QUALITY ASSESSMENT OF VITAMIN D METABOLITE ASSAYS USED BY CLINICAL AND RESEARCH LABORATORIES

Publication date: Available online 15 March 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): G.D. Carter, J. Berry, R. Durazo-Arvizu, E. Gunter, G. Jones, J. Jones, H.L.J Makin, P. Pattni, K.W. Phinney, C.T. Sempos, E.L. Williams
The Vitamin D External Quality Assessment Scheme (DEQAS) was launched in 1989 and monitors the performance of 25-hydroxyvitamin D (25-OHD) and 1,25- dihydroxyvitamin D (1,25(OH)2D) assays. In April 2015 a pilot scheme for 24,25-dihydroxyvitamin D (24,25(OH)2D) was introduced. The 25-OHD scheme is accuracy − based with target values assigned by the NIST Reference Measurement Procedure (RMP) for 25-OHD2 and 25-OHD3. A similar method is used to assign values for 3-epi-25-OHD. Five samples of human serum are distributed quarterly to over 1000 participants in 58 countries (April 2016) and clinical laboratories are expected to submit results within approximately 5 weeks. Research laboratories with assays run less frequently are not given a deadline. Archived samples with NIST- assigned values are also available. Performance is assessed on the first four samples with the fifth reserved for investigations e.g. recovery experiments or to assess the influence of other serum constituents such as lipids. DEQAS provides rapid feedback, with an on-line preliminary report available immediately after a participant submits results and a comprehensive report soon after the results deadline. In 2015, DEQAS investigations revealed that several 25-OHD immunoassays under-recovered 25-OHD2 and 25-OHD results were falsely low on a sample with a modestly raised triglyceride concentration. An RMP for 1,25 (OH)2D is not yet available and results are judged against the Method Mean. Free advice is available from the DEQAS Advisory Panel which includes experts on methodology and biostatistics. DEQAS collaborates closely with the Vitamin D Standardization Program (VDSP) and both organizations have successfully worked with participants and manufacturers to improve the accuracy of vitamin D assays.



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Robust Guidewire Tracking under Large Deformations Combining Segment-Like Features (SEGlets)

Publication date: Available online 15 March 2017
Source:Medical Image Analysis
Author(s): Alessandro Vandini, Ben Glocker, Mohamad Hamady, Guang-Zhong Yang
Robust tracking of interventional tools, such as guidewires and catheters, in X-ray fluoroscopic video sequences has a wide range of clinical applications for endovascular procedures. Thus far, the tracking is usually achieved by finding the optimal displacement of the control points of a spline, which models the guidewire, between consecutive frames. The displacement of the control points is typically driven by a data term and smoothed by a regularization term. In the presence of large deformation and changes in length of the tool, the current tracking methods may fail to recover the guidewire motion. This can occur because of the limitation of the data and regularization terms, and the absence of an explicit solution for coping with elongations of the guidewire. The purpose of this paper is to present an algorithm that can robustly track guidewires under these challenging conditions. The algorithm is based on two main contributions: (a) new robust features termed SEGlets for segment-like features are introduced to overcome the limitations of the current data terms; (b) a tracking formulation based on the generation of tracking hypotheses by organizing the SEGlets in plausible guidewire shapes. The proposed method allows high flexibility of the guidewire between consecutive frames in contrast to the spline model, which can suffer from the limitations of the regularization terms. Furthermore, the technique models elongations of the guidewire which makes it possible for robust tracking under motion. A tool model which is recursively updated by employing a Kalman filter, is also proposed for modelling the regularization term. A detailed evaluation and a comparative study with three state-of-the-art guidewire tracking methods have been performed to demonstrate the potential clinical value of the technique. The proposed method achieves an overall guidewire tracking precision of 2.40 pixels, tip precision of 25.55 pixels, false tracking rate of 5.73%, missing tracking rate of 9.69%, and F1 score of 0.92. The implementation of the proposed technique and the three tracking methods will be made publicly available as software libraries.



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Diffuse large B-Cell lymphoma developing in erythrodermic cutaneous T-cell lymphoma: a case series

Abstract

Mycosis fungoides (MF) and its leukemic form, Sezary Syndrome (SS), are the most common forms of cutaneous T-cell lymphoma (CTCL). CTCL is associated with an increased risk of secondary cancers, including lymphomas.¹ Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL) in the western world and can involve both nodal and extranodal sites including the skin.² DLBCL is invariably associated with an aggressive course if left untreated.

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Cutaneous Adverse Drug Reactions Referrals to a Liaison Dermatology Service

Abstract

Adverse drug reactions (ADRs) are a common consequence of medications, with an estimated 10-20% of all hospitalised patients experiencing a drug side effect^1-2; those affecting the skin being the most frequently recorded. The need to optimise management of cutaneous ADRs has been underlined by the recent publication of NICE Guidelines on Drug Allergy³, setting out a range of standards to enhance the diagnosis and management of patients developing allergic reactions to drugs. This study was undertaken to assess the number of drug allergy referrals, and the types of cutaneous drug reaction encountered in the in-patient population.

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Interleukin-32 is highly expressed in lesions of hidradenitis suppurativa

Summary

Background

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Its immunopathogenic mechanisms are still poorly understood. Previous studies could demonstrate that the pro-inflammatory cytokine Interleukin-32 (IL-32) is implicated in the pathogenesis of other inflammatory diseases.

Objectives

The aim of our study was to investigate the tissue expression and systemic levels of IL-32 as well as its cellular sources in HS patients in comparison to healthy donors and to patients suffering from two other inflammatory skin diseases: psoriasis (PS) and atopic dermatitis (AD).

Methods

Tissue samples were obtained from healthy skin and lesional HS, PS and AD skin to analyse the expression of IL-32 by immunohistochemistry and semi-quantitative real-time PCR. The cellular source of the cytokine was determined by double immunofluorescence staining. Serum of the four donors groups was used to measure systemic levels of IL-32 by enzyme-linked immunosorbent assay (ELISA).

Results

IL-32 was upregulated in HS patients in both lesional skin and serum when compared to healthy donors or AD and PS patients. In HS, IL-32 was found to be expressed by NK cells, T cells, macrophages and dendritic cells in highly infiltrated areas of the dermis. High IL-32 mRNA levels in lesional HS skin coincided with high amounts of T cells and macrophages present. Additionally, IL-32 mRNA levels in lesional HS skin correlate positively with IFNγ and IL-17 and negatively with IL-13.

Conclusions

Our findings suggest that IL-32 is overexpressed in HS. Targeting IL-32 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease.

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Response to “Frontal fibrosing alopecia in men—an association with facial moisturisers and sunscreen”

Abstract

We applaud Debroy-Kidambi et al for repeating their questionnaire study in male patients to determine possible environmental exposures that could be contributing to the increasing incidence of frontal fibrosing alopecia (FFA). In fact, in our own clinic we have noted that patients are often as interested in the possible causes of this condition as they are in available treatment methods. The discrepancy in facial moisturizer use between men with FFA compared to controls (94% versus 32%, p<0.0001) and the consistent use of primary sunscreens among FFA patients (35% versus 4%, p=0.0012) lends support to the hypothesis that a component of leave-on cosmetics may be contributing to the development of this condition.

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Cutaneous squamous cell carcinoma and the PARK2 gene

Abstract

We read with great interest the excellent review by Green and Olsen on the epidemiology of cutaneous squamous cell carcinoma of skin (cSCC). The authors reported that one of the genes found to be associated with SCC in GWAS studies is PARK2, and that its' function is unknown. Parkinson's disease (PD) literature may provide some insights to the contribution of PARK2 to skin cancers. PD patients are at higher risk than the general population for skin cancers.

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A Topical Treatment Optimisation Programme (TTOP) improves clinical outcome to calcipotriol/betamethasone gel in psoriasis: Results of the 64-week, multinational, randomized, phase IV study in 1790 patients (PSO-TOP)

Abstract

Background

Around two-thirds of psoriasis patients do not adhere to topical treatment. The 'Topical Treatment Optimisation Programme' (TTOP), a five-element tool, includes guidance for the conversation between dermatologists/nurses and patients, patient information material, telephone/email helpdesks and treatment reminders. It has been developed by patients and dermatologists to help increase adherence in psoriasis.

Objective

To compare TTOP with standard of care ('non-TTOP') within a large European investigator-initiated study, PSO-TOP (Clinicaltrials. gov NCT01587755).

Methods

Patients with mild to moderate psoriasis received calcipotriol/betamethasone dipropionate gel as standardized study medication and were randomized 1:1 to either TTOP or non-TTOP management. Study medication was applied once-daily for 8 weeks followed by 'as-needed' application for additional 56 weeks. A physicians' global assessment (PGA) of 'clear' or 'almost clear' was defined as response.

Results

In 1790 patients (full-analysis set), response rates after 8 weeks (primary objective) were significantly higher for TTOP (36.3%) than for non-TTOP (31.3%; P=0.0267). Better clinical outcome was accompanied by higher rates of patients feeling well informed about their skin condition and treatment and other factors related to adherence, but the dermatology life quality index (DLQI) was not statistically different. TTOP patients regarded the structured one-to-one conversations with their dermatologist/nurse as the most important element of TTOP.

Conclusions

Patients randomized to the TTOP intervention had a better clinical response than patients receiving standard of care. Improved communication between the healthcare provider and patient might be an important element in increasing adherence to topical therapy in psoriasis.

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Cover Image, Volume 86, Issue 4

The cover image, by J. Münzker et al., is based on the Original article "High salivary testosterone-to-androstenedione ratio and adverse metabolic phenotypes in women with polycystic ovary syndrome," DOI: 10.1111/cen.13299

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Androgen Receptor–Targeted Therapies in Breast Cancer

This review examines androgen receptor (AR)-related pathways, specific AR-targeted therapies, and the development of predictive biomarkers to stratify patients by likelihood of response to AR-targeted therapies.

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To ProtecT Our Patients With Prostate Cancer

This Viewpoint examines the conclusions of the ProtecT randomized clinical trial and argues that, instead of radical therapy, appropriate patients for active surveillance should be chosen and active surveillance strategies optimized to avoid the small increased risk of distant metastasis seen in ProtecT.

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Brain Metastases in Newly Diagnosed Breast Cancer

This population-based cohort study uses the SEER database to characterize the incidence proportion of brain metastases at the time of cancer diagnosis among patients with breast cancer on a population-based level.

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The effect of Co and In combinational or individual doping on the structural, optical and selective sensing properties of ZnO nanoparticles

Publication date: August 2017
Source:Sensors and Actuators B: Chemical, Volume 247
Author(s): Mpho William Maswanganye, K.E. Rammutla, T.E. Mosuang, B.W. Mwakikunga
Variably doped ZnO samples by the sol-gel process have been tested for response to humidity and industrial gases of CO, CH4, NH3 and H2. The elements of Cobalt (Co) and Indium (In) either singly doped or co-doped at 5wt% and annealed at varying temperature were observed to increase their grain sizes with annealing temperature while their lattice parameter decrease or increase depending on the dopant ionic radii when compared to the ionic radius of Zn. Co-doping of In and Co, at 5wt% each, is found to increase the response to all stimuli to higher values than undoped or singly doped ZnO sensors at the expense of selectivity where In-Co-ZnO as well as undoped ZnO and Co-ZnO sensors have similar selectivity value of below 44% to CO. In-doped ZnO shows a distinct selectivity of 60% to NH3. Ionic radii of the In and Co as well as the ionization potentials of the gases have been used to explain the mechanisms of these selective responses.

Graphical abstract

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A novel relay-sensor for highly sensitive and selective detection of Zn2+/Pic− and fluorescence on/off switch response of H+/OH−

Publication date: August 2017
Source:Sensors and Actuators B: Chemical, Volume 247
Author(s): Bao-Jun Wang, Wen-Kui Dong, Yang Zhang, Sunday Folaranmi Akogun
A novel naphthalenediol-based bis(Salamo)-type tetraoxime compound (H4L) was synthesized and characterized. Its Zn²⁺ complex was found to be highly sensitive for the detection of Pic⁻ when dissolved in water-containing organic solvent. Sensor H4L acts as a relay-sensor for recognition of Zn²⁺ while the L-Zn²⁺ complex recognizes Pic⁻ with high selectivity and sensitivity in acceptable physiological pH range. Moreover, The L-Zn²⁺ and its Pic⁻ polymer complex display successive sensing of H⁺/OH⁻ via increase (ON) and decrease (OFF) in fluorescence intensity. The crystal structure of the Zn²⁺ complex has been determined by single-crystal X-ray diffraction.

Graphical abstract

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Adsorption of arginine, glycine and aspartic acid on Mg and Mg-based alloy surfaces: A first-principles study

Publication date: 1 July 2017
Source:Applied Surface Science, Volume 409
Author(s): Zhe Fang, Jianfeng Wang, Xiaofan Yang, Qiang Sun, Yu Jia, Hairong Liu, Tingfei Xi, Shaokang Guan
Studying the adsorption behaviors of biomolecules on the surface of Mg and Mg-based alloy has a fundamental and important role for related applications in biotechnology. In the present work, we systematically investigate and compare the adsorption properties of three typical amino acids, i.e., Arg (arginine), Gly (glycine) and Asp (aspartic acid), which form RGD tripeptide, on the Mg (0001) surface with various doping (Zn, Y, and Nd), and aim to realize proper binding between biomolecules and Mg and Mg-based biomedical materials. Our results show that flat adsorption configurations of the functional groups binding to the surfaces are favored in energy for all the three selected amino acids. In specific, for the amino acids adsorped on clean Mg (0001) surface, the adsorption energy (Eads) of Arg is found to be −1.67eV for the most stable configuration, with amino and guanidyl groups binding with the surface. However, Gly (Asp) is found to binding with the surface through amino and carboxyl groups, with a −1.16eV (−1.15eV) binding energy. On the 2% Zn doped Mg (0001) alloy surface (Mg–Zn (2%)), the Eads are significantly increased to be −1.91eV, −1.32eV and −1.35eV for Arg, Gly and Asp, respectively. While the Mg–Y (1%) and Mg–Nd (1%) slightly weaken the adsorption of three amino acids. Moreover, we have performed detail discussions of the binding properties between amino acids and surfaces by projected density of states (PDOS) combined with charge transfer analyses. Our studies provide a comprehensive understanding on the interactions between amino acids and Mg and Mg-based alloy surfaces, with respect to facilitate the applications of Mg and Mg-based biomedical alloys in biosensing, drug delivery, biomolecule coating and other fields in biotechnology.



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Long-term in vivo corrosion behavior, biocompatibility and bioresorption mechanism of a bioresorbable nitrided iron scaffold

Publication date: Available online 15 March 2017
Source:Acta Biomaterialia
Author(s): Wenjiao Lin, Li Qin, Haiping Qi, Deyuan Zhang, Gui Zhang, Runlin Gao, Hong Qiu, Ying Xia, Ping Cao, Xiang Wang, Wei Zheng
Pure iron as a potential bioresorbable material for bioresorbable coronary scaffold has major disadvantages of slow corrosion and bioresorption. However, so far, there are neither quantitative data of long-term in vivo corrosion nor direct experimental evidence for bioresorption of pure iron and its alloys, which are fundamental and vital for developing novel Fe-based alloys overcoming the intrinsic drawbacks of pure iron. This work systemically investigated scaffold performance, long-term in vivo corrosion behavior and biocompatibility of a nitrided iron coronary scaffold and explored its bioresorption mechanism. It was found that the 70μm Fe-based scaffold was superior to a state of the art Co-Cr alloy stent (Xience Prime^TM) in terms of crossing profile, recoil and radial strength. Mass loss was 76.0 ± 8.5 wt.% for the nitrided iron scaffold and 44.2 ± 11.4 wt.% for the pure iron scaffold after 36 months implantation in rabbit abdominal aorta (p<0.05). The Fe-based scaffold showed good long-term biocompatibility in both rabbit and porcine model. Its insoluble corrosion products were demonstrated biosafe and could be cleared away by macrophages from in situ to adventitia to be indiscernible by Micro Computed Tomography and probably finally enter the lymphatics and travel to lymph nodes after 53 months implantion in porcine coronary artery. The results indicate that the nitrided iron scaffold with further improvements shall be promising for coronary application.Statement of SignificancePure iron as a potential bioresorbable material has major disadvantages of slow corrosion and bioresorption. However, So far, there are neither quantitative data of long-term in vivo corrosion nor direct experimental evidence for bioresorption of pure iron and its alloys. Only this work systemically investigated long-term in vivo corrosion behavior and biocompatibility of a nitrided iron (Fe-0.07N) coronary scaffold up to 53 months after implantation and explored its bioresorption mechanism. These are fundamental and vital for developing novel Fe-based alloys overcoming the intrinsic drawbacks of pure iron. Novel testing and section-preparing methods were also provided in this work to facilitate future research and development of novel Fe-based alloy scaffolds.

Graphical abstract

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Legumain-cleavable 4-arm Poly(ethylene glycol)-Doxorubicin Conjugate for Tumor Specific Delivery and Release

Publication date: Available online 15 March 2017
Source:Acta Biomaterialia
Author(s): Huicong Zhou, Huanjiao Sun, Shixian Lv, Dawei Zhang, Xuefei Zhang, Zhaohui Tang, Xuesi Chen
Traditional chemotherapy strategy exists undesirable toxic side-effects to normal tissues due to the low selectively to cancer cells of micromolecule cytotoxic drugs. One considered method to realizing the targeted delivery and increasing the specificity to tumor tissues of the cytotoxic drug is to transporting and discharging it through an environment-sensitive mechanism. In this study, a novel enzyme-sensitive polymer-doxorubicin conjugate was designed to delivery chemotherapeutic drug in a tumor-specific behavior and selectively activated in tumor tissue. Briefly, doxorubicin (DOX) was conjugated to carboxyl-terminated 4-arm poly(ethylene glycol) through a tetrapeptide linker, alanine-alanine-asparagine-leucine (AANL), which was one of the substrates of legumain, an asparaginyl endopeptidase that was found presented in plants, mammals and also highly expressed in human tumor tissues. Hereinafter, the polymer-DOX conjugate was termed as 4-arm PEG-AANL-DOX. Dynamic laser scattering (DLS) and transmission electron microscopy (TEM) measurements indicated that the 4-arm PEG-AANL-DOX could self-assemble into micelles in aqueous solution. Drug release and in vitro cytotoxicity studies revealed that the 4-arm PEG-AANL-DOX could be cleaved by legumain. Ex vivo DOX fluorescence imaging measurements demonstrated that the 4-arm PEG-AANL-DOX had an improved tumor-targeting delivery as compared with the free DOX·HCl. In vivo studies on nude mice bearing MDA-MB-435 tumors revealed that the 4-arm PEG-AANL-DOX had a comparable anticancer efficacy with the free DOX·HCl but without DOX-related toxicities to normal tissues as measured by body weight change and histological assessments, indicating that the 4-arm PEG-AANL-DOX had an improved therapeutic index for cancer therapy.Statement of significance: Herein we describe the construction of a novel tumor environment-sensitive delivery system through the instruction of a legumain-cleavable linkage to a polymer-DOX conjugate (4-arm PEG-AANL-DOX). This particular design strategy allows for polymer-DOX conjugates to be delivered in a tumor-specific manner and selectively activable in tumor microenvironment so that it can combine the advantages of tumor-specific delivery and tumor intracellular microenvironment-triggered release systems.

Graphical abstract

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Reaching complete or near complete resolution of psoriasis: benefit and risk considerations

Abstract

The incremental benefits of obtaining higher levels of skin clearance for patients with psoriasis have been established across several patient reported outcomes (PROs). Patients who obtain clear or almost clear skin are more likely to report no impact of psoriasis on health-related quality of life (HRQoL) and other symptom measures. While the benefits of obtaining higher skin clearance have been reported with different therapeutic agents, the question of whether the benefits of such high levels of response may be offset by an increased risk for adverse outcomes has not been fully explored with biologics.

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Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14

Summary

Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which ~1 in 20 affected individuals show autosomal dominant inheritance. In such cases, there may be gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14) that activates the non-canonical nuclear factor-kappa B (NF-κB) pathway, thereby promoting cutaneous inflammation. Here, we report a mother and son with PRP due to a new missense mutation in CARD14 and describe the beneficial clinical effects of ustekinumab, a monoclonal antibody against interleukins-12 and -23, in both subjects. A 49 year-old female and her 20 year-old son had lifelong, generalised, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalised PRP. Topical steroids, phototherapy and oral retinoids proved ineffective therapies. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single nucleotide transversion in exon 16, c.356T>G, resulting in the missense mutation, p.Met119Arg. Ustekinumab, at a dose of 45mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing. This report highlights the therapeutic potential of biologics that downregulate NF-kB signalling in familial PRP with mutations in CARD14.

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American Board of Dermatology Examination Dates

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