatosis characterized by Bier anemic spots, cyanosis, and urticaria-like eruption. We report a case of a 13-year-old girl with cutaneous lesions consistent with Bascule syndrome who had had three exercise-related syncopal episodes. It would be recommended to exclude orthostatic intolerance or postural orthostatic tachycardia syndrome when evaluating patients with Bascule syndrome.
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Subacute cutaneous lupus erythematosus presenting in twins
Abstract
Subacute cutaneous lupus erythematosus is a clinically distinct form of cutaneous lupus erythematosus, with age of onset typically in the second to fifth decades. Eleven cases have been reported in childhood, and we present the first known case of subacute cutaneous lupus erythematosus in identical twins. Although flares are typically photo-induced, we present an annular eruption typical of subacute cutaneous lupus erythematosus with concurrent pinworm infestation, with recurrence of disease with cutaneous larva migrans. The patient's identical twin had a similar eruption with pinworm infection. This case highlights the possibility of parasitic infestation as a trigger for subacute cutaneous lupus erythematosus in genetically susceptible individuals.
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Parental use of sun protection for their children—does skin color matter?
Abstract
Background/Objectives
Excessive sun exposure during childhood is a risk factor for skin cancer. This study aimed to compare the frequency of ideal sun protection use between parents with lighter- and darker-skinned children and explore their attitudes and beliefs on sun safety and their choice of sun protection.
Methods
Parents of children aged 6 months to 6 years completed self-administered questionnaires about sun protection practices for their children. Parents assessed their child's Fitzpatrick phototype and were divided into lighter- (Fitzpatrick phototype I-III) and darker-skinned (Fitzpatrick phototype IV-VI) groups. Sun safety guidelines from the Canadian Dermatology Association were used to qualify ideal sun protection.
Results
A total of 183 parents were included. Overall, 31 parents (17%) used ideal sun protection for their children. As their children grew older, parents were less likely to use ideal sun protection (odds ratio = 0.69, 95% confidence interval = 0.53-0.90). Parents in the lighter-skinned group were more likely to use ideal sun protection for their children (odds ratio = 7.4, 95% confidence interval = 2.7-20.1), believe that sun exposure was harmful (odds ratio = 17.2, 95% confidence interval = 4.0-74.9), and perceive value in sun protection (odds ratio = 11.4, 95% confidence interval = 3.3-39.0); the darker-skinned group believed that darker skin tones provided more sun protection (odds ratio = 12.4, 95% confidence interval = 6.1-25.4).
Conclusion
Ideal parental sun protection efforts are overall low, particularly in parents of darker-skinned children. The identified attitudes toward and beliefs about sun safety may aid in delivery of future sun protection interventions, especially in multiracial populations.
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Treatment outcomes of vitiligo in Asian children
Abstract
This retrospective study aimed to identify factors that predict treatment response in a cohort of Asian children with vitiligo. Shorter duration of vitiligo was associated with better repigmentation. Patients with focal vitiligo of short duration have a good chance of achieving repigmentation with topical agents alone.
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The safe use of Doliocarpus dentatus in the gestational period: Absence of changes in maternal reproductive performance, embryo-fetal development and DNA integrity
Publication date: 10 May 2018
Source:Journal of Ethnopharmacology, Volume 217
Author(s): Raissa Borges Ishikawa, Juliana Miron Vani, Silvia Cordeiro das Neves, Ana Paula Maluf Rabacow, Cândida Aparecida Leite Kassuya, Júlio Croda, Claudia Andrea Lima Cardoso, Antônio Carlos Duenhas Ferreira Monreal, Andreia Conceição Milan Brochado Antoniolli, Andréa Luiza Cunha – Laura, Rodrigo Juliano Oliveira
Ethnopharmacological relevanceDoliocarpus dentatus (Dilleniaceae) is commonly used in Brazil for the treatment of inflammatory process pain and urinary retention. Previous studies of our group have demonstrated the anti-inflammatory and antimycobacterial action of the ethanolic extract of Doliocarpus dentatus (EEDd) as well as the safety of its use.Aim of the studywe investigated the effects of EEDd on reproductive performance, fetal development and DNA integrity in pregnant female Swiss mice.Material and methodsthirty female Swiss mice were divided into three experimental groups (n = 10): control group treated with 1% tween-80 and EEDd1 and EEDd2 groups treated with EEDd at doses of 100 and 1000 mg/kg, respectively. The treatment occurred by oral gavage throughout the gestational period. At the end of pregnancy, parameters related to reproductive performance, embryofoetal development and DNA integrity was evaluated.Resultsboth doses of the extract tested did not alter the reproductive parameters, did not present significant differences in the embryofetal development when compared to the control group and also did not induce the formation of micronuclei.Conclusionthe EEDd do not alter the reproductive parameters, embryofetal development and DNA integrity, ensuring its safe use during pregnancy.
Graphical abstract
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Editorial Board
Publication date: 6 April 2018
Source:Journal of Ethnopharmacology, Volume 215
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Pediatric Intracranial Hypertension: a Current Literature Review
Abstract
Purpose of Review
The purpose of this review is to provide an update on pediatric intracranial hypertension.
Recent Findings
The annual pediatric incidence is estimated at 0.63 per 100,000 in the USA and 0.71 per 100,000 in Britain. The Idiopathic Intracranial Hypertension Treatment Trial found improvement in visual fields, optical coherence tomography, Frisen grade, and quality of life with acetazolamide compared to placebo in adult patients, and these findings have been translated to the pediatric population.
Summary
Pediatric intracranial hypertension is a disorder that if left untreated can lead to poor quality of life and morbidity. There are no current treatment studies in pediatrics, but adult data suggests acetazolamide remains an acceptable first-line medication.
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Skin lesions serve as clues to relapse of pediatric blastic plasmacytoid dendritic cell neoplasm
Abstract
A 10-year-old girl with a history of blastic plasmacytoid dendritic cell neoplasm, a rare malignancy in children, presented with recurrent skin eruptions beginning while on maintenance chemotherapy, including mildly pruritic skin-colored plaques, tender indurated nodules, and violaceous bound-down plaques. This case highlights an unusual presentation of relapsed blastic plasmacytoid dendritic cell neoplasm on chemotherapy, with skin lesions providing important clues to the progression of systemic disease.
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Maternal Thyrotropin Receptor Antibody Concentration and the Risk of Fetal and Neonatal Thyrotoxicosis: A Systematic Review
Thyroid Feb 2018, Vol. 28, No. 2: 257-264.
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Rapid Remission of Graves' Hyperthyroidism Without Thionamides Under Immunosuppressive Treatment for Concomitant Autoimmune Hepatitis
Thyroid Feb 2018, Vol. 28, No. 2: 276-278.
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Clinical Impact of Detectable Antithyroglobulin Antibodies Below the Reference Limit (Borderline) in Patients with Papillary Thyroid Carcinoma with Undetectable Serum Thyroglobulin and Normal Neck Ultrasonography After Ablation: A Prospective Study
Thyroid Feb 2018, Vol. 28, No. 2: 229-235.
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Time-resolved fluorescence spectroscopy for the diagnosis of oral lichen planus
Summary
Background
Lichen planus (LP) is a T-cell mediated autoimmune disorder of unknown aetiology that affects the skin, nails, oral and genital mucous membranes. Conventionally, oral LP (OLP) is diagnosed through clinical assessment and histopathological confirmation by oral biopsy.
Aim
To explore the use of time-resolved fluorescence spectroscopy (TRFS) to detect fluorescence lifetime changes between lesional OLP and perilesional normal mucosa.
Methods
In this pilot study, measurements of lesional and perilesional buccal and mouth floor mucosa were conducted in vivo with a TRFS system. Histopathological findings were consistent with OLP in 8 out of 10 patients biopsied. Two patients with histopathological diagnoses of frictional hyperkeratosis and oral candidiasis, respectively, were excluded from the study.
Results
Our preliminary data show that lifetime values in the 360–560 nm spectral range indicate a significant differentiation between normal and diseased tissue. In contrast to the standard oral biopsy procedure, this technique is noninvasive, painless, time-efficient and safe.
Conclusions
Future studies are needed to better elucidate the diagnostic capability of TRFS and to further explore the sources of fluorescence contrast. This pilot study suggests that, based on fluorescence lifetime parameters, TRFS is a very promising technology for the development of a novel OLP diagnostic technique.
http://ift.tt/2Ekk2SO
Time-resolved fluorescence spectroscopy for the diagnosis of oral lichen planus
Summary
Background
Lichen planus (LP) is a T-cell mediated autoimmune disorder of unknown aetiology that affects the skin, nails, oral and genital mucous membranes. Conventionally, oral LP (OLP) is diagnosed through clinical assessment and histopathological confirmation by oral biopsy.
Aim
To explore the use of time-resolved fluorescence spectroscopy (TRFS) to detect fluorescence lifetime changes between lesional OLP and perilesional normal mucosa.
Methods
In this pilot study, measurements of lesional and perilesional buccal and mouth floor mucosa were conducted in vivo with a TRFS system. Histopathological findings were consistent with OLP in 8 out of 10 patients biopsied. Two patients with histopathological diagnoses of frictional hyperkeratosis and oral candidiasis, respectively, were excluded from the study.
Results
Our preliminary data show that lifetime values in the 360–560 nm spectral range indicate a significant differentiation between normal and diseased tissue. In contrast to the standard oral biopsy procedure, this technique is noninvasive, painless, time-efficient and safe.
Conclusions
Future studies are needed to better elucidate the diagnostic capability of TRFS and to further explore the sources of fluorescence contrast. This pilot study suggests that, based on fluorescence lifetime parameters, TRFS is a very promising technology for the development of a novel OLP diagnostic technique.
http://ift.tt/2Ekk2SO
Effect of matrix metalloproteinase 8 inhibitor on resin–dentin bonds
Publication date: Available online 12 February 2018
Source:Dental Materials
Author(s): Qianmin Ou, Ya Hu, Siqi Yao, Yan Wang, Xuefeng Lin
ObjectivesThis study investigated the effect of matrix metalloproteinase 8 (MMP-8) on resin–dentin bonds, assessed the mechanical properties of the interfaces over time, and discussed the potential application of MMP-8 inhibitor I (MMP8-I) as a specific MMP-8 inhibitor to be incorporated into dental adhesives.MethodsThe activation and inhibition of MMP-8 was detected by colorimetric assay. After 1 day, 6 months and 1 year of storage of Control, MMP8-I, and chlorhexidine (CHX) groups, the microtensile bond strengths (μTBS) were used to evaluate the bond strength and failure mode distributions, and nanoleakage analysis was used to evaluate the minor scattered silver particles.ResultsColorimetric assay showed that the activated MMP-8 was enhanced by adhesive procedures, while it was inhibited by the additional treatment of MMP8-I or CHX. Compared with the Control and CHX groups, the MMP8-I group had significantly higher bond strength and the hybrid layer from the MMP8-I-treated dentin exhibited structural integrity of the collagen network and decreased silver nitrate penetration after 1 year of storage.SignificanceMMP-8 inhibition I protects against the degradation of resin–dentin bonds over time, which is better than broad-scale enzyme inhibitor CHX. It shows that MMP8-I may be used in dentistry for preventing collagen degradation within hybrid layers to extend the longevity of resin–dentin bonds.
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Fatigue resistance of all-ceramic fixed partial dentures – Fatigue tests and finite element analysis
Publication date: Available online 12 February 2018
Source:Dental Materials
Author(s): S.D. Heintze, D. Monreal, M. Reinhardt, A. Eser, A. Peschke, J. Reinshagen, V. Rousson
ObjectiveTo estimate the fatigue resistance of a new translucent zirconia material in comparison to lithium disilicate for 3-unit fixed partial dentures (FPDs).MethodsEighteen 3-unit FPDs (replacement of first upper molar) with a connector size of 4mm×4mm were dry milled with a five-axis milling machine (Zenotec Select, Wieland, Germany) using discs made of a new translucent zirconia material (IPS e.max ZirCAD MT, Ivoclar Vivadent). Another 9 FPDs with a reduced connector size (3mm×4mm) were milled. The zirconia FPDs were sintered at 1500°C. For a comparison, 9 FPDs were made of IPS e.max Press, using the same dimensions. These IPS e.max Press FPDs were ground from a wax disc (Wieland), invested and pressed at 920°C. All FPDs were glazed twice. The FPDs were adhesively luted to PMMA dies with Multilink Automix. Dynamic cyclic loading was carried out on the molar pontic using Dyna-Mess testing machines (Stolberg, Germany) with 2×106 cycles at 2Hz in water (37°C). Two specimens per group and load were subjected to decreasing load levels (at least 4) until the two specimens no longer showed any failures. Another third specimen was subjected to this load to confirm the result. All the specimens were evaluated under a stereo microscope (20× magnification). The number of cycles reached before observing a failure, and their dependence on the load and on the material, were modeled, using a Weibull model. This made it possible to estimate the fatigue resistance as the maximum load for which one would observe less than 1% failure after 2×106 cycles. In addition to the experimental study, Finite Element Modeling (FEM) simulations were conducted to predict the force to failure for IPS e.max ZirCAD MT and IPS e.max Press with a reduced cross-section of the connectors.ResultsThe failure mode of the zirconia FPDs was mostly the fracture of the distal connector, whereas the failure mode of the lithium disilicate FPDs observed to be the fracture of the connectors or multiple cracks of the pontic. The fatigue resistance with 1% fracture probability was estimated to be 488N for the IPS e.max ZirCAD MT FPDs (453N for repeated test), 365N for IPS e.max ZirCAD MT FPDs with reduced connector size and 286N for the e.max Press FPDs. All three IPS e.max ZirCAD groups statistically performed significantly better than IPS e.max Press (p<0.001). On the other hand, no significant difference could be established between the two IPS e.max ZirCAD MT3 groups with a 4mm×4mm connector size (p>0.05). The allowable maximum principal stress (σmax) which did not lead to failure during fatigue testing for IPS e.max ZirCAD MT3 was calculated between 208MPa and 223MPa for FPDs with 4mm×4mm connectors for 2×106 cycles. This value could also be verified for the FPDs of the same material with 3mm×4mm connectors. On the other hand fatigue strength in terms of σmax at 2×106 cycles of IPS e.max Press was calculated to be between 78 and 90MPa.SignificanceThe fatigue resistance of the translucent zirconia 3-unit FPDs was about 60–70% higher than that of the lithium disilicate 3-unit FPDs, which may justify their use for molar replacements, provided that a minimal connector size of 4mm×4mm is observed. Even with a limited number of specimens (n=9) per group it was possible to statistically differentiate between the tested groups.
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Clinical outcomes and prognostic factors in cisplatin versus cetuximab chemoradiation for locally advanced p16 positive oropharyngeal carcinoma
Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Christian L. Barney, Steve Walston, Pedro Zamora, Erin H. Healy, Nicole Nolan, Virginia M. Diavolitsis, Anterpreet Neki, Robert Rupert, Panos Savvides, Amit Agrawal, Matthew Old, Enver Ozer, Ricardo Carrau, Stephen Kang, James Rocco, Theodoros Teknos, John C. Grecula, Jessica Wobb, Darrion Mitchell, Dukagjin Blakaj, Aashish D. Bhatt
ObjectivesRandomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response.Materials and methodsCases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups.ResultsWe identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings.ConclusionWhen treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC.
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‘The Unhealthy Other’: How vaccine rejecting parents construct the vaccinating mainstream
Publication date: Available online 12 February 2018
Source:Vaccine
Author(s): Katie Attwell, David T. Smith, Paul R. Ward
To address the phenomenon of vaccine hesitancy and rejection, researchers increasingly recognise the need to engage with the social context of parents' decision-making. This study examines how vaccine rejecting parents socially construct the vaccinating mainstream in opposition to themselves. We analyse qualitative data from interviews with parents in Adelaide, South Australia. Applying insights from Social Identity Theory (SIT), we show how these parents bolster their own sense of identity and self-belief by employing a discourse that casts vaccinators as an Unhealthy Other. We demonstrate how the parents identify vaccination as a marker of parental conformity to the 'toxic practices of mass industrial society', linking it to other ways in which membership of the consumerist mainstream requires individuals to 'neglect their health.' This is explored through themes of appearance, diet, (over) consumption of pharmaceuticals, inadequate parenting values and wilful or misguided ignorance. This construction of the Unhealthy Other elevates the self-concept of vaccine hesitant and rejecting parents, who see themselves as part of an enlightened, but constantly besieged, group of healthy and virtuous parents. It is common for the vaccinating mainstream to present vaccine hesitant and rejecting parents as a group subject to epistemic closure, groupthink, confirmation bias and over-confidence in their own expertise. However, vaccine hesitant and rejecting parents also see mainstream society as a group—a much larger one—subject to the same problems. We suggest the need to mitigate the 'groupness' of vaccination and non-vaccination by extending the practice of vaccination to recognisable practitioners of holistic health.
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Cost of goods sold and total cost of delivery for oral and parenteral vaccine packaging formats
Publication date: Available online 12 February 2018
Source:Vaccine
Author(s): Jeff Sedita, Stefanie Perrella, Matt Morio, Michael Berbari, Jui-Shan Hsu, Eugene Saxon, Courtney Jarrahian, Annie Rein-Weston, Darin Zehrung
Despite limitations of glass packaging for vaccines, the industry has been slow to implement alternative formats. Polymer containers may address many of these limitations, such as breakage and delamination. However, the ability of polymer containers to achieve cost of goods sold (COGS) and total cost of delivery (TCOD) competitive with that of glass containers is unclear, especially for cost-sensitive low- and lower-middle-income countries.COGS and TCOD models for oral and parenteral vaccine packaging formats were developed based on information from subject matter experts, published literature, and Kenya's comprehensive multiyear plan for immunization. Rotavirus and inactivated poliovirus vaccines (IPV) were used as representative examples of oral and parenteral vaccines, respectively. Packaging technologies evaluated included glass vials, blow-fill-seal (BFS) containers, preformed polymer containers, and compact prefilled auto-disable (CPAD) devices in both BFS and preformed formats.For oral vaccine packaging, BFS multi-monodose (MMD) ampoules were the least expensive format, with a COGS of $0.12 per dose. In comparison, oral single-dose glass vials had a COGS of $0.40. BFS MMD ampoules had the lowest TCOD of oral vaccine containers at $1.19 per dose delivered, and ten-dose glass vials had a TCOD of $1.61 per dose delivered. For parenteral vaccines, the lowest COGS was achieved with ten-dose glass vials at $0.22 per dose. In contrast, preformed CPAD devices had the highest COGS at $0.60 per dose. Ten-dose glass vials achieved the lowest TCOD of the parenteral vaccine formats at $1.56 per dose delivered. Of the polymer containers for parenteral vaccines, BFS MMD ampoules achieved the lowest TCOD at $1.89 per dose delivered, whereas preformed CPAD devices remained the most expensive format, at $2.25 per dose delivered.Given their potential to address the limitations of glass and reduce COGS and TCOD, polymer containers deserve further consideration as alternative approaches for vaccine packaging.
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Hepatitis A vaccination coverage among adolescents (13–17 years) in the United States, 2008–2016
Publication date: Available online 12 February 2018
Source:Vaccine
Author(s): Noele P. Nelson, David Yankey, James A. Singleton, Laurie D. Elam-Evans
BackgroundThe hepatitis A (HepA) vaccine was recommended by the Advisory Committee on Immunization Practices (ACIP) incrementally from 1996 to 1999. In 2006, HepA vaccine was recommended (1) universally for children aged 12–23 months, (2) for persons who are at increased risk for infection, or (3) for any person wishing to obtain immunity. Catch-up vaccination can be considered.ObjectiveTo assess HepA vaccine coverage among adolescents and factors independently associated with vaccination administration in the US.MethodsThe 2008–2016 National Immunization Survey–Teen was utilized to determine 1 and ≥2 dose HepA vaccination coverage among adolescents aged 13–17 years. Factors associated with HepA vaccine series initiation (1 dose) were determined by bivariate and multivariable analyses. Data were stratified by state groups based on ACIP recommendation: universal child vaccination recommended since 1999 (group 1); child vaccination considered since 1999 (group 2); universal child vaccination recommendation since 2006 (group 3).ResultsIn 2016, national vaccination coverage for 1 and ≥2 doses of HepA vaccine among adolescents was 73.9% and 64.4%, respectively. Nationally, a 40 percentage point increase in vaccination coverage occurred among adolescents born in 1995 compared to adolescents born in 2003. Nationally, the independent factors associated with increased vaccine initiation was race/ethnicity (Hispanic, American Indian/Alaskan Native, Asian), military payment source and provider recommendation for HepA vaccination (2008–2013). Living in a suburban or rural region, living in poverty (level <1.33–5.03), and absence of state daycare or school HepA requirement were common factors associated with decreased likelihood of vaccine initiation.ConclusionsEfforts to increase HepA vaccine coverage in adolescents in all regions of the country would strengthen population protection from hepatitis A virus (HAV).
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Laryngeal recurrence sites in patients previously treated with transoral laser microsurgery for squamous cell carcinoma
Abstract
Background
The laryngeal framework provides a natural barrier preventing tumour spread to extralaryngeal structures. Transoral laser microsurgery (TLM) for laryngeal squamous cell carcinoma (SCC) may violate these boundaries, altering the pathways of tumor spread for potential recurrences. Our project objective is to describe laryngeal SCC recurrence patterns and overall survival in patients requiring total laryngectomy (TL) after TLM.
Methods
Patients undergoing TLM for laryngeal SCC requiring salvage TL were identified from a prospective CO2 laser database containing all patients undergoing TLM for head and neck malignancies at the QEII Health Sciences Center in Halifax, Nova Scotia between March 2002 – May 2014. Surgical pathology reports were analyzed for tumor characteristics, extent of recurrence and invasion of local structures. Kaplan-Meier analyses were performed to evaluate overall survival, disease specific survival (DSS) and locoregional control.
Results
Fifteen patients were identified from the database as receiving salvage TL for recurrent disease after initial TLM resection for laryngeal SCC. Final pathology reports demonstrated that 67% (10/15) of patients had thyroid cartilage involvement while 53% (9/15) of patients had cricoid cartilage involvement on salvage TL pathology. 33% (5/15) of patients had perineural invasion and 27% (4/15) had lymphovascular invasion. Mean and median follow-up times were 36.7 months and 26.8 months respectively (range 3.9–112.6). The Kaplan-Meier estimate for overall survival at 36 months was 40% post TL with a standard error (SE) of 13.6%. DSS was 47% (SE 14.2%), and locoregional control was 55% (SE 14.5%) post TL.
Conclusions
Laryngeal recurrence sites following TLM seem to be consistent with historical data at known laryngeal sites of vulnerability. Treatment with TLM does not predispose patients to a lower rate of locoregional control and overall survival after total laryngectomy and salvage outcomes are consistent with literature values.
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c-Raf in KRas Mutant Cancers: A Moving Target
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Frank McCormick
Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRasG12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.
Teaser
Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRasG12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.http://ift.tt/2G7IvY0
Glycans Pave the Way for Immunotherapy in Triple-Negative Breast Cancer
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Mariana Salatino, María Romina Girotti, Gabriel A. Rabinovich
The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.
Teaser
The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.http://ift.tt/2H9lxBj
HIPPO Stampede in Nerve Sheath Tumors
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): M. Laura Feltri, Yannick Poitelon
Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.
Teaser
Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.http://ift.tt/2H97j38
An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back)
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Verena Wagner, Jesús Gil
Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.
Teaser
Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.http://ift.tt/2G8KGuk
Cellular Pliancy and the Multistep Process of Tumorigenesis
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Alain Puisieux, Roxane M. Pommier, Anne-Pierre Morel, Fabrice Lavial
Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.
Teaser
Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.http://ift.tt/2H9lt4x
Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Donald P. McDonnell, John D. Norris, Ching-yi Chang
In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.
Teaser
In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.http://ift.tt/2G7Yy87
Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Rinath Jeselsohn, Johann S. Bergholz, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Agostina Nardone, Tengfei Xiao, Wei Li, Xintao Qiu, Gilles Buchwalter, Ariel Feiglin, Kayley Abell-Hart, Teng Fei, Prakash Rao, Henry Long, Nicholas Kwiatkowski, Tinghu Zhang, Nathanael Gray, Diane Melchers, Rene Houtman, X. Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P. Winer, Jean Zhao, Myles Brown
Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER+) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.
Graphical abstract
Teaser
Jeselsohn et al. show that estrogen receptor α (ER) mutations found in endocrine treatment-resistant metastatic breast cancers confer not only ligand-independent ER functions, but also allele-specific neomorphic properties. Importantly, the authors identify potential approaches for treating these breast cancers.http://ift.tt/2H9lqWp
Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Chia-Wei Li, Seung-Oe Lim, Ezra M. Chung, Yong-Soo Kim, Andrew H. Park, Jun Yao, Jong-Ho Cha, Weiya Xia, Li-Chuan Chan, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Chao-Kai Chou, Yen-Liang Liu, Hsin-Chih Yeh, Evan P. Perillo, Andrew K. Dunn, Chu-Wei Kuo, Kay-Hooi Khoo, Jennifer L. Hsu, Yun Wu, Jung-Mao Hsu, Hirohito Yamaguchi, Tzu-Hsuan Huang, Aysegul A. Sahin, Gabriel N. Hortobagyi, Stephen S. Yoo, Mien-Chie Hung
Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.
Teaser
Li et al. show that glycosylation of PD-L1 is essential for PD-L1/PD-1 interaction and immunosuppression in triple-negative breast cancer (TNBC). They generate a glycosylation-specific antibody that induces PD-L1 internalization and an antibody-drug conjugate with potent anti-tumor activities in TNBC models.http://ift.tt/2G7IeUY
The Integrated Genomic Landscape of Thymic Epithelial Tumors
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Milan Radovich, Curtis R. Pickering, Ina Felau, Gavin Ha, Hailei Zhang, Heejoon Jo, Katherine A. Hoadley, Pavana Anur, Jiexin Zhang, Mike McLellan, Reanne Bowlby, Thomas Matthew, Ludmila Danilova, Apurva M. Hegde, Jaegil Kim, Mark D.M. Leiserson, Geetika Sethi, Charles Lu, Michael Ryan, Xiaoping Su, Andrew D. Cherniack, Gordon Robertson, Rehan Akbani, Paul Spellman, John N. Weinstein, D. Neil Hayes, Ben Raphael, Tara Lichtenberg, Kristen Leraas, Jean Claude Zenklusen, Junya Fujimoto, Cristovam Scapulatempo-Neto, Andre L. Moreira, David Hwang, James Huang, Mirella Marino, Robert Korst, Giuseppe Giaccone, Yesim Gokmen-Polar, Sunil Badve, Arun Rajan, Philipp Ströbel, Nicolas Girard, Ming S. Tsao, Alexander Marx, Anne S. Tsao, Patrick J. Loehrer
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
Graphical abstract
Teaser
Radovich et al. perform multi-platform analyses of thymic epithelial tumors. They identify high prevalence of GTF2I mutations and enrichment of mutations in HRAS, NRAS, and TP53 and link overexpression of muscle autoantigens and increased aneuploidy in thymoma and patients' risk of having myasthenia gravis.http://ift.tt/2HcH2Rx
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Christopher A.G. Booth, Nikolaos Barkas, Wen Hao Neo, Hanane Boukarabila, Elizabeth J. Soilleux, George Giotopoulos, Noushin Farnoud, Alice Giustacchini, Neil Ashley, Joana Carrelha, Lauren Jamieson, Deborah Atkinson, Tiphaine Bouriez-Jones, Rab K. Prinjha, Thomas A. Milne, David T. Teachey, Elli Papaemmanuil, Brian J.P. Huntly, Sten Eirik W. Jacobsen, Adam J. Mead
Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.
Graphical abstract
Teaser
Booth et al. show that inactivation of Ezh2 and Runx1 in early thymic progenitors (ETPs) causes cell expansion and gene expression changes similar to those seen in human ETP leukemia. Addition of Flt3-ITD to the Ezh2−/−;Runx1−/− ETP cells leads to aggressive leukemia, which is sensitive to BET inhibition.http://ift.tt/2G7Iaoc
Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Lai Man Natalie Wu, Yaqi Deng, Jincheng Wang, Chuntao Zhao, Jiajia Wang, Rohit Rao, Lingli Xu, Wenhao Zhou, Kwangmin Choi, Tilat A. Rizvi, Marc Remke, Joshua B. Rubin, Randy L. Johnson, Thomas J. Carroll, Anat O. Stemmer-Rachamimov, Jianqiang Wu, Yi Zheng, Mei Xin, Nancy Ratner, Q. Richard Lu
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
Graphical abstract
Teaser
Wu et al. find that HIPPO-TAZ/YAP expression is elevated in malignant peripheral nerve sheath tumors (MPNST). Lats1/2 deficiency in Schwann cells induces hyperactivation of TAZ/YAP and increased PDGFR signaling, leading to the development of MPNST in mice. Inhibition of TAZ/YAP and PDGFR reduces MPNST growth.http://ift.tt/2H9lmpD
DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W. Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L.F. Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A. Zahnow, Nita Ahuja, Stephen B. Baylin, Hariharan Easwaran
Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention.
Graphical abstract
Teaser
Xie et al. show that transformation-associated methylation changes arise stochastically and evolve independently of senescence. A subset of transformation-associated hypermethylated genes favoring cell self-renewal and survival exhibits highest methylation gains during aging and early tumorigenesis.http://ift.tt/2G7I4gk
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma
Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Yong Yu, Kolja Schleich, Bin Yue, Sujuan Ji, Philipp Lohneis, Kristel Kemper, Mark S. Silvis, Nouar Qutob, Ellen van Rooijen, Melanie Werner-Klein, Lianjie Li, Dhriti Dhawan, Svenja Meierjohann, Maurice Reimann, Abdel Elkahloun, Steffi Treitschke, Bernd Dörken, Christian Speck, Frédérick A. Mallette, Leonard I. Zon, Sheri L. Holmen, Daniel S. Peeper, Yardena Samuels, Clemens A. Schmitt, Soyoung Lee
Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases—the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)—disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo.
Graphical abstract
Teaser
Yu et al. show that two different types of histone H3 lysine 9 (H3K9) demethylases, LSD1 and JMJD2C, disable oncogenic Ras- or Braf-induced senescence by enabling the expression of E2F target genes, which permits transformation. Inhibition of the H3K9 demethylases restores senescence and controls tumor growth.http://ift.tt/2HbzIpa
To fee or not to fee? The ethical issues of concierge medicine/dermatology
Concierge medicine is an emerging practice model that involves direct contracting with patients for medical services, often charging a flat monthly or yearly fee. There is considerable variation among concierge practices, but most include administrative service fees with an upfront annual payment to remain on a smaller patient panel.1
http://ift.tt/2nWRIvx
An open-label exploratory study evaluating the efficacy and safety of ingenol mebutate gel 0.05% for the treatment of verruca vulgaris
To the Editor: Current therapies for common warts (verruca vulgaris) often require months of treatment and focus on destruction, removal of callus, or stimulation of a local immune response.1-3 Topical use of ingenol mebutate gel, 0.05%, indicated for the treatment of actinic keratosis, induces necrosis and an inflammatory reaction.4 A recent case study series provided evidence for the efficacy of ingenol mebutate against anogenital warts.5
http://ift.tt/2o0kBWQ
Frontal fibrosing alopecia and cutaneous comorbidities: A potential relationship with rosacea
To the Editor: Frontal fibrosing alopecia (FFA) is an increasingly prevalent lymphocytic, cicatricial alopecia with a yet unknown etiopathogenesis. Some cutaneous diseases have been associated with FFA, but the existing literature is limited to retrospective studies and case reports.1-3 The objective of our study was to analyze the frequency of associated cutaneous conditions in a large cohort of FFA patients.
http://ift.tt/2nV5Up2
A cross-sectional study of YouTube videos about atopic dermatitis
To the Editor: Patients are increasingly looking to online platforms for health information.1 One popular online platform is YouTube, which is a free video-streaming service. The loose content regulations of YouTube allow users to broadcast false information as easily as accurate information. One study found that most of the YouTube videos about tanning beds portrayed them in a positive light and another found that half of YouTube videos on immunizations did not explicitly support them.2,3 We conducted a cross-sectional study on the information on YouTube about atopic dermatitis (AD) by performing 5 searches on YouTube using the search terms "atopic dermatitis," "eczema," "eczema tips," "eczema cure," and "eczema treatment." We screened the first 2 pages of results for inclusion.
http://ift.tt/2o2J4uP
Reply to: “The microbial flora of taxane therapy–associated nail disease in cancer patients”
See related letter on page 607
http://ift.tt/2nVkxbS
Reply to: “Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials”
I want to thank Dr Rieder1 for drawing attention to the challenges faced by brodalumab. I agree with nearly all the points made, although I hope Dr Rieder's prediction that the Risk Evaluation and Mitigation Strategies (REMS) program will doom this drug prove to be untrue.
http://ift.tt/2nVdNe0
In response to Lebwohl et al, “Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials”
To the Editor: I would like to commend Lebwohl et al for their thorough and transparent analysis of the psychiatric adverse events associated with the brodalumab trials.1 One of the first systemic agents for psoriasis to be examined in a study enrolling a population with no specific psychiatrically related exclusion criteria, brodalumab in some ways fell victim to its own noble aims. In retrospect, it should not have been unexpected that a trial enrolling a large cohort of middle-aged white men with moderate-to-severe psoriasis, some of whom had additional suicide risk factors, resulted in several episodes of suicidal ideation and behavior (SIB).
http://ift.tt/2o3eoJR
Reconstruction of Tragus and External Auditory Meatus using Remnant Auricle during Microtia Reconstruction
Facial plast Surg
DOI: 10.1055/s-0037-1617436
This article investigates an effective method with which to reconstruct the tragus and external auditory meatus for microtia reconstruction. The external ear was reconstructed using a delayed postauricular skin flap in patients with congenital microtia. After the first stage of delaying the postauricular skin flap and the second stage of otoplasty with ear framework fabricated from autogenous rib cartilage draping with the delayed skin flap, the third stage involved tragus and external auditory meatus canaloplasty. After designing the remnant auricle flap, the lower part was trimmed and the tragus was reconstructed. The upper part was trimmed into a thin skin flap, which was rotated and used to cover the hollowed wound posterosuperior to the tragus so as to mimic the external auditory meatus. If remnant wounds were present, skin grafting was conducted. In total, 121 patients with congenital microtia were treated from March 2010 to March 2016. The reconstructed tragus and external auditory meatus were well formed, and all wounds healed well. No severe complications such as flap necrosis occurred. Six months postoperatively, the morphology of the reconstructed tragus and external auditory meatus was good. Overall, the patients and their families were satisfied. The use of remnant auricle to reconstruct the tragus and external auditory meatus is an effective auricular reconstruction technique.
[...]
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Article in Thieme eJournals:
Table of contents | Abstract | Full text
http://ift.tt/2Bq5r5B
Alum-adjuvanted allergoids induce functional IgE-blocking antibodies
Abstract
The only therapy that is able to modulate the cause of IgE-mediated allergy and to attain a long-term effect is allergen-specific immunotherapy (AIT). In conventional subcutaneous AIT, the vaccine consists of an extract from an allergen source that contains major and minor allergens as well as non-allergenic proteins. To reduce IgE-mediated side effects caused by the injection of intact allergens, chemically modified extracts with less IgE-binding activity, named allergoids, have been used for AIT since the 1980′s.
This article is protected by copyright. All rights reserved.
http://ift.tt/2ElgJXw
Global Impact of 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A Perspective From China.
Author: Wang, Ji-Guang MD, PhD; Liu, Lisheng MD
Page: 546-548
http://ift.tt/2EC5r4B
Global Impact of 2017 American Heart Association/American College of Cardiology Hypertension Guidelines: A Perspective From India.
Author: Wander, Gurpreet S. MD, DM; Ram, C. Venkata S. MD
Page: 549-550
http://ift.tt/2ssmuBe
Validation of DAPT Score (Dual Antiplatelet Therapy) in East Asian Patients.
Author: Yabushita, Hiroto MD; Goto, Shinya MD, PhD
Page: 563-566
http://ift.tt/2stf290
Higher Risk of Vascular Dementia in Myocardial Infarction Survivors.
Author: Sundboll, Jens MD, PhD; Horvath-Puho, Erzsebet PhD; Adelborg, Kasper MD, PhD; Schmidt, Morten MD, PhD; Pedersen, Lars PhD; Botker, Hans Erik MD, PhD, DMSc; Henderson, Victor W. MD, MS; Toft Sorensen, Henrik MD, PhD, DMSc
Page: 567-577
http://ift.tt/2EzH6fP
Survivor's Remorse: Is There an Increased Risk of Dementia After Surviving a Myocardial Infarction?.
Author: Gottesman, Rebecca F. MD, PhD
Page: 578-580
http://ift.tt/2sqsfiP
Duct Stenting Versus Modified Blalock-Taussig Shunt in Neonates With Duct-Dependent Pulmonary Blood Flow: Associations With Clinical Outcomes in a Multicenter National Study.
Author: Bentham, James R. MD, PhD; Zava, Ngoni K.; Harrison, Wendy J. PhD; Shauq, Arjamand MD; Kalantre, Atul MD; Derrick, Graham MD; Chen, Robin H. MD; Dhillon, Rami MD; Taliotis, Demetris MD; Kang, Sok-Leng MD; Crossland, David MD; Adesokan, Akintayo MD; Hermuzi, Anthony MD; Kudumula, Vikram MD; Yong, Sanfui MD; Noonan, Patrick MD; Hayes, Nicholas MD; Stumper, Oliver MD, PhD; Thomson, John D.R. MD
Page: 581-588
http://ift.tt/2EC5Tj7
Postoperative Complications Decrease Long-Term Survival After Thoracic Aneurysm Repair Despite Apparently Successful "Rescue" From Early Mortality.
Author: Patterson, Benjamin O. PhD; Stenson, Kate MD; Grima, Matthew MD; de Bruin, Jorg MD; Al-Subaie, Nawaf MD; Loftus, Ian M. MD; Thompson, Matt M. MD; Holt, Peter J. PhD
Page: 636-638
http://ift.tt/2EoD6PS
Letter by Koh Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)".
Author: Koh, Kwang Kon MD, PhD
Page: 639-640
http://ift.tt/2Cg1ZHD
Letter by Jin-shan and Xue-bin Regarding Article, "Idiopathic Ventricular Fibrillation in a 29-Year-Old Man".
Author: Jin-shan, He MD; Xue-bin, Li MD
Page: 643-644
http://ift.tt/2CfjR5u
Response by Beach et al to Letter Regarding Article, "Idiopathic Ventricular Fibrillation in a 29-Year-Old Man".
Author: Beach, Leila Y. MD; Goldschlager, Nora MD; Moss, Joshua D. MD; Scheinman, Melvin M. MD
Page: 645
http://ift.tt/2EmX4KT
Editorial Advisory Board
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
http://ift.tt/2ChA3TQ
3-D Quantitative Dynamic Contrast Ultrasound for Prostate Cancer Localization
Publication date: Available online 12 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Stefan G. Schalk, Jing Huang, Jia Li, Libertario Demi, Hessel Wijkstra, Pintong Huang, Massimo Mischi
To investigate quantitative 3-D dynamic contrast-enhanced ultrasound (DCE-US) and, in particular 3-D contrast-ultrasound dispersion imaging (CUDI), for prostate cancer detection and localization, 43 patients referred for 10–12-core systematic biopsy underwent 3-D DCE-US. For each 3-D DCE-US recording, parametric maps of CUDI-based and perfusion-based parameters were computed. The parametric maps were divided in regions, each corresponding to a biopsy core. The obtained parameters were validated per biopsy location and after combining two or more adjacent regions. For CUDI by correlation (r) and for the wash-in time (WIT), a significant difference in parameter values between benign and malignant biopsy cores was found (p < 0.001). In a per-prostate analysis, sensitivity and specificity were 94% and 50% for r, and 53% and 81% for WIT. Based on these results, it can be concluded that quantitative 3-D DCE-US could aid in localizing prostate cancer. Therefore, we recommend follow-up studies to investigate its value for targeting biopsies.
http://ift.tt/2ChzWYq
Masthead
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
http://ift.tt/2ElWi0S
Comparison between Several Ultrasound Hand Joint Scores and Conventional Radiography in Diagnosing Hand Osteoarthritis
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Priyanka Sivakumaran, Sidra Hussain, Coziana Ciurtin
This is the first study to investigate the usefulness of a standardized ultrasound (US) examination protocol in diagnosing hand osteoarthritis (OA). We conducted a cross-sectional study including 62 patients, ultimately diagnosed with hand OA based on imaging evidence of osteoarthritic changes with the particular distribution required for fulfilment of American College of Radiology diagnosis criteria. We compared a 32-joint US score (wrists, metacarpophalangeal [MCP], proximal interphalangeal [PIP] or distal interphalangeal [DIP] and carpometacarpal [CMC]-1 joints), with smaller, predefined joint scores, assessing 22 joints (wrists, MCPs and PIPs or PIPs, DIPs and CMC-1), 10 joints (MCP 2–3, PIP 2–3 and CMC-1 or PIP 2–3, DIP 2–3 and CMC-1) and 6 joints (DIP 2–3, CMC-1), respectively. The US findings were correlated with radiographic scores for erosions and osteophytes. Radiographic osteophyte scores correlated well with all the US scores mentioned earlier (R = 0.381 to 0.645, p < 0.05), despite low sensitivity for detection of osteophytes (43.5%) and erosions (28.9%), compared with the 32 joint US score. Both 10 joint US protocols (assessing MCP 2–3, PIP 2–3 and CMC-1 or PIP 2–3, DIP 2–3 and CMC-1 joints) performed better than conventional radiography, by identifying osteophytes in an additional 25.6% and 23.9% of patients, respectively. The conclusion of this study is that the US examination of 10 preselected hand joints is more sensitive than conventional radiography in diagnosing hand OA in patients who do not fulfill American College of Radiology clinical criteria, a finding likely to have practical implications for facilitating diagnosis of hand OA.
http://ift.tt/2ChzN7k
Local Texture Anisotropy as an Estimate of Muscle Quality in Ultrasound Imaging
Publication date: Available online 7 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Guillaume J.R. Dubois, Damien Bachasson, Lilian Lacourpaille, Olivier Benveniste, Jean-Yves Hogrel
This study introduces local pattern texture anisotropy as a novel parameter to differentiate healthy and disordered muscle and to gauge the severity of muscle impairments based on B-mode ultrasound images. Preliminary human results are also presented. A local pattern texture anisotropy index (TAI) was computed in one region of interest in the short head of the biceps brachii. The effects of gain settings and box sizes required for TAI computation were investigated. Between-day reliability was studied in patients with sporadic inclusion body myositis (n = 26). The ability of the TAI to discriminate dystrophic from healthy muscle was evaluated in patients with Duchenne muscular dystrophy and healthy controls (n = 16). TAI values were compared with a gray-scale index (GSI). TAI values were less influenced by gain settings than were GSI values. TAI had lower between-day variability (typical error = 2.3%) compared with GSI (typical error = 2.3% vs. 8.3%, respectively). Patients with Duchenne muscular dystrophy had lower TAIs than controls (0.76 ± 0.06 vs. 0.87 ± 0.03, respectively, p < 0.05). At 40% gain, TAI values correlated with percentage predicted elbow flexor strength in inclusion body myositis (R = 0.63, p < 0.001). The TAI may be a promising addition to other texture-based approaches for quantitative muscle ultrasound imaging.
http://ift.tt/2EnnhsX
Calendar
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
http://ift.tt/2EoboCK
The Dependence of Glomerular Capillary Hemorrhage Induced by Contrast Enhanced Diagnostic Ultrasound on Microbubble Diameter
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Douglas L. Miller, Xiaofang Lu, Chunyan Dou, Mario L. Fabiilli, Charles C. Church
A recently proposed two-criterion model for cavitational bioeffects in tissue with microbubbles (MBs) was tested. The glomerular capillary hemorrhage bioeffect was observed in rat kidney for contrast agent MB suspensions with mean diameters of 1.6, 3.1 and 5.5 µm. A diagnostic ultrasound machine was used at 3.6 MHz and 5.5 MHz for intermittent scans at power settings 2 dB apart. Petechial hemorrhage counts scored on the surface of the kidneys, and glomeruli were scored in histology. Thresholds for the petechial hemorrhage measurements were the same for the large and medium MB suspensions but substantially higher for the small MBs. For the histology, the medium MBs gave a higher threshold than the large MBs at 5.5 MHz. The pressure amplitude thresholds are in approximate agreement with theory, and the optimum MB size counterintuitively increased for increasing ultrasound frequency, as predicted. The two-criterion model of MB-associated capillary hemorrhage is supported.
http://ift.tt/2ElKaN6
Pulmonary Capillary Hemorrhage Induced by Different Imaging Modes of Diagnostic Ultrasound
Publication date: Available online 7 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Douglas L. Miller, Zhihong Dong, Chunyan Dou, Krishnan Raghavendran
The induction of pulmonary capillary hemorrhage (PCH) is a well-established non-thermal biological effect of pulsed ultrasound in animal models. Typically, research has been done using laboratory pulsed ultrasound systems with a fixed beam and, recently, by B-mode diagnostic ultrasound. In this study, a GE Vivid 7 Dimension ultrasound machine with 10 L linear array probe was used at 6.6 MHz to explore the relative PCH efficacy of B-mode imaging, M-mode (fixed beam), color angio mode Doppler imaging and pulsed Doppler mode (fixed beam). Anesthetized rats were scanned in a warmed water bath, and thresholds were determined by scanning at different power steps, 2 dB apart, in different groups of six rats. Exposures were performed for 5 min, except for a 15-s M-mode group. Peak rarefactional pressure amplitude thresholds were 1.5 MPa for B-mode and 1.1 MPa for angio Doppler mode. For the non-scanned modes, thresholds were 1.1 MPa for M-mode and 0.6 MPa for pulsed Doppler mode with its relatively high duty cycle (7.7 × 10−3 vs. 0.27 × 10−3 for M-mode). Reducing the duration of M-mode to 15 s (from 300 s) did not significantly reduce PCH (area, volume or depth) for some power settings, but the threshold was increased to 1.4 MPa. Pulmonary sonographers should be aware of this unique adverse bio-effect of diagnostic ultrasound and should consider reduced on-screen mechanical index settings for potentially vulnerable patients.
http://ift.tt/2CfhsaY
Impact of Acoustic Radiation Force Excitation Geometry on Shear Wave Dispersion and Attenuation Estimates
Publication date: Available online 5 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Samantha L. Lipman, Ned C. Rouze, Mark L. Palmeri, Kathryn R. Nightingale
Shear wave elasticity imaging (SWEI) characterizes the mechanical properties of human tissues to differentiate healthy from diseased tissue. Commercial scanners tend to reconstruct shear wave speeds for a region of interest using time-of-flight methods reporting a single shear wave speed (or elastic modulus) to the end user under the assumptions that tissue is elastic and shear wave speeds are not dependent on the frequency content of the shear waves. Human tissues, however, are known to be viscoelastic, resulting in dispersion and attenuation. Shear wave spectroscopy and spectral methods have been previously reported in the literature to quantify shear wave dispersion and attenuation, commonly making an assumption that the acoustic radiation force excitation acts as a cylindrical source with a known geometric shear wave amplitude decay. This work quantifies the bias in shear dispersion and attenuation estimates associated with making this cylindrical wave assumption when applied to shear wave sources with finite depth extents, as commonly occurs with realistic focal geometries, in elastic and viscoelastic media. Bias is quantified using analytically derived shear wave data and shear wave data generated using finite-element method models. Shear wave dispersion and attenuation bias (up to 15% for dispersion and 41% for attenuation) is greater for more tightly focused acoustic radiation force sources with smaller depths of field relative to their lateral extent (height-to-width ratios <16). Dispersion and attenuation errors associated with assuming a cylindrical geometric shear wave decay in SWEI can be appreciable and should be considered when analyzing the viscoelastic properties of tissues with acoustic radiation force source distributions with limited depths of field.
http://ift.tt/2CfhoYM
Quantitative Analysis of Helical Flow with Accuracy Using Ultrasound Speckle Image Velocimetry: In Vitro and in Vivo Feasibility Studies
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Sang Joon Lee, Jun Hong Park, Jeong Ju Kim, Eunseop Yeom
Venous valve dysfunction and induced secondary abnormal flows are closely associated with venous diseases. Thus, detailed analysis of venous valvular flow is invaluable from biological and medical perspectives. However, most of the previous studies on venous perivalvular flows were based on qualitative analysis. On the contrary, quantitative analysis of perivalvular flows has not been fully understood. In this study, we used the ultrasound speckle image velocimetry (SIV) technique, which utilizes the speckle patterns of red blood cells (RBCs) created by ultrasound waves to measure 3-D valvular flows quantitatively. The flow structures obtained with the proposed SIV technique for an in vitro model were compared with those obtained by numerical simulation and the color Doppler method to validate the measurement accuracy of the ultrasound SIV technique. Blood flow in the human great saphenous vein was then measured at various distances from the valve with and without exercise. 3-D valvular flow was analyzed in accordance with the dimensionless index, helical intensity. The results obtained by the proposed method matched well with those obtained by numerical simulation and the color Doppler method. The hemodynamic characteristics of 3-D valvular helical flow which were analyzed experimentally using the SIV method would be used for quantitative diagnosis of venous valvular diseases.
http://ift.tt/2CfYvVt
Inter-Scan Reproducibility of Carotid Plaque Volume Measurements by 3-D Ultrasound
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Benjamin V. Sandholt, Antoine Collet-Billon, Robert Entrekin, Henrik H. Sillesen
We tested a novel 3-D matrix transducer with respect to inter-scan reproducibility of carotid maximum plaque thickness (MPT) and volume measurements. To improve reproducibility while focusing on the largest plaque/most diseased part of the carotid artery, we introduced a new partial plaque volume (PPV) measure centered on MPT. Total plaque volume (TPV), PPV from a 10-mm segment and MPT were measured using dedicated semi-automated software on 38 plaques from 26 patients. Inter-scan reproducibility was assessed using the t-test, Bland–Altman plots and Pearson's correlation coefficient. There was a mean difference of 0.01 mm in MPT (limits of agreement: −0.45 to 0.42 mm, Pearson's correlation coefficient: 0.96). Both volume measurements exhibited high reproducibility, with PPV being superior (limits of agreement: −35.3 mm3 to 33.5 mm3, Pearson's correlation coefficient: 0.96) to TPV (limits of agreement: −88.2 to 61.5 mm3, Pearson's correlation coefficient: 0.91). The good reproducibility revealed by the present results encourages future studies on establishing plaque quantification as part of cardiovascular risk assessment and for follow-up of disease progression over time.
http://ift.tt/2EoBtBK
Double-Stage Delay Multiply and Sum Beamforming Algorithm Applied to Ultrasound Medical Imaging
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Moein Mozaffarzadeh, Masume Sadeghi, Ali Mahloojifar, Mahdi Orooji
In ultrasound (US) imaging, delay and sum (DAS) is the most common beamformer, but it leads to low-quality images. Delay multiply and sum (DMAS) was introduced to address this problem. However, the reconstructed images using DMAS still suffer from the level of side lobes and low noise suppression. Here, a novel beamforming algorithm is introduced based on expansion of the DMAS formula. We found that there is a DAS algebra inside the expansion, and we proposed use of the DMAS instead of the DAS algebra. The introduced method, namely double-stage DMAS (DS-DMAS), is evaluated numerically and experimentally. The quantitative results indicate that DS-DMAS results in an approximately 25% lower level of side lobes compared with DMAS. Moreover, the introduced method leads to 23%, 22% and 43% improvement in signal-to-noise ratio, full width at half-maximum and contrast ratio, respectively, compared with the DMAS beamformer.
http://ift.tt/2Cg9L4i
Acoustic Properties of Small Animal Soft Tissue in the Frequency Range 12–32 MHz
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Adela Rabell-Montiel, Adrian J. Thomson, Tom A. Anderson, Stephen D. Pye, Carmel M. Moran
Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties of which mimic those of soft tissue. However, the acoustic properties of many soft tissue types have not been measured at ultrasonic frequencies >9 MHz. With the increasing use of high-frequency ultrasound for both clinical and pre-clinical applications, it is of increasing interest to ensure that TMMs accurately reflect the acoustic properties of soft tissue at these higher frequencies. In this study, the acoustic properties of ex vivo brain, liver and kidney samples from 50 mice were assessed in the frequency range 12–32 MHz. Measurements were performed within 6 min of euthanasia in a phosphate-buffered saline solution maintained at 37.2 ± 0.2 °C. The measured mean values for the speed of sound for all organs were found to be higher than the International Electrotechnical Commission guideline recommended value for TMMs. The attenuation coefficients measured for brain, liver and kidney samples were compared with the results of previous studies at lower frequencies. Only the measured kidney attenuation coefficient was found to be in good agreement with the International Electrotechnical Commission guideline. The information provided in this study can be used as a baseline on which to manufacture a TMM suitable for high-frequency applications.
http://ift.tt/2EkVDg5
Ultrasound Characterization of Bone Demineralization Using a Support Vector Machine
Publication date: March 2018
Source:Ultrasound in Medicine & Biology, Volume 44, Issue 3
Author(s): Max Denis, Leighton Wan, Mostafa Fatemi, Azra Alizad
We propose an ultrasound-guided remote measurement technique, utilizing an acoustic radiation force beam as our excitation source and a receiving hydrophone, to assess non-invasively a bone's mechanical properties. Features, such as velocity, were extracted from the acoustic pressure received from the bone surface. The typical velocity of an intact bone (3540 m/s) was higher in comparison to that of a demineralized bone (2231 m/s). According to the receiver operating characteristic curve, the optimal velocity cutoff value of ≥3096 m/s yields 80% sensitivity and 82.61% specificity between intact and demineralized bone. Utilizing a support vector machine, the hours of bone demineralization were successfully classified with maximum accuracy >80% using 18% training data. The results indicate the potential application of our proposed technique and support vector machine for monitoring bone mechanical properties.
http://ift.tt/2CfNWlu
A role for Glucagon-Like Peptide-1 in the regulation of β-cell autophagy
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Catherine Arden
Autophagy is a highly conserved intracellular recycling pathway that serves to recycle damaged organelles/proteins or superfluous nutrients during times of nutritional stress to provide energy to maintain intracellular homeostasis and sustain core metabolic functions. Under these conditions, autophagy functions as a cell survival mechanism but impairment of this pathway can lead to pro-death stimuli. Due to their role in synthesising and secreting insulin, pancreatic β-cells have a high requirement for robust degradation pathways. Recent research suggests that functional autophagy is required to maintain β-cell survival and function in response to high fat diet suggesting a pro-survival role. However, a role for autophagy has also been implicated in the pathogenesis of type 2 diabetes. Thus, the pro-survival vs pro-death role of autophagy in regulating β-cell mass requires discussion. Emerging evidence suggests that Glucagon-Like Peptide-1 (GLP-1) may exert beneficial effects on glucose homeostasis via autophagy-dependent pathways both in pancreatic β-cells and in other cell types. The aim of the current review is to: i) summarise the literature surrounding β-cell autophagy and its pro-death vs pro-survival role in regulating β-cell mass; ii) review the literature describing the impact of GLP-1 on β-cell autophagy and in other cell types; iii) discuss the potential underlying mechanisms.
http://ift.tt/2Cge7Zd
Glucagon receptor signaling in metabolic diseases
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Nicolai J. Wewer Albrechtsen
Glucagon is a peptide hormone secreted from the pancreatic alpha cells in response to hypoglycemia but in some patients with type 2 diabetes a paradoxical hypersecretion results from the intake of glucose. In rodent, antagonizing the actions of glucagon have been shown to be effective for lowering blood glucose levels and this has recently have been solidified in patients with type 2 diabetes. Although the reported increases of liver enzymes, hyperglucagonemia, and alpha cell hyperplasia resulting from glucagon receptor antagonism may potentially limit the clinical applicability of glucagon receptor antagonists, they may serve as an instrumental toolbox for delineating the physiology of glucagon. Agonizing glucagon receptor signaling may be relevant, in particular when combined with glucagon-like peptide-1 receptor analogues in the perspective of body weight lowering therapy. Here, we will focus on new conceptual aspects of glucagon biology and how this may led to new diagnostics and treatment of metabolic diseases.
http://ift.tt/2Ch4clY
Tissue expression of DPP-IV in obesity-diabetes and modulatory effects on peptide regulation of insulin secretion
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Aine M. McKillop, Claire L. Stevenson, Brian M. Moran, Yasser H.A. Abdel-Wahab, Peter R. Flatt
Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent an important class of glucose-lowering drug for type 2 diabetes. DPP-4 enzyme activity has been observed to be significantly altered in type 2 diabetes. Here, the role of DPP-4 was examined in a high fat fed (HFF) mouse model of insulin resistance. HFF mice had an increased bodyweight (p < .01), were hyperglycaemic (p < .01) and hyperinsulinaemic (p < .05). Compared to normal diet, HFF mice exhibited increased plasma DPP-4 activity (p < .01). Tissue distribution patterns in lean and HFF mice demonstrated highest levels of DPP-4 activity in lung (20–26 μmol/min/mg protein) and small intestine (13–14 μmol/min/mg protein), and lowest activity in the spleen (3.8 μmol/min/mg protein). Modulation of DPP-4 activity by high fat feeding was observed in several tissues with increases in the lung (p < .05), liver (p < .05), kidney (p < .05) and pancreas (p < .05). With a high fat diet, DPP-4 gene expression was upregulated in the liver (p < .001) and downregulated in the pancreas (p < 0.001) and small intestine (p < .001). Immunohistochemical analysis revealed increased DPP-4 immunostaining localised primarily in the pancreatic islets of HFF mice (p < .01) with no change in islet GLP-1 expression. Treatment of HFF mice with metformin for 21-days resulted in inhibition of circulating DPP-4 activity (p < .05), decreased blood glucose (p < .05) and increased GLP-1 gene expression (p < .001). These data indicate that DPP-4 is modulated in a tissue specific manner and is dependent on physiological conditions such as hyperglycaemia and insulin resistance, suggesting a significant role in disorders such as diabetes.
http://ift.tt/2ElDE96
Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity
Publication date: April 2018
Source:Peptides, Volume 102
Author(s): Mitsuaki Takeuchi, Masayuki Okamoto, Ryuji Okamoto, Hiroshi Kinoshita, Yu Yamaguchi, Nobuhide Watanabe
In the course of our search for new GLP-1 analogs, we screened a number of [Ser8]-GLP-1 analogs using the C-terminal helix 3 of the albumin binding domain 3 of protein G from bacterial Streptococcal G strain 148 (G148-ABD3) as appendage. Our efforts led to the discovery of [Ser8]-GLP-1 (7-35)-GVKALIDEILAA-NH2, peptide 6, as a long-acting GLP-1 analog with enhanced self-associated aggregation. Peptide 6 showed enhanced stability in rat and human plasma and an extended half-life of 5.4 h with good bioavailability in rats and subsequently prolonged therapeutic effects in diabetic mice. Analytical ultracentrifugation and TLC suggest that 6 remains oligomeric in the circulation, which accounts for its extended in vivo half-life. The present work shows the possible enhancement of medium-sized oligopeptides aggregation propensity and highlights the potential advantages of peptide aggregates for long-acting peptide drugs.
Graphical abstract
http://ift.tt/2Env75P
GLP-1 receptor agonists show neuroprotective effects in animal models of diabetes
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Victor A. Gault, Christian Hölscher
Enzyme-resistant receptor agonists of the incretin hormone glucagon-like peptide-1 (GLP-1) have shown positive therapeutic effects in people with type 2 diabetes mellitus (T2DM). T2DM has detrimental effects on brain function and impairment of cognition and memory formation has been described. One of the underlying mechanisms is most likely insulin de-sensitization in the brain, as insulin improves cognitive impairments and enhances learning. Treatment with GLP-1 receptor agonists improves memory formation and impairment of synaptic plasticity observed in animal models of diabetes-obesity. Furthermore, it has been shown that diabetes impairs growth factor signalling in the brain and reduces energy utilization in the cortex. Inflammation and apoptotic signalling was also increased. Treatment with GLP-1 receptor agonists improved neuronal growth and repair and reduced inflammation and apoptosis as well as oxidative stress. In comparison with the diabetes drug metformin, GLP-1 receptor agonists were able to improve glycemic control and reverse brain impairments, whereas metformin only normalized blood glucose levels. Clinical studies in non-diabetic patients with neurodegenerative disorders showed neuroprotective effects following administration with GLP-1 receptor agonists, demonstrating that neuroprotective effects are independent of blood glucose levels.
http://ift.tt/2Cjo48o
Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Clifford J. Bailey
This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised 'closed loop' artificial pancreas systems. Proof of concept has been established for non-cellular glucose-responsive insulin delivery ('smart insulins') to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia.
http://ift.tt/2EmfVFT
Targeted intestinal delivery of incretin secretagogues—towards new diabetes and obesity therapies
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Fiona M. Gribble, Claire L. Meek, Frank Reimann
A new strategy under development for the treatment of type 2 diabetes and obesity is to mimic some of the effects of bariatric surgery by delivering food-related stimuli to the distal gastrointestinal tract where they should enhance the release of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Methods include inhibition of food digestion and absorption in the upper GI tract, or oral delivery of stimuli in capsules or pelleted form to protect them against gastric degradation. A variety of agents have been tested in humans using capsules, microcapsules or pellets, delivering nutrients, bile acids, fatty acids and bitter compounds. This review examines the outcomes of these different approaches and supporting evidence from intestinal perfusion studies.
http://ift.tt/2CfTegD
LmrBPP9: A synthetic bradykinin-potentiating peptide from Lachesis muta rhombeata venom that inhibits the angiotensin-converting enzyme activity in vitro and reduces the blood pressure of hypertensive rats
Publication date: April 2018
Source:Peptides, Volume 102
Author(s): Ernesto Lopes Pinheiro-Júnior, Johara Boldrini-França, Luciana Mattoso Pires de Campos Araújo, Norival Alves Santos-Filho, Lusiane Maria Bendhack, Eduardo Maffud Cilli, Eliane Candiani Arantes
Bradykinin-potentiating peptides (BPPs) are an important group of toxins present in Lachesis muta rhombeata venom. They act directly at renin-angiotensin-aldosterone system, through the inhibition of angiotensin-converting enzyme (ACE). This action may contribute to the hypotensive shock observed during the envenoming by this species. Thus, the main goal of this study was the solid-phase synthesis of a BPP found in L. m. rhombeata venom and its in vitro and in vivo characterization in relation to ACE inhibition and hypotensive activity, respectively. The LmrBPP9 peptide was synthesized using an automated solid-phase peptide synthesizer and purified by reversed-phase fast protein liquid chromatography (FPLC). The in vitro IC50 of the synthetic peptide is 4.25 ± 0.10 μM, showing a great capacity of ACE inhibition. The in vivo studies showed that LmrBPP9 induces blood pressure reduction, both in normotensive and hypertensive rats, being more pronounced in the last ones. These results agree with the in vitro results, showing that the synthetic peptide LmrBPP9 is a potential molecule to the development of a new antihypertensive drug.
Graphical abstract
http://ift.tt/2EmuZTR
Oral delivery of anti-diabetes therapeutics using cell penetrating and transcytosing peptide strategies
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Sahrish Rehmani, James E. Dixon
Oral delivery of insulin and other anti-diabetic peptides is inhibited by low intestinal absorption caused by the poor permeability across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules by electrostatic or covalent conjugation on in conjunction with nanotechnology. Endogenous cellular uptake mechanisms present in the intestine can be exploited by engineering peptide conjugates that transcytose; entering cells by endocytosis and leaving by exocytosis. Efficiently delivering hydrophilic and sensitive peptide drugs to safely transverse the digestive barrier with no effect on gut physiology using remains a key driver for formulation research. Here we review the use of CPP and transcytosis peptide approaches, their modification and use in delivering anti-diabetic peptides (with the primary example of Insulin and engineered homologues) by direct oral administration to treat diabetes and associated metabolic disorders.
http://ift.tt/2Cgj6sE
Alpha cell dysfunction in type 1 diabetes
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Gina L.C. Yosten
Type 1 diabetes is characterized by selective loss of beta cells and insulin secretion, which significantly impact glucose homeostasis. However, this progressive disease is also associated with dysfunction of the alpha cell component of the islet, which can exacerbate hyperglycemia due to paradoxical hyperglucagonemia or lead to severe hypoglycemia as a result of failed counterregulation. In this review, the physiology of alpha cell secretion and the potential mechanisms underlying alpha cell dysfunction in type 1 diabetes will be explored. Because type 1 diabetes is a progressive disease, a synthesized timeline of aberrant alpha cell function will be presented as an attempt to delineate the natural history of type 1 diabetes with respect to the alpha cell.
http://ift.tt/2EnhOSX
Intestinal peptide changes after bariatric and minimally invasive surgery: Relation to diabetes remission
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Lidia Castagneto Gissey, James Casella Mariolo, Geltrude Mingrone
Bariatric surgery is very effective in achieving and maintaining weight loss but it is also associated with improvement of obesity metabolic complications, primarily type 2 diabetes (T2D). Remission of T2D or at least a net improvement of glycemic control persists for at least 5 years. The bypass of duodenum and of the first portion of the jejunum up to the Treitz ligament as in Roux-en-Y Gastric Bypass (RYGB), or the bypass of the duodenum, the entire jejunum and the first tract of the ileum, such as in Bilio-Pancreatic Diversion (BPD), achieve different results on insulin sensitivity. Insulin resistance is the major driver of T2D manifesting long before insulin secretion failure. In fact, T2D development can be prevented by treatment with insulin sensitizing agents. Interestingly, RYGB improves hepatic insulin sensitivity while BPD ameliorates whole-body insulin sensitivity.Two major theories have been advocated to explain the early remission of T2D following RYGB or BPD before a meaningful weight loss takes place, the foregut and the hindgut hypotheses. The former holds that the bypass of the proximal intestine, i.e. duodenum and jejunum, prevents the secretion of signals − including nervous transmitters and hormones − promoting insulin resistance, the latter instead states that the delivery of nutrients directly into the ileum stimulates the secretion of hormones improving glucose disposal. The most studied candidate is Glucagon Like Peptide 1 (GLP1). However, while there is unambiguous evidence that GLP-1 stimulates insulin secretion, its direct action in lowering insulin resistance, independently of the effect on weight loss secondary to its satiety action, is utterly controversial.In this review we examine the effects on T2D and gastrointestinal peptide secretion produced by different types of metabolic surgery and by minimally invasive endoscopic surgery, whose utilization for the treatment of obesity and T2D is gaining wider interest and acceptance.
http://ift.tt/2Eqns6s
Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes
Publication date: February 2018
Source:Peptides, Volume 100
Author(s): Carolyn F. Deacon
Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
http://ift.tt/2Cjo1JK
The cationic tetradecapeptide mastoparan as a privileged structure for drug discovery: Enhanced antimicrobial properties of mitoparan analogues modified at position-14
Publication date: March 2018
Source:Peptides, Volume 101
Author(s): John Howl, Lewis Howl, Sarah Jones
Mastoparan (MP) peptides, distributed in insect venoms, induce a local inflammatory response post envenomation. Most endogenous MPs share common structural elements within a tetradecapeptide sequence that adopts an amphipathic helix whilst traversing biological membranes and when bound to an intracellular protein target. Rational modifications to increase cationic charge density and amphipathic helicity engineered mitoparan (MitP), a mitochondriotoxic bioportide and potent secretagogue. Following intracellular translocation, MitP is accreted by mitochondria thus indicating additional utility as an antimicrobial agent. Hence, the objectives of this study were to compare the antimicrobial activities of a structurally diverse set of cationic cell penetrating peptides, including both MP and MitP sequences, and to chemically engineer analogues of MitP for potential therapeutic applications. Herein, we confirm that, like MP, MitP is a privileged structure for the development of antimicrobial peptides active against both prokaryotic and eukaryotic pathogens. Collectively, MitP and target-selective chimeric analogues are broad spectrum antibiotics, with the Gram-negative A. baumannii demonstrating particular susceptibility. Modifications of MitP by amino acid substitution at position-14 produced peptides, Δ14MitP analogues, with unique pharmacodynamic properties. One example, [Ser14]MitP, lacks both cytotoxicity against human cell lines and mast cell secretory activity yet retains selective activity against the encapsulated yeast C. neoformans.
http://ift.tt/2ElDApS
RFRP-3, the mammalian ortholog of GnIH, induces cell cycle arrest at G2/M in porcine ovarian granulosa cells
Publication date: March 2018
Source:Peptides, Volume 101
Author(s): Xiaoye Wang, Xun Li, Chuanhuo Hu
RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of gonadotropin-inhibitory hormone (GnIH), has been proposed as a key inhibitory regulator of mammal reproduction. Our previous studies have demonstrated that RFRP-3 inhibited the expression of proliferation-related proteins in porcine granulose cells (GCs), but the inhibitory mechanism causing this has not been discovered. Here, we aim to elucidate the underlying mechanism and determine the cell cycle regulatory sites of action of RFRP-3 on porcine GC proliferation. To this end, the viability of porcine GCs was initially estimated by cell counting kit-8 (CCK-8). We confirmed that different doses of RFRP-3 decreased the cellular viability, suggesting that RFRP-3 could inhibit the proliferation of GCs. Subsequently, we evaluated the direct effects of RFRP-3 on the expression of cell cycle regulators. Compared to the control treated cells, 10−6 and 10−8 M of RFRP-3 effectively reduced the transcription of Cyclin B1 and CDK1 mRNAs. However, treatment with RFRP-3 did not alter Cyclin A2, Cyclin D1, CDK2, or CDK4 mRNA levels. These results suggest that RFRP-3 might be inducing G2/M-phase arrest in porcine GCs. Finally, to further determine the molecular mechanism underlying RFRP-3-mediated G2/M cell cycle arrest, we observed the levels of G2/M cell cycle regulatory factors in RFRP-3-treated porcine GCs. The results showed that RFRP-3 treatment significantly increased the expression of Myt1, p-Wee1 and p-Cdc2, whereas the level of Cyclin B1 significantly decreased in porcine GCs treated with 10−6 M of RFRP-3. Taken together, our data suggest that RFRP-3 regulates the phosphorylation or expression of G2/M cell cycle regulatory factors to induce G2/M-phase arrest via inhibition Cyclin B-CDK1 complex activation in porcine GCs, which might provide an unfavorable condition for porcine GC proliferation.
http://ift.tt/2Cgj5VC
Protective effects of antioxidin-RL from Odorrana livida against ultraviolet B-irradiated skin photoaging
Publication date: March 2018
Source:Peptides, Volume 101
Author(s): Di Qin, Wen-Hui Lee, Zhiqin Gao, Weifen Zhang, Meiyu Peng, Tongyi Sun, Yuanyuan Gao
The unavoidable daily exposure of the skin to ultraviolet (UV) B radiation is proven to have deleterious effects. The action mechanism of antioxidin-RL, an antioxidant peptide purified from skin secretions of frog Odorrana livida with amino acid sequence of AMRLTYNRPCIYAT, is well characterized by NMR titration and mutation based on ABTS+ scavenging activities. In order to explore the protective effects of antioxidin-RL against UVB-irradiated skin photoaging, cell uptake assay was used to detect the location of antioxidin-RL molecules serving various biological functions in the cells. The protective effects of antioxidin-RL on UVB-induced response were examined in vitro and in vivo. Results showed that antioxidin-RL successfully penetrated the cell membrane and exerted a positive effect on cell migration. It also effectively inhibited the UVB-induced excessive production of ROS and prevented oxidative damage to DNAs and proteins. Moreover, the mRNA expressions of MMP-1, VEGF, COX-2, and pro-inflammatory cytokines, such as IL-6 and TNF-α in antioxidin-RL-treated HaCaT and HSF cells were significantly down-regulated whereas those of FGF, procollagen type I and TGF-β1 up-regulated. Antioxidin-RL effectively prevented UVB-induced erythema on mouse skin, thereby inhibiting UVB-induced skin thickening and inflammation and increasing collagen deposition as demonstrated by in vivo experiments. Hence, the novel antioxidant peptide antioxidin-RL can effectively reduce UVB-induced skin reactions in vivo and in vitro, providing potential molecules against UVB-induced inflammation and photoaging.
http://ift.tt/2ElDA9m
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