Medicine by Sfakianakis Alexandros: 06/10/17

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Bilateral ocular ischemia-induced blindness as a presenting manifestation of Takayasu arteritis: a case report

Takayasu arteritis is a granulomatous panarteritis that predominantly affects the aorta and its major branches. The initial manifestations of this large-vessel vasculitis are usually nonspecific; however, as t...

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Very accelerated radiotherapy or concurrent chemoradiotherapy for N3 head and neck squamous cell carcinoma: Pooled analysis of two GORTEC randomized trials

Publication date: August 2017
Source:Oral Oncology, Volume 71
Author(s): Yungan Tao, Anne Aupérin, Pierre Graff, Michel Lapeyre, Vincent Grégoire, Philippe Maingon, Lionel Geoffrois, Pierre Verrelle, Gilles Calais, Bernard Gery, Laurent Martin, Marc Alfonsi, Patrick Deprez, Etienne Bardet, Thierry Pignon, Michel Rives, Christian Sire, Jean Bourhis
ObjectiveTo analyze the outcome of N3 patients treated with very accelerated radiotherapy (VART) or different schedules of concurrent chemoradiotherapy (CRT) within two phase III trials.Patients and methodsData of 179 patients with N3 HNSCC from two GORTEC randomized trials (96-01 and 99-02) were pooled. Patients received either VART: 64.8Gy/3.5weeks or one of the 3 following CRT regimens: Conventional CRT: 70Gy/7weeks+3 cycles carboplatin-5FU; Moderately accelerated CRT: 70Gy/6weeks+2 cycles carboplatin-5FU; Strongly intensified CRT: 64Gy/5weeks+cisplatin (days 2, 16, 30) and 5 FU (days 1–5, 29–33) followed by 2 cycles adjuvant cisplatin-5FU.ResultsMedian follow-up was 13.3 and 5.2years for GORTEC 96-01 and GORTEC 99-02, respectively. Five-year overall survival (OS) was 13.8%. No significant difference was observed between CRT versus VART in terms of OS (hazard ratio [HR]: 0.93, p=0.68), loco-regional progression (HR: 0.70, p=0.13), or distant progression (HR: 0.86, p=0.53). OS was worse for patients with T3-4 tumors versus early T stage (11.0% versus 25.7%, p=0.015). In multivariate analysis, the oropharyngeal subsite presented a higher risk of distant metastasis (as first event 46.5% vs 19.2%, p<0.001),). A significant interaction between treatment modalities and subsites has been observed concerning loco-regional and distant failures.ConclusionThe outcome of N3 HNSCC was extremely poor despite treatment intensification and no difference between CRT and VART. Both distant metastases and loco-regional failures remain important treatment challenge.

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Nutritional changes in patients with locally advanced head and neck cancer during treatment

Publication date: August 2017
Source:Oral Oncology, Volume 71
Author(s): L. Arribas, L. Hurtós, M. Taberna, I. Peiró, E. Vilajosana, A. Lozano, S. Vazquez, R. Mesia, N. Virgili
ObjectiveThe purpose of the study is to evaluate changes in body composition and nutritional status that occur throughout the oncological treatment in head and neck cancer patients.MethodsA prospective cohort observational study in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) that underwent treatment with induction chemotherapy (iCT) followed by chemoradiotherapy or bioradiotherapy were invited to participate. All patients had dietetic counseling from the diagnosis and a close monitoring throughout the treatment implementing nutritional support as needed.ResultsFrom June 2011 until October 2012, 20 patients were included. Nutritional and anthropometric parameters were collected at diagnosis, post iCT, after radiotherapy, 1 and 3months post radiotherapy. According to Patient Generated Subjective Global Assessment, 30% of patients were malnourished at diagnosis. After iCT there was an increase in weight, body mass index (BMI) and fat free mass (FFM) with almost complete improvement in dysphagia and odynophagia. Nevertheless a significant nutritional deterioration (p=0.0022) occurred at the end of radiotherapy with 95% of patients becoming severe or moderate malnourished. Nutritional parameters such as weight, BMI and hand grip strength also decrease significantly during treatment.ConclusionsDespite an intensive nutritional support from the diagnosis throughout the oncological treatment in advanced HNSCC cancer patients, nutritional status deteriorates during radiotherapy. Our findings suggest that iCT may help improve nutritional status by ameliorating the symptoms that limit the oral intake. This improvement in the nutritional status could contribute to minimize further deterioration. Further investigations are needed involving novel approaches to avoid nutritional deterioration.

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Nicorandil modulated macrophages activation and polarization via NF-κb signaling pathway

Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Fengyun Zhang, Yongli Xuan, Jinjin Cui, Xinxin Liu, Zhiying Shao, Bo Yu
Nicorandil, a drug with both nitrate-like and ATP-sensitive potassium (KATP) channel-activating properties, has been well demonstrated in various aspects of myocardial infarction (MI), especially in inhibiting cell apoptosis and increasing coronary flow. However, the role of nicorandil in regulating inflammation and angiogenesis following myocardial infarction is still unrevealed. In the present study, we explored the effect of nicorandil on macrophage phenotype transition and inflammation regulation and the potential underlying mechanisms. For the phenotype transition and phagocytosis ability of macrophages detection, flow cytometry analysis was used. The inflammation factors were measured with ELISA and qRT-PCR. Western blot was used to assess the levels of NF-κb and its target genes and VEGF expression. The tube formation ability of endothelial cells was examined on matrigel. We discovered that nicorandil can obviously inhibit the differentiation of monocytes into mature macrophages and decrease M1 phenotype transition both in peritoneal macrophages and cultured macrophage cell line in normal or hypoxia and serum deprivation (H/SD) conditions. Meanwhile, nicorandil can induce an anti-inflammatory M2 phenotype. Thereby, nicorandil regulated macrophages switching to M1/M2 status. Our data further showed that NF-κb and the expression of its target genes were pivotal players in the regulation of macrophages phenotype. Besides, we also showed that nicorandil can promote the tube formation and VEGF expression in endothelial cells. We concluded that nicorandil may serve as an effective modulator of NF-κb signaling pathway during the pathogenesis of MI via regulating M1/M2 status and promoting angiogenesis.

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Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses

Publication date: Available online 10 June 2017
Source:Molecular Immunology
Author(s): Per H. Nilsson, Anub Mathew Thomas, Grethe Bergseth, Alice Gustavsen, Elena B. Volokhina, Lambertus P. van den Heuvel, Andreas Barratt-Due, Tom E. Mollnes
The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.

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Deterrence in Cyberspace: a Silver Bullet or a Sacred Cow?

Abstract

This commentary briefly reviews the challenges associated with the concept of cyber deterrence. It considers the concept of deterrence more broadly before identifying the specific issues that make both deterrence by denial and by punishment particularly difficult in cyberspace. However, overall, it argues that the concept is valid and indeed essential in contributing to delivering strategic stability.

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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection

Transfer of innovation on allergic rhinitis and asthma multimorbidity in the elderly (MACVIA-ARIA) - Reference Site Twinning (EIP on AHA)

Abstract

The overarching goals of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) are to enable European citizens to lead healthy, active and independent lives while ageing. The EIP on AHA includes 74 Reference Sites. The aim of this study is to transfer innovation from an App developed by the MACVIA-France EIP on AHA reference site (Allergy Diary) to other reference sites. The phenotypic characteristics of rhinitis and asthma multimorbidity in adults and the elderly will be compared using validated information and communication technology (ICT) tools (i.e. the Allergy Diary and CARAT: Control of Allergic Rhinitis and Asthma Test) in 22 Reference Sites or regions across Europe. This will improve understanding, assessment of burden, diagnosis and management of rhinitis in the elderly by comparison with an adult population. Specific objectives will: (i) assess the percentage of adults and elderly who are able to use the Allergy Diary, (ii) study phenotypic characteristics and treatment over a period of one year of rhinitis and asthma multimorbidity at baseline (cross-sectional study) and (iii) follow-up using visual analogue scale (VAS). This part of the study may provide some insight into the differences between the elderly and adults in terms of response to treatment and practice. Finally (iv) work productivity will be examined in adults.

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Influences of environmental bacteria and their metabolites on allergies, asthma and host microbiota

Abstract

The prevalence of allergic diseases and asthma has dramatically increased over the last decades, resulting in a high burden for patients and health care systems. Thus, there is an unmet need to develop preventative strategies for these diseases.

Epidemiological studies show that reduced exposure to environmental bacteria in early life (e.g birth by cesarian section, being formula-fed, growing up in an urban environment or with less contact to various persons) is associated with an increased risk to develop allergies and asthma later in life. Conversely, a reduced risk for asthma is consistently found in children growing up on traditional farms, thereby being exposed to a wide spectrum of microbes. However, clinical studies are still rare and to some extent contradicting. A detailed mechanistic understanding how environmental microbes influence the development of the human microbiome and the immune system is important to enable the development of novel preventative approaches that are based on the early modulation of the host microbiota and immunity.

In this mini-review we summarize current knowledge and experimental evidence for the potential of bacteria and their metabolites to be used for the prevention of asthma and allergic diseases.

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Spontaneous food allergy in Was-/- mice occurs independent of FcεRI-mediated mast cell activation

Abstract

Background

Food allergies are a growing health problem and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was^-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy.

Methods

Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was^-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed and the role of the high affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was^-/-Fcer1a^-/- mice.

Results

Polysensitization to food was detected in both WAS and food allergic patients which was recapitulated in the Was^-/- model. Oral administration of OVA in Was^-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was^-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was^-/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells and basophils.

Conclusions

Was^-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.

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Télédermatologie en milieu carcéral : mieux former le médecin de première ligne

Publication date: Available online 9 June 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): T. Badri

http://ift.tt/2rMkUb5

Mélanome : alcool ou café, il faut choisir

Publication date: Available online 9 June 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): J.-L. Schmutz

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Postoperative pulmonary complications following non-cardiothoracic surgery

1H022A073A03

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The meta-analysis

Publication date: Available online 9 June 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Fernando de Andrade Quintanilha Ribeiro

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Computational analysis of multimorbidity between asthma, eczema and rhinitis

by Daniel Aguilar, Mariona Pinart, Gerard H. Koppelman, Yvan Saeys, Martijn C. Nawijn, Dirkje S. Postma, Mübeccel Akdis, Charles Auffray, Stéphane Ballereau, Marta Benet, Judith García-Aymerich, Juan Ramón González, Stefano Guerra, Thomas Keil, Manolis Kogevinas, Bart Lambrecht, Nathanael Lemonnier, Erik Melen, Jordi Sunyer, Rudolf Valenta, Sergi Valverde, Magnus Wickman, Jean Bousquet, Baldo Oliva, Josep M. Antó

Background

The mechanisms explaining the co-existence of asthma, eczema and rhinitis (allergic multimorbidity) are largely unknown. We investigated the mechanisms underlying multimorbidity between three main allergic diseases at a molecular level by identifying the proteins and cellular processes that are common to them.

Methods

An in silico study based on computational analysis of the topology of the protein interaction network was performed in order to characterize the molecular mechanisms of multimorbidity of asthma, eczema and rhinitis. As a first step, proteins associated to either disease were identified using data mining approaches, and their overlap was calculated. Secondly, a functional interaction network was built, allowing to identify cellular pathways involved in allergic multimorbidity. Finally, a network-based algorithm generated a ranked list of newly predicted multimorbidity-associated proteins.

Results

Asthma, eczema and rhinitis shared a larger number of associated proteins than expected by chance, and their associated proteins exhibited a significant degree of interconnectedness in the interaction network. There were 15 pathways involved in the multimorbidity of asthma, eczema and rhinitis, including IL4 signaling and GATA3-related pathways. A number of proteins potentially associated to these multimorbidity processes were also obtained.

Conclusions

These results strongly support the existence of an allergic multimorbidity cluster between asthma, eczema and rhinitis, and suggest that type 2 signaling pathways represent a relevant multimorbidity mechanism of allergic diseases. Furthermore, we identified new candidates contributing to multimorbidity that may assist in identifying new targets for multimorbid allergic diseases.

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Computational analysis of multimorbidity between asthma, eczema and rhinitis

Background

Methods

Results

Conclusions

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Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection

Abstract

Background

Head and neck cancer of unknown primary (HNCUP) is rare and prospective studies are lacking. The impact of different prognostic factors such as age and N stage is not completely known, the optimal treatment is not yet established, and the reported survival rates vary. In the last decade, human papilloma virus (HPV) has been identified as a common cause of and important prognostic factor in oropharyngeal cancer, and there is now growing interest in the importance of HPV for HNCUP. The aim of the present study on curatively treated HNCUP was to investigate the prognostic importance of different factors, including HPV status, treatment, and overall survival.

Methods

A search for HNCUP was performed in the Swedish Cancer Registry, Western health district, between the years 1992–2009. The medical records were reviewed, and only patients with squamous cell carcinoma or undifferentiated carcinoma treated with curative intent were included. The tumor specimens were retrospectively analyzed for HPV with p16 immunostaining.

Results

Sixty-eight patients were included. The mean age was 59 years. The majority were males, and had N2 tumors. Sixty-nine percent of the tumors were HPV positive using p16 staining. Patients who were older than 70 years, patients with N3-stage tumors, and patients with tumors that were p16 negative had a significantly worse prognosis. The overall 5-year survival rate for patients with p16-positive tumors was 88% vs 61% for p16-negative tumors. Treatment with neck dissection and postoperative radiation or (chemo) radiation had 81 and 88% 5-year survival rates, respectively. The overall and disease-free 5-year survival rates for all patients in the study were 82 and 74%.

Conclusions

Curatively treated HNCUP had good survival. HPV infection was common. Independent prognostic factors for survival were age over 70 years, HPV status and N3 stage. We recommend that HPV analysis should be performed routinely for HNCUP. Treatment with neck dissection and postoperative radiation or (chemo) radiation showed similar survival rates.

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Update on Intranasal Medications in Rhinosinusitis

Abstract

This review describes beneficial effects and adverse events of various intranasal medications in treating rhinosinusitis. Application of intranasal steroids has been described in treating all subtypes of adult rhinosinusitis, but reports are limited in pediatrics and mostly in acute pediatric subgroups resulted in benefits While saline irrigation is effective for patients with chronic rhinosinusitis without polyps and in pediatric acute rhinosinusitis, there is no evidence yet for saline drips and sprays. Application of intranasal antifungals and nasal irrigation with surfactant brings more harm than benefits. There is no evidence supporting the use of intranasal antibiotics. We also review influence of devices, methods, and patient head position on nasal and paranasal sinus drug delivery.

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TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

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Update on Intranasal Medications in Rhinosinusitis

Abstract

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Drug allergy/hypersensitivity in adults and children.

No abstract available

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Chapter Four Technology of Minor Ingredients for Wafers and Waffles

Publication date: 2017
Source:Wafer and Waffle
Author(s): Karl F. Tiefenbacher
This chapter provides technological information ingredients in wafers and waffles that are minor in quantity but are quite frequently important for the final product's quality in terms of look, texture and taste. The discussion on a few other minor ingredients is included in other chapters of the book due to some factual context.

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Drug allergy/hypersensitivity in adults and children.

No abstract available

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Xenon as an Adjuvant to Propofol Anesthesia in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery: A Pragmatic Randomized Controlled Clinical Trial.

BACKGROUND: Xenon was shown to cause less hemodynamic instability and reduce vasopressor needs during off-pump coronary artery bypass (OPCAB) surgery when compared with conventionally used anesthetics. As xenon exerts its organ protective properties even in subanesthetic concentrations, we hypothesized that in patients undergoing OPCAB surgery, 30% xenon added to general anesthesia with propofol results in superior hemodynamic stability when compared to anesthesia with propofol alone. METHODS: Fifty patients undergoing elective OPCAB surgery were randomized to receive general anesthesia with 30% xenon adjuvant to a target-controlled infusion of propofol or with propofol alone. The primary end point was the total intraoperative dose of norepinephrine required to maintain an intraoperative mean arterial pressure >70 mm Hg. Secondary outcomes included the perioperative cardiorespiratory profile and the incidence of adverse and serious adverse events. RESULTS: Adding xenon to propofol anesthesia resulted in a significant reduction of norepinephrine required to attain the predefined hemodynamic goals (cumulative intraoperative dose: median [interquartile range]: 370 [116-570] vs 840 [335-1710] [micro]g, P = .001). In the xenon-propofol group, significantly less propofol was required to obtain a similar depth of anesthesia as judged by clinical signs and the bispectral index (propofol effect site concentration [mean +/- SD]: 1.8 +/- 0.5 vs 2.8 +/- 0.3 mg, P

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Perioperative Temperature Measurement Considerations Relevant to Reporting Requirements for National Quality Programs Using Data From Anesthesia Information Management Systems.

Background: Perioperative hypothermia may increase the incidences of wound infection, blood loss, transfusion, and cardiac morbidity. U.S. national quality programs for perioperative normothermia specify the presence of at least 1 "body temperature" >=35.5[degrees]C during the interval from 30 minutes before to 15 minutes after the anesthesia end time. Using data from 4 academic hospitals, we evaluated timing and measurement considerations relevant to the current requirements to guide hospitals wishing to report perioperative temperature measures using electronic data sources. METHODS: Anesthesia information management system databases from 4 hospitals were queried to obtain intraoperative temperatures and intervals to the anesthesia end time from discontinuation of temperature monitoring, end of surgery, and extubation. Inclusion criteria included age >16 years, use of a tracheal tube or supraglottic airway, and case duration >=60 minutes. The end-of-case temperature was determined as the maximum intraoperative temperature recorded within 30 minutes before the anesthesia end time (ie, the temperature that would be used for reporting purposes). The fractions of cases with intervals >30 minutes between the last intraoperative temperature and the anesthesia end time were determined. RESULTS: Among the hospitals, averages (binned by quarters) of 34.5% to 59.5% of cases had intraoperative temperature monitoring discontinued >30 minutes before the anesthesia end time. Even if temperature measurement had been continued until extubation, averages of 5.9% to 20.8% of cases would have exceeded the allowed 30-minute window. Averages of 8.9% to 21.3% of cases had end-of-case intraoperative temperatures

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Anesthetic and Obstetric Management of Syringomyelia During Labor and Delivery: A Case Series and Systematic Review.

BACKGROUND: Syringomyelia is a rare, slowly progressive neurological condition characterized by the presence of a syrinx within the spinal cord. Consensus regarding the safest mode of delivery and anesthetic management in patients with syringomyelia remains controversial and presents management dilemmas. This study reviews the cases of syringomyelia at our institution and provides a systematic review of the literature to guide decisions regarding labor and delivery management. METHODS: A retrospective review of cases at our hospital from 2002 to 2014 and a systematic review of the literature from 1946 to 2014 were undertaken. Hospital records and electronic databases were interrogated using International Classification of Diseases, 10th Revision codes and the keywords "syringomyelia," "syringobulbia," and "pregnancy". Data regarding demographics, diagnosis, radiology reports, neurological symptoms, mode of delivery, anesthetic management, and maternal-fetal outcomes were collected. RESULTS: We collected and analyzed data on a total of 43 pregnancies in 39 patients. The most common location for syrinx was in the cervicothoracic region (41.9%). The large majority of patients (n = 34; 87%) demonstrated signs and symptoms associated with syringomyelia before delivery. Syringomyelia associated with Arnold Chiari malformation was documented in 49% (n = 21) cases. General anesthesia was the most commonly used (n = 21/30, 70%) anesthetic technique for cesarean delivery. The majority (n = 9/13, 69%) of patients had an epidural sited for labor analgesia. There were no maternal or neonatal complications associated with neuraxial anesthesia; however, 3 cases (14%) raised concerns regarding general anesthesia including difficult intubation, transient worsening of neurological symptoms postpartum, and prolonged muscle paralysis after atracurium. CONCLUSIONS: Despite concerns regarding aggravation of the syrinx with vaginal delivery, this mode of delivery has never caused any documented long-term worsening of neurological condition. All techniques of anesthesia have been performed successfully without major lasting complications. All cases necessitate patient counseling and individualized multidisciplinary involvement to ensure maternal safety. (C) 2017 International Anesthesia Research Society

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Protective Lung Ventilation and Morbidity After Pulmonary Resection: A Propensity Score-Matched Analysis.

BACKGROUND: Protective lung ventilation (PLV) during one-lung ventilation (OLV) for thoracic surgery is frequently recommended to reduce pulmonary complications. However, limited outcome data exist on whether PLV use during OLV is associated with less clinically relevant pulmonary morbidity after lung resection. METHODS: Intraoperative data were prospectively collected in 1080 patients undergoing pulmonary resection with OLV, intentional crystalloid restriction, and mechanical ventilation to maintain inspiratory peak airway pressure =8 mL/kg (predicted body weight) mean tidal volume. The primary outcome was the occurrence of pneumonia and/or acute respiratory distress syndrome (ARDS). Propensity score matching was used to generate PLV and non-PLV groups with comparable characteristics. Associations between outcomes and PLV status were analyzed by exact logistic regression, with matching as cluster in the anatomic and nonanatomic lung resection cohorts. RESULTS: In the propensity score-matched analysis, the incidence of pneumonia and/or ARDS among patients who had an anatomic lung resection was 9/172 (5.2%) in the non-PLV compared to the PLV group 7/172 (4.1%; odds ratio, 1.29; 95% confidence interval, 0.48-3.45, P= .62). The incidence of pneumonia and/or ARDS in patients who underwent nonanatomic resection was 3/118 (2.5%) in the non-PLV compared to the PLV group, 1/118 (0.9%; odds ratio, 3.00; 95% confidence interval, 0.31-28.84, P= .34). CONCLUSIONS: In this prospective observational study, we found no differences in the incidence of pneumonia and/or ARDS between patients undergoing lung resection with tidal volumes =8 mL/kg. Our data suggest that when fluid restriction and peak airway pressures are limited, the clinical impact of PLV in this patient population is small. Future randomized trials are needed to better understand the benefits of a small tidal volume strategy during OLV on clinically important outcomes. (C) 2017 International Anesthesia Research Society

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Improving Performance by Monitoring the Success Rate of Peripheral Nerve Blocks.

In our hospital, we introduced a system to measure the collective and individual efficacy of brachial plexus and popliteal nerve blocks with the objective to create transparency as an instrument for monitoring and improvement. Initially, individual results were anonymous, but after 1 year anonymity was lifted within the team of anesthesiologists and results are now discussed quarterly. Collective performance of interscalene, supraclavicular, and popliteal blocks improved significantly over time. Sharing and discussing collective and individual performance has resulted in critical self-appraisal and increased willingness to learn from each other and strengthened the team's ambition for further improvement. (C) 2017 International Anesthesia Research Society

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Falls From the O.R. or Procedure Table.

Patient safety secured by constant vigilance remains a primary responsibility of every anesthesia professional. Although significant attention has been focused on patient falls occurring before and after surgery, a potentially catastrophic complication is when patients fall off an operating room or procedure table during anesthesia care. Because such events are (fortunately) uncommon, and because very little information is published in our literature, we queried 2 independent closed claims databases (the American Society of Anesthesiologists Closed Claims Project and the secure records of a private, anesthesia specialty-specific liability insurer) for information. We acquired documentation of patient events where a fall occurred during anesthesia care, noting the surrounding conditions of the provider, the patient, and the environment at the time of the event. We identified 21 claims (1.2% of cases) from the American Society of Anesthesiologists Closed Claims Project, while information from a private liability insurer identified falls in only 0.07% of cases. The percentage of these patients under general, regional, or monitored anesthesia care anesthesia was 71.5%, 19.5%, and 9.5%, respectively. To educate personnel about these uncommon events, we summarized this cohort with illustrative examples in a series of mini-case reports, noting that both inpatients and outpatients undergoing a broad array of procedures with various anesthetic techniques within and outside operating rooms may be vulnerable to patient falls. Based on detailed reports, we created 2 supplementary videos to further illuminate some of the unique mechanisms by which these events and their resulting injuries occur. When such information was available, we also noted the associated liability costs of defending and settling malpractice claims associated with these events. Our goal is to inform anesthesia and perioperative personnel about the common patient, provider, and environmental risk factors that appear to contribute to these mishaps, and suggest key strategies to mitigate the risks. (C) 2017 International Anesthesia Research Society

http://ift.tt/2so95Jl

Cardiorespiratory Alterations Following Acute Normovolemic Hemodilution in a Pediatric and an Adult Porcine Model: A Prospective Interventional Study.

BACKGROUND: Acute normovolemic hemodilution (ANH) is considered as a blood-sparing intervention during the perioperative management. We aimed at comparing the cardiopulmonary consequences of ANH between adult pigs and weaned piglets to establish the effects of lowering hematocrit in these age groups, and thereby testing the hypothesis that difference in the age-related physiological behavior will be reflected in the cardiorespiratory changes following ANH. METHODS: ANH was achieved in anesthetized, mechanically ventilated adult minipigs and 5-week-old weaned piglets by stepwise blood withdrawal (10 mL/kg) with crystalloids replacement. Cardiorespiratory assessments consisted of measuring airway resistance, respiratory tissue elastance, effective lung volume, extravascular lung water, mean arterial pressure, pulmonary blood flow, and cardiac output. Respiratory and hemodynamic measurements were made at control conditions and following each ANH condition obtained with 5 to 7 steps. RESULTS: ANH induced immediate and progressive increases in airway resistance and tissue elastance in both groups, with more pronounced worsening in adults despite the similar decreases in hematocrit. The increases in extravascular lung water were significantly greater in the adult population with the differences in mean (DM) of 25.1% (95% confidence interval [CI], 5.3%-44.9%). Progressive ANH led to significant decreases in the DM of pulmonary blood flow (45.3%; 95% CI, 19.8%-70.8%) and mean arterial pressure (36.3%; 95% CI, 18.7%-53.9%) only in adults, whereas cardiac output increased significantly only in the piglets (DM, 51.6; 95% CI, 14.2%-89.0%). CONCLUSIONS: While ANH led to mild detrimental cardiorespiratory changes in weaned piglets, gradual developments of bronchoconstriction, lung tissue extravasation and stiffening, and deteriorations in systemic and pulmonary hemodynamics were observed in adults. ANH may exert age-dependent cardiorespiratory effect. (C) 2017 International Anesthesia Research Society

http://ift.tt/2r4KZiK

Aerosolized Vasodilators for the Treatment of Pulmonary Hypertension in Cardiac Surgical Patients: A Systematic Review and Meta-analysis.

BACKGROUND: In cardiac surgery, pulmonary hypertension is an important prognostic factor for which several treatments have been suggested over time. In this systematic review and meta-analysis, we compared the efficacy of inhaled aerosolized vasodilators to intravenously administered agents and to placebo in the treatment of pulmonary hypertension during cardiac surgery. We searched MEDLINE, CENTRAL, EMBASE, Web of Science, and clinicaltrials.gov databases from inception to October 2015. The incidence of mortality was assessed as the primary outcome. Secondary outcomes included length of stay in hospital and in the intensive care unit, and evaluation of the hemodynamic profile. METHODS: Of the 2897 citations identified, 10 studies were included comprising a total of 434 patients. RESULTS: Inhaled aerosolized agents were associated with a significant decrease in pulmonary vascular resistance (-41.36 dyne[middle dot]s/cm5, P= .03) and a significant increase in mean arterial pressure (8.24 mm Hg, P= .02) and right ventricular ejection fraction (7.29%, P

http://ift.tt/2sofWm0

Virtual Reality as an Adjunctive Nonpharmacological Sedative During Orthopedic Surgery Under Regional Anesthesia: A Pilot and Feasibility Study.

This pilot study assessed the feasibility and potential for any possible sedation sparing effect of immersive virtual reality (IVR) therapy on patients undergoing joint replacement surgery under regional anesthesia. Nine participants were given IVR, regional anesthetic, and sedation. Ten received conventional care. Mean propofol usage was 155 +/- 45 mg/h in the conventional care group and 63 +/- 21 mg/h in the IVR group (P = .088, mean difference -91.6 mg/h, 95% confidence interval -200 to 16.87 mg/h). There was no significant difference in postoperative satisfaction between the 2 groups. This pilot study demonstrates that it is possible to safely provide IVR in an operating theater environment and may confer a sedation sparing effect. A larger, more powered, and randomized study is needed to assess this effect. (C) 2017 International Anesthesia Research Society

http://ift.tt/2r52iQU

Retrograde Type B Aortic Dissection Caused by Intraaortic Balloon Counterpulsation.

No abstract available

http://ift.tt/2so2X3T

Readmissions to Different Hospitals After Common Surgical Procedures and Consequences for Implementation of Perioperative Surgical Home Programs.

BACKGROUND: We consider whether there should be greater priority of information sharing about postacute surgical resources used: (1) at skilled nursing facilities or inpatient rehabilitation hospitals to which patients are transferred upon discharge (when applicable) versus (2) at different hospitals where readmissions occur. Obtaining and storing data electronically from these 2 sources for Perioperative Surgical Home initiatives are dissimilar; both can be challenging depending on the country and health system. METHODS: Using the 2013 US Nationwide Readmissions Database, we studied discharges of surgical diagnosis-related group (DRG) with US national median length of stay (LOS) >= 3 days and >= 10 hospitals each with >= 100 discharges for the Medicare Severity DRG. RESULTS: Nationwide, 16.15% (95% confidence interval [CI], 15.14%-17.22%) of discharges were with a disposition of "not to home" (ie, transfer to a skilled nursing facility or an inpatient rehabilitation hospital). Within 30 days, 0.88% of discharges (0.82%-0.95%) were followed by readmission and to a different hospital than the original hospital where the surgery was performed. Among all discharges, disposition "not to home" versus "to home" was associated with greater odds that the patient would have readmission within 30 days and to a different hospital than where the surgery was performed (2.11, 95% CI, 1.96-2.27; P

http://ift.tt/2r56Kim

Resuscitative Endovascular Balloon Occlusion of the Aorta: Principles, Initial Clinical Experience, and Considerations for the Anesthesiologist.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an endovascular technique that allows for temporary occlusion of the aorta in patients with severe, life-threatening, trauma-induced noncompressible hemorrhage arising below the diaphragm. REBOA utilizes a transfemoral balloon catheter inserted in a retrograde fashion into the aorta to provide inflow control and support blood pressure until definitive hemostasis can be achieved. Initial retrospective and registry clinical data in the trauma surgical literature demonstrate improvement in systolic blood pressure with balloon inflation and improved survival compared to open aortic cross-clamping via resuscitative thoracotomy. However, there are no significant reports of anesthetic implications and perioperative management in this challenging cohort. In this narrative, we review the principles, technique, and logistics of REBOA deployment, as well as initial clinical outcome data from our level-1 American College of Surgeons-verified trauma center. For anesthesiologists who may not yet be familiar with REBOA, we make several suggestions and recommendations for intraoperative management based on extrapolation from these initial surgical-based reports, opinions from a team with increasing experience, and translated experience from emergency aortic vascular surgical procedures. Further prospective data will be necessary to conclusively guide anesthetic management, especially as potential complications and implications for global organ function, including cerebral and renal, are recognized and described. (C) 2017 International Anesthesia Research Society

http://ift.tt/2so7GlW

Endoscopic Sleeve Gastroplasty: A Concern of Anesthesiologists.

No abstract available

http://ift.tt/2r4ZEKJ

Enhancing Feedback on Professionalism and Communication Skills in Anesthesia Residency Programs.

BACKGROUND: Despite its importance, training faculty to provide feedback to residents remains challenging. We hypothesized that, overall, at 4 institutions, a faculty development program on providing feedback on professionalism and communication skills would lead to (1) an improvement in the quantity, quality, and utility of feedback and (2) an increase in feedback containing negative/constructive feedback and pertaining to professionalism/communication. As secondary analyses, we explored these outcomes at the individual institutions. METHODS: In this prospective cohort study (October 2013 to July 2014), we implemented a video-based educational program on feedback at 4 institutions. Feedback records from 3 months before to 3 months after the intervention were rated for quality (0-5), utility (0-5), and whether they had negative/constructive feedback and/or were related to professionalism/communication. Feedback records during the preintervention, intervention, and postintervention periods were compared using the Kruskal-Wallis and [chi]2 tests. Data are reported as median (interquartile range) or proportion/percentage. RESULTS: A total of 1926 feedback records were rated. The institutions overall did not have a significant difference in feedback quantity (preintervention: 855/3046 [28.1%]; postintervention: 896/3327 [26.9%]; odds ratio: 1.06; 95% confidence interval, 0.95-1.18; P = .31), feedback quality (preintervention: 2 [1-4]; intervention: 2 [1-4]; postintervention: 2 [1-4]; P = .90), feedback utility (preintervention: 1 [1-3]; intervention: 2 [1-3]; postintervention: 1 [1-2]; P = .61), or percentage of feedback records containing negative/constructive feedback (preintervention: 27%; intervention: 32%; postintervention: 25%; P = .12) or related to professionalism/communication (preintervention: 23%; intervention: 33%; postintervention: 24%; P = .03). Institution 1 had a significant difference in feedback quality (preintervention: 2 [1-3]; intervention: 3 [2-4]; postintervention: 3 [2-4]; P = .001) and utility (preintervention: 1 [1-3]; intervention: 2 [1-3]; postintervention: 2 [1-4]; P = .008). Institution 3 had a significant difference in the percentage of feedback records containing negative/constructive feedback (preintervention: 16%; intervention: 28%; postintervention: 17%; P = .02). Institution 2 had a significant difference in the percentage of feedback records related to professionalism/communication (preintervention: 26%; intervention: 57%; postintervention: 31%; P

http://ift.tt/2soh215

Intraoperative "Analgesia Nociception Index"-Guided Fentanyl Administration During Sevoflurane Anesthesia in Lumbar Discectomy and Laminectomy: A Randomized Clinical Trial.

BACKGROUND: The "Analgesia Nociception Index" (ANI; MetroDoloris Medical Systems, Lille, France) is a proposed noninvasive guide to analgesia derived from an electrocardiogram trace. ANI is scaled from 0 to 100; with previous studies suggesting that values >=50 can indicate adequate analgesia. This clinical trial was designed to investigate the effect of intraoperative ANI-guided fentanyl administration on postoperative pain, under anesthetic conditions optimized for ANI functioning. METHODS: Fifty patients aged 18 to 75 years undergoing lumbar discectomy or laminectomy were studied. Participants were randomly allocated to receive intraoperative fentanyl guided either by the anesthesiologist's standard clinical practice (control group) or by maintaining ANI >=50 with boluses of fentanyl at 5-minute intervals (ANI group). A standardized anesthetic regimen (sevoflurane, rocuronium, and nonopioid analgesia) was utilized for both groups. The primary outcome was Numerical Rating Scale pain scores recorded from 0 to 90 minutes of recovery room stay. Secondary outcomes included those in the recovery room period (total fentanyl administration, nausea, vomiting, shivering, airway obstruction, respiratory depression, sedation, emergence time, and time spent in the recovery room) and in the intraoperative period (total fentanyl administration, intraoperative-predicted fentanyl effect-site concentrations over time [CeFent], the correlation between ANI and predicted CeFent and the incidence of movement). Statistical analysis was performed with 2-tailed Student t tests, [chi]2 tests, ordinal logistic generalized estimating equation models, and linear mixed-effects models. Bonferroni corrections for multiple comparisons were made for primary and secondary outcomes. RESULTS: Over the recovery room period (0-90 minutes) Numerical Rating Scale pain scores were on average 1.3 units lower in ANI group compared to the control group (95% confidence interval [CI], -0.4 to 2.4; P= .01). Patients in the ANI group additionally had 64% lower recovery room total fentanyl administration (95% CI, -12% to 85%; P= .44, unadjusted P= .026), 82% lower nausea scores (95% CI, -19% to 96%; P= .43, unadjusted P= .03), and a reduced incidence of shivering (ANI 4%, control 27%, P= .80, unadjusted P= .047) compared to the control group. Intraoperatively, ANI group patients had on average 27% higher predicted CeFent levels during the highly nociceptive periods of intubation and first incision (5-30 minutes) compared with control group patients (95% CI, 3%-57%; P= .51, unadjusted P= .03). For a 1-unit decrease in ANI scores, predicted CeFent on average increased by an estimated 1.98% in the ANI group (95% CI, 1.7%-2.26%; P

http://ift.tt/2r4UGO7

Cardiac Output Measurements Based on the Pulse Wave Transit Time and Thoracic Impedance Exhibit Limited Agreement With Thermodilution Method During Orthotopic Liver Transplantation.

BACKGROUND: Orthotopic liver transplantation (OLT) is characterized by significant intraoperative hemodynamic variability. Accurate and real-time cardiac output (CO) monitoring aids clinical decision making during OLT. The purpose of this study is to compare accuracy, precision, and trending ability of CO estimation obtained noninvasively using pulse wave transit time (estimated continuous cardiac output [esCCO; Nihon Kohden, Tokyo, Japan]) or thoracic bioimpedance (ICON; Osypka Medical GmbH, Berlin, Germany) to thermodilution cardiac output (TDCO) measured with a pulmonary artery catheter. METHODS: Nineteen patients undergoing OLT were enrolled. CO measurements were collected with esCCO, ICON, and thermodilution at 5 time points: (T1) pulmonary artery catheter insertion; (T2) surgical incision; (T3) portal reperfusion; (T4) hepatic arterial reperfusion; and (T5) abdominal closure. The results were analyzed with Bland-Altman plot, percentage error (the percentage of the difference between the CO estimated with the noninvasive monitoring device and CO measured with the thermodilution technique), 4-quadrant plot with concordance rate(the percentage of the total number of points in the I and III quadrant of the 4-quadrant plot), and concordance correlation coefficient (a measure of how well the pairs of observations deviate from the 45-degree line of perfect agreement). RESULTS: Although TDCO increased at T3-T5, both esCCO and ICON failed to track the changes of CO with sufficient accuracy and precision. The mean bias of esCCO and ICON compared to TDCO were -2.0 L/min (SD, +/-2.7 L/min) and -3.3 L/min (SD, +/-2.8 L/min), respectively. The percentage error was 69% for esCCO and 77% for ICON. The concordance correlation coefficient was 0.653 (95% confidence interval [CI], 0.283-0.853) for esCCO and 0.310 (95% CI, -0.167 to 0.669) for ICON. Nonetheless, esCCO and ICON exhibited reasonable trending ability of TDCO (concordance rate: 95% [95% CI, 88-100] and 100% [95% CI, 93-100]), respectively. The mean bias was correlated with systemic vascular resistance (SVR) and arterial elastance (Ea) for esCCO (SVR, r = 0.610, 95% CI, 0.216-0.833, P

http://ift.tt/2soqFwS

Absent societies: Contouring urban citizenship in postcolonial Chennai

Arabindoo, P; (2008) Absent societies: Contouring urban citizenship in postcolonial Chennai. Doctoral thesis, London School of Economics and Political Science. Green open access

http://ift.tt/2se0Tvx

The content and acquisition of lexical concepts

Horsey, RS; (2006) The content and acquisition of lexical concepts. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2sNskcL

Cranial functional (psychogenic) movement disorders

Kaski, D; Bronstein, AM; Edwards, MJ; Stone, J; (2015) Cranial functional (psychogenic) movement disorders. Lancet Neurology , 14 (12) pp. 1196-1205. 10.1016/S1474-4422(15)00226-4 .

http://ift.tt/2sdE1Mv

Planning and sharing learning designs: cross-cultural use of a learning design support tool

Zhang, Y; Laurillard, D; (2015) Planning and sharing learning designs: cross-cultural use of a learning design support tool. Learning: Research and Practice , 1 (2) pp. 152-161. 10.1080/23735082.2015.1020909 .

http://ift.tt/2sNal67

The body part in contemporary sculpture: A thematic consideration of fragmentation during the 1990s

Hutchinson, K; (2007) The body part in contemporary sculpture: A thematic consideration of fragmentation during the 1990s. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2sdzkSW

Hydrophilic surface modification of PDMS for droplet microfluidics using a simple, quick, and robust method via PVA deposition

Trantidou, T; Elani, Y; Parsons, E; Ces, O; (2017) Hydrophilic surface modification of PDMS for droplet microfluidics using a simple, quick, and robust method via PVA deposition. Microsystems & Nanoengineering , 3 , Article 16091. 10.1038/micronano.2016.91 . Green open access

http://ift.tt/2sNtd4L

Identification of Prdm genes in human corneal endothelium

Rolev, K; O'Donovan, DG; Georgiou, C; Rajan, MS; Chittka, A; (2017) Identification of Prdm genes in human corneal endothelium. Experimental Eye Research , 159 (C) pp. 114-122. 10.1016/j.exer.2017.02.009 . Green open access

http://ift.tt/2sdoaxz

Metacognitive ability correlates with hippocampal and prefrontal microstructure

Allen, M; Glen, JC; Mullensiefen, D; Schwarzkopf, DS; Fardo, F; Frank, D; Callaghan, MF; Allen, M; Glen, JC; Mullensiefen, D; Schwarzkopf, DS; Fardo, F; Frank, D; Callaghan, MF; Rees, G; - view fewer (2017) Metacognitive ability correlates with hippocampal and prefrontal microstructure. NEUROIMAGE , 149 pp. 415-423. 10.1016/j.neuroimage.2017.02.008 . Green open access

http://ift.tt/2sNdLps

Infections from 7 Clinical Trials of Ixekizumab, an Anti-Interleukin-17A Monoclonal Antibody, in Patients with Moderate-to-Severe Psoriasis

Abstract

Background

Infections are associated with biologic therapies in psoriasis.

Objectives

To summarise the incidence of infections in moderate-to-severe psoriasis patients treated with ixekizumab, an anti-interleukin (IL)-17A monoclonal antibody.

Methods

Infections are summarised from an integrated database of 7 controlled and uncontrolled ixekizumab psoriasis trials. Data are presented from placebo-controlled induction (Weeks 0-12; UNCOVER-1, -2, and -3) and maintenance periods (Weeks 12-60; UNCOVER-1 and -2) as well as all ixekizumab-exposed patients pooled from all 7 trials. Comparisons to etanercept were made during the induction period of two trials (UNCOVER-2 and -3). Incidence and exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) are reported.

Results

Overall, 4209 patients were treated with ixekizumab (6480PY). During induction (Weeks 0-12), overall infection rates were higher in ixekizumab-treated patients (27%) versus placebo (23%, p<0.05); however, specific infection rates were overall comparable across treatment groups. IRs of infections did not increase with longer-term exposure. For all ixekizumab-treated patients (all 7 trials), the incidence of serious infections was low (2%; IR 1.3). Candida infections, including 8 oesophageal candidiasis cases, were adequately managed with anti-fungal therapy, were non-invasive, and did not lead to discontinuation.

Conclusions

Infections overall occurred in a higher percentage of ixekizumab-treated patients versus placebo during the first 12 weeks of treatment; however, specific infection rates were overall comparable across treatment groups. Incidences of serious infections were low and similar across treatment groups.

http://ift.tt/2rWCl7r

Response to MF Holick “Can you have your cake and eat it too? The sunlight D-lema”

Abstract

We read with interest the recent paper by Felton and colleagues (1) describing the effects of solar-simulated ultraviolet radiation (UVR) on cutaneous DNA damage and vitamin D production. However, we were disappointed by the accompanying editorial by Dr Holick (2) proclaiming that healthcare regulators (and by inference, doctors and the public) "could have their cake and eat it too". In particular, his assertion that "sensible sun exposure that does not cause burning" should raise "little concern" about skin cancer risk is at odds with the photodamage observed by Felton and colleagues in the epidermal cells of fair-skinned participants following repeated, low-level sun exposure.

http://ift.tt/2rbGU0s

Inhibition of p38MAPK signaling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis

Abstract

Background

Pemphigus vulgaris (PV) is a skin blistering disease caused by autoantibodies targeting the desmosomal adhesion proteins desmoglein (Dsg) 3 and 1. The mechanisms underlying pemphigus skin blistering are not fully elucidated but p38MAPK activation is one of the signaling events necessary for full loss of cell cohesion. However, it is unclear whether ultrastructural hallmarks of desmosome morphology as observed in patients' lesions are mediated by p38MAPK signaling.

Objective

In this study, we tested the relevance of p38MAPK for blister formation and the ultrastructural changes induced by PV autoantibodies in human skin.

Methods Human skin samples were injected with IgG fractions of one patient suffering from mucocutaneous PV (mcPV-IgG), one from mucosal-dominant PV (mdPV-IgG) or AK23, a pathogenic monoclonal Dsg3 antibody derived from a pemphigus mouse model. Samples were processed for histological and electron microscopy analyses.

Results

McPV-IgG and AK23 but not mdPV-IgG reduced desmosome size, caused interdesmosomal widening and formation of split desmosomes, and altered keratin filament insertion. In contrast, full epidermal blister formation and lower desmosome number were evident in tissue samples exposed to mcPV-IgG only. Pharmacologic inhibition of p38MAPK blunted the reduction of desmosome number and size, ameliorated interdesmosomal widening and loss of keratin insertion and prevented mcPV-IgG-induced blister formation.

Conclusion

Our data demonstrate that blistering can be prevented by inhibition of p38MAPK in human epidermis. Moreover, typical morphologic alterations induced by mcPV-IgG such as interdesmosomal widening and the reduction of desmosome size at least in part require p38MAPK signaling.

http://ift.tt/2rWfRTT

Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a Phase 3b, randomized, double-blinded, active-controlled, multicenter study (PSTELLAR)

Abstract

Background

Phase 3 studies showed some patients maintained response for ≥6 months post-ustekinumab discontinuation.

Objectives

To assess clinical responses with extended ustekinumab maintenance dosing intervals.

Methods

Adults with moderate-to-severe plaque psoriasis received ustekinumab (45mg/90mg for weight ≤100 kg/>100 kg) at Week0, Week4, Week16 during open-label treatment. Patients achieving a Week 28 Physician's Global Assessment score of cleared/minimal (PGA=0/1) were randomized 1:4 to Group1 (approved every-12-weeks [q12wk] maintenance) or Group2 (q12-24wk response-based dosing determined by time–to-loss-of-PGA=0/1). Key endpoints included number of visits with PGA=0/1 (primary endpoint) and ≥75% improvement in Psoriasis Area and Severity Index (PASI75) between Weeks88-112, and PGA/PASI responses between Weeks28-112.

Results

378 patients achieved PGA=0/1 at Week28 and were randomized to Group1 (n=76) or Group2 (n=302). Group1 patients had numerically greater mean numbers of visits with PGA=0/1 than Group2 (4.5 and 4.1, respectively; mean-difference [95%CI]: -0.46 [-1.20; 0.29]) and PASI75 (5.8 and 5.4, respectively; -0.32 [-0.96;0.33]) from Week88-112. A higher proportion of patients in Group1 (55.3%) than Group2 (38.7%) had PGA=0/1 at all seven Week88-112 visits. Maintenance of response was observed with dose-interval extension beyond q12wk (q16wk, q20wk, q24wk) in a subset of patients (28% of patients randomized to Group 2 extended maintenance dosing to q24wks and maintained high levels of response). Extending dosing interval did not affect antibody development or safety.

Conclusions

Efficacy was better maintained among Week28 PGA-responders randomized to continue q12wk ustekinumab versus extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24wk dosing.

http://ift.tt/2rbZw0b

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Σάββατο 10 Ιουνίου 2017

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