Publications by authors named "Mette Mogensen"

67 Publications

Assessing Light and Energy-Based Therapy by Optical Coherence Tomography and Reflectance Confocal Microscopy: A Randomized Trial of Photoaged Skin.

Dermatology 2021 Aug 27:1-8. Epub 2021 Aug 27.

Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.

Background And Objectives: Image-guided quantitative and semi-quantitative assessment of skin can potentially evaluate treatment efficacy. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) are ideal for this purpose. This study assessed clinically relevant statistical changes in RCM and OCT features in photoaged skin after light and energy-based therapy.

Methods: Novel statistical analyses were performed using OCT and RCM data collected during a previously published trial: a 12-week study of female décolleté skin randomized to four areas treated with thulium laser (L), photodynamic therapy (PDT), combined L-PDT, and control. Eight semi-quantitative RCM scores of photodamage and OCT measurements of skin roughness, blood flow, and epidermal thickness (ET) were evaluated and compared to dermoscopy and clinical skin scores. In statistical analysis, estimated treatment difference (ETD) was calculated.

Results: Twelve women with moderate to severe photodamage were included. RCM and OCT data demonstrated a trend towards rejuvenation of epidermis with increased ET, changes in skin surface, and improved honeycomb pattern in RCM. In angiographic OCT, non-significant changes towards more regular capillary meshes were shown, which matched a decline in appearance of gross telangiectasias in dermoscopy. Improved skin tone after laser and L-PDT was identified in RCM, showing less edged papillae in 36% and 45%, and lentigo number declined in 55% of patients after treatments in dermoscopy. Based on clinical scores, L-PDT provided the greatest clinical improvement, which corresponded to superior ETD outcomes in ET and edged papillae shown in OCT and RCM, respectively.

Conclusion: Objective OCT and RCM assessment of skin rejuvenation was demonstrated in this study. Importantly, image-based improvements corresponded to favorable clinical skin scores and fewer photoaging characteristics in dermoscopy. Importantly, most changes did not reach statistical significance, prompting further studies and emphasizing the modest value of non-randomized, non-blinded anti-aging trials.
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http://dx.doi.org/10.1159/000517960DOI Listing
August 2021

First patient with ILNEB syndrome due to pathogenic variants in ITGA3 surviving to adulthood.

Eur J Med Genet 2021 Sep 4;64(11):104335. Epub 2021 Sep 4.

Dpt. of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Denmark.

Interstitial Lung disease, Nephrotic syndrome and Epidermolysis Bullosa, also referred to as ILNEB syndrome is an extremely rare autosomal recessive condition, caused by pathogenic variants in ITGA3. 11 patients have previously been diagnosed with ILNEB syndrome of whom 7 died in infancy or early childhood. We report the only patient with ILNEB syndrome who survived past adolescence, partly due to a double lung transplant. Additionally, our patient showed oral, nasal and gynecological symptoms not previously reported in patients with ILNEB syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2021.104335DOI Listing
September 2021

Delineating papillary dermis around basal cell carcinomas by high and ultrahigh resolution optical coherence tomography-A pilot study.

J Biophotonics 2021 Jul 10:e202100083. Epub 2021 Jul 10.

DTU Fotonik, Department of Photonics Engineering, Technical University of Denmark, Kongens Lyngby, Denmark.

Bedside diagnosis of skin cancer remains a challenging task. The real-time noninvasive technology of optical coherence tomography (OCT) masters a high diagnostic accuracy in basal cell carcinoma (BCC) but a lower specificity in recognizing imitators and other carcinomas. We investigate the delicate signal of papillary dermis using an in-house developed ultrahigh resolution OCT (UHR-OCT) system with shadow compensation and a commercial multi-focus high resolution OCT (HR-OCT) system for clinical BCC imaging. We find that the HR-OCT system struggled to resolve the dark band signal of papillary dermis where the UHR-OCT located this in all cases and detected changes in signal width. UHR-OCT is able to monitor extension and position of papillary dermis suggesting a novel feature for delineating superficial BCCs in pursuit of a fast accurate diagnosis. Comprehensive studies involving more patients are imperative in order to corroborate results.
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http://dx.doi.org/10.1002/jbio.202100083DOI Listing
July 2021

Shot-noise limited, supercontinuum-based optical coherence tomography.

Light Sci Appl 2021 Jun 28;10(1):133. Epub 2021 Jun 28.

DTU Fotonik, Dept. of Photonics Engineering, Technical University of Denmark, Ørsteds Plads, 2800, Kongens Lyngby, Denmark.

We present the first demonstration of shot-noise limited supercontinuum-based spectral domain optical coherence tomography (SD-OCT) with an axial resolution of 5.9 μm at a center wavelength of 1370 nm. Current supercontinuum-based SD-OCT systems cannot be operated in the shot-noise limited detection regime because of severe pulse-to-pulse relative intensity noise of the supercontinuum source. To overcome this disadvantage, we have developed a low-noise supercontinuum source based on an all-normal dispersion (ANDi) fiber, pumped by a femtosecond laser. The noise performance of our 90 MHz ANDi fiber-based supercontinuum source is compared to that of two commercial sources operating at 80 and 320 MHz repetition rate. We show that the low-noise of the ANDi fiber-based supercontinuum source improves the OCT images significantly in terms of both higher contrast, better sensitivity, and improved penetration. From SD-OCT imaging of skin, retina, and multilayer stacks we conclude that supercontinuum-based SD-OCT can enter the domain of shot-noise limited detection.
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http://dx.doi.org/10.1038/s41377-021-00574-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239030PMC
June 2021

Topical Zinc Oxide Assessed in Two Human Wound-healing Models.

Acta Derm Venereol 2021 May 26;101(5):adv00465. Epub 2021 May 26.

Department of Dermatology and Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark. E-mail:

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http://dx.doi.org/10.2340/00015555-3829DOI Listing
May 2021

Closing of surgical wounds on ala nasi with an autologous patch: A case series and in vivo wound imaging using Reflectance Confocal Microscopy.

Skin Res Technol 2021 Mar 4. Epub 2021 Mar 4.

Department of Dermatology and Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1111/srt.13024DOI Listing
March 2021

Meiosis and beyond - understanding the mechanistic and evolutionary processes shaping the germline genome.

Biol Rev Camb Philos Soc 2021 06 1;96(3):822-841. Epub 2021 Jan 1.

School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, U.K.

The separation of germ cell populations from the soma is part of the evolutionary transition to multicellularity. Only genetic information present in the germ cells will be inherited by future generations, and any molecular processes affecting the germline genome are therefore likely to be passed on. Despite its prevalence across taxonomic kingdoms, we are only starting to understand details of the underlying micro-evolutionary processes occurring at the germline genome level. These include segregation, recombination, mutation and selection and can occur at any stage during germline differentiation and mitotic germline proliferation to meiosis and post-meiotic gamete maturation. Selection acting on germ cells at any stage from the diploid germ cell to the haploid gametes may cause significant deviations from Mendelian inheritance and may be more widespread than previously assumed. The mechanisms that affect and potentially alter the genomic sequence and allele frequencies in the germline are pivotal to our understanding of heritability. With the rise of new sequencing technologies, we are now able to address some of these unanswered questions. In this review, we comment on the most recent developments in this field and identify current gaps in our knowledge.
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http://dx.doi.org/10.1111/brv.12680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246768PMC
June 2021

Photoacoustic tomography for assessment and quantification of cutaneous and metastatic malignant melanoma - A systematic review.

Photodiagnosis Photodyn Ther 2021 Mar 11;33:102095. Epub 2020 Nov 11.

Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Bispebjerg Bakke 23, Copenhagen, 2400, NV, Denmark.

Background: Photoacoustic tomography (PAT) is an emerging noninvasive imaging technique combining high sensitivity optical absorption contrast, such as melanin, with high-resolution ultrasound for deep tissue imaging. The ability of PAT to provide real-time images of skin structures at depth has been studied for diagnosis of primary and metastatic malignant melanoma (MM).

Objective: To provide an overview of the rapidly expanding clinical use of PAT for determination of melanoma thickness and architecture, visualization of metastases in lymph nodes and detection of circulating melanoma cells.

Methods: Medline, PubMed, EMBASE, Web of Science, Google Scholar, and Cochrane Library were searched for papers using PAT to assess cutaneous malignant melanoma and melanoma metastases in humans or human specimens.

Results: The research resulted in 14 articles which met the search criteria.

Conclusions: Results from current studies suggest that PAT is a promising tool for assessing both primary and metastatic malignant melanoma in the clinic. The potential of PAT to noninvasively visualize tumour boundaries, as well as assist in the evaluation of metastatic status, could facilitate more effective treatment, resulting in better clearance and reducing the need for additional biopsies. However, larger and methodologically sound studies are warranted.
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http://dx.doi.org/10.1016/j.pdpdt.2020.102095DOI Listing
March 2021

Skin tags imaged by reflectance confocal microscopy, optical coherence tomography and multispectral optoacoustic tomography at the bedside.

Skin Res Technol 2021 May 11;27(3):324-331. Epub 2020 Oct 11.

Department of Dermatology, Bispebjerg and Frederiksberg, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Skin tags are common and mostly benign, but occasionally contain skin cancers. This study analysed skin tags by combining three advanced optical imaging technologies: reflectance confocal microscopy (RCM), optical coherence tomography (OCT) and multispectral optoacoustic imaging (MSOT) supplemented by dermoscopy MATERIALS AND METHODS: A prospective clinical study recruiting patients with skin tags from a university hospital clinic over a 2-week period. OCT, RCM and MSOT imaging were performed prior to excisional biopsies. Image features such as pigmentation, cell types and skin architecture, angiographic information demonstrating vascular pattern were captured, analysed, and compared to melanin and haemoglobin content in MSOT as well as histopathology.

Results: Six patients with dermal naevi (2); compound naevi (3); neurofibroma (1) were included. All skin tags except the neurofibroma were pigmented (5/6), with sparse (5/6) and dense (4/6) hyperreflective nests and band-like collagen in dermis in 6/6 lesions on RCM. Dermoscopy showed dots (5/6) and coiled vessels (5/6). Linear vertical vessels were present in all OCT images. MSOT images consisted of a compact shell-like superficial melanin area, same shape and size as the skin tag, dermal vessels were visible in 4/5 naevi, HbO signal clearly demarcated blood vessels located below the melanin signal.

Conclusion: OCT showed linear vessels in all lesions. Pigmentation was identified by RCM as benign nests of melanocytes. MSOT supplemented with spatial distribution of melanin and HbO that indicated all skin tags were benign with no infiltration of vessels inside the melanin signal. Each advanced method proved indispensable for fast diagnosis. Larger studies are warranted for validation.
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http://dx.doi.org/10.1111/srt.12943DOI Listing
May 2021

Efficacy and Safety of Laser-Assisted Combination Chemotherapy: An Explorative Imaging-Guided Treatment With 5-Fluorouracil and Cisplatin for Basal Cell Carcinoma.

Lasers Surg Med 2021 01 22;53(1):119-128. Epub 2020 Sep 22.

Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Copenhagen NV, 2400, Denmark.

Background And Objectives: Rising incidences of basal cell carcinoma (BCC) have increased the need for effective topical therapies. By enhancing cutaneous uptake of the chemotherapeutic agents, cisplatin and 5-fluorouracil (5-FU), laser-assisted delivery may provide a new combination treatment for BCC. Accordingly, this study aimed to evaluate tumor response, safety, and drug biodistribution in tumors and blood after topical laser-assisted 5-FU + CIS treatment in BCC patients.

Study Design/materials And Methods: This open-label, proof-of-concept trial investigated laser-assisted combination cisplatin + 5-FU treatment in 20 patients with histologically verified, low-risk superficial or nodular BCCs on the face (<20 mm) or trunk/extremities (<50 mm). After tumor demarcation guided by optical coherence tomography (OCT), BCCs were exposed to ablative fractional CO laser followed by 60 minutes topical cisplatin solution and 7-day exposure to 5% 5-FU cream under occlusion. After 30 days, treatment was repeated if any tumor residual was identified. Tumor response at day 30 and month 3 was assessed clinically as well as by OCT, reflectance confocal microscopy, and ultrasound, supplemented by histological verification at 3 months. Local skin reactions (LSRs) and side effects were evaluated on days 1, 3-5, 14, 30, and month 3. Drug detection in tumors and blood was performed in a subset of patients 1- and 24 hours after treatment.

Results: Nineteen patients completed the trial, with 32% (6/19) receiving a single treatment and 68% (13/19) treated twice. At 3 months, clinical clearance was seen in 18/19 patients with a corresponding 94% (17/18) achieving histological clearance. Baseline tumor thickness and subtype did not influence treatment number or clearance rate (P ≥ 0.61). LSRs were well-tolerated and consisted of erythema, edema, and erosion, followed by crusting by day 14. Erythema declined gradually by month 3, with 94% of patients and 79% of physicians rating cosmesis as "good" or "excellent." Scarring or hyperpigmentation was noted in 50% and 56%, respectively, while pain and infection were not observed during the follow-up period. Although chemotherapy uptake was visualized extending to deep skin layers, no systemic exposure to cisplatin or 5-FU was detected in patient blood.

Conclusion: Laser-assisted cisplatin + 5-FU shows potential as an effective and tolerable treatment option for low-risk BCC, particularly in instances where self-application is not possible or where in-office, non-surgical therapy is preferred. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/lsm.23323DOI Listing
January 2021

Automatic Segmentation of Epidermis and Hair Follicles in Optical Coherence Tomography Images of Normal Skin by Convolutional Neural Networks.

Front Med (Lausanne) 2020 4;7:220. Epub 2020 Jun 4.

Instituto de Investigación e Innovación en Bioingeniería, I3B, Universitat Politècnica de València, Valencia, Spain.

Optical coherence tomography (OCT) is a well-established bedside imaging modality that allows analysis of skin structures in a non-invasive way. Automated OCT analysis of skin layers is of great relevance to study dermatological diseases. In this paper, an approach to detect the epidermal layer along with the follicular structures in healthy human OCT images is presented. To the best of the authors' knowledge, the approach presented in this paper is the only epidermis detection algorithm that segments the pilosebaceous unit, which is of importance in the progression of several skin disorders such as folliculitis, acne, lupus erythematosus, and basal cell carcinoma. The proposed approach is composed of two main stages. The first stage is a Convolutional Neural Network based on U-Net architecture. The second stage is a robust post-processing composed by a Savitzky-Golay filter and Fourier Domain Filtering to fully define the borders belonging to the hair follicles. After validation, an average Dice of 0.83 ± 0.06 and a thickness error of 10.25 μ is obtained on 270 human skin OCT images. Based on these results, the proposed method outperforms other state-of-the-art methods for epidermis segmentation. It demonstrates that the proposed image segmentation method successfully detects the epidermal region in a fully automatic way in addition to defining the follicular skin structures as main novelty.
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http://dx.doi.org/10.3389/fmed.2020.00220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287173PMC
June 2020

Fractional 1,927 nm Thulium Laser Plus Photodynamic Therapy Compared and Combined for Photodamaged Décolleté Skin: A Side-by-Side Randomized Controlled Trial.

Lasers Surg Med 2020 01 1;52(1):44-52. Epub 2019 Dec 1.

Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Nielsine Nielsens Vej 17, 2400, Copenhagen, Denmark.

Background And Objectives: Décolleté photodamage is a common condition typically treated with light and energy-based devices. This study investigated the efficacy and safety of a fractional 1,927 nm thulium laser (TL) alone and combined with photodynamic therapy (PDT).

Study Design/materials And Methods: In a 12-week follow-up study, participant décolletés were divided into four treatment areas and randomized to receive a single treatment with field-directed TL, PDT, combination TL-PDT, or lesion-directed curettage control. All actinic keratoses (AKs) underwent lesion-directed curettage before randomization. TL was delivered at 20 mJ/mb, 500 mJ/cm fluence, 5 W, and 8 (n = 6 pts.) or 16 (n = 6 pts.) passes. PDT was performed with 16% methyl aminolevulinate (MAL) creme incubated for 3 h, followed by red light-emitting diode light at 37 J/cm . Outcome measures included clinical assessment of overall photodamage and specific subcomponents, assisted by optical coherence tomography (OCT) imaging.

Results: Twelve women with moderate to severe photodamage on the décolleté and a cumulative total of 184 thin grade I AKs were included. Field-directed treatments TL and combination TL-PDT equally improved the overall photodamage, mottled pigmentation, and rhytides compared with lesion-directed control (P < 0.05). The skin texture improved by TL alone and was further improved by combining TL and PDT (P < 0.05). Median AK complete responses were similar for field-directed interventions TL-PDT (100%), TL (90%), PDT (82%), and lesion-directed curettage control (52%) (P = 0.464). Patients presented with mild local skin responses, slightly more pronounced when combining TL with PDT versus individual treatments (P < 0.05). No scarring or adverse events were observed.

Conclusions: The 1,927 nm fractional thulium laser is an effective, tolerable, and safe field-directed treatment for décolleté photodamage. Provided alone, TL proved to be as effective as combined TL-PDT for overall photodamage, while a greater improvement in skin texture was achieved using TL and PDT in combination. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23194DOI Listing
January 2020

In Vivo Reflectance Confocal Microscopy of Gold Microparticles Deposited in the Skin. A Case Report on Cutaneous Chrysiasis.

Lasers Surg Med 2020 01 10;52(1):13-16. Epub 2019 Nov 10.

Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, DK-2200, Denmark.

Cutaneous chrysiasis is gold deposition in the dermis, described after parenteral administration of gold salts or after topical exposure to gold-containing materials. Gold microparticles (GMPs) have versatile therapeutic effects and are increasingly used in medicine. This case report describes the development of a blue-gray macule following the facial application of GMPs and laser treatment of acne vulgaris. Dermoscopy showed a nonspecific homogenous blue-gray pattern, gradually fading over an 8-month-period. Reflectance confocal microscopy (RCM) detected hyperreflective, subcellular particles in the papillary dermis, localized around hair follicles, eccrine glands, and inside macrophages. Histopathological evaluation, darkfield illumination with hyperspectral imaging, and neutron activation analysis confirmed the presence of GMPs in the dermis. RCM allowed non-invasive fast visualization of aggregates of hyperreflective particles in the dermis and can potentially be used for monitoring localized cutaneous chrysiasis and other metal deposition conditions over time. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23179DOI Listing
January 2020

Trends in incidence, mortality, and causes of death associated with systemic sclerosis in Denmark between 1995 and 2015: a nationwide cohort study.

BMC Rheumatol 2018 7;2:36. Epub 2018 Dec 7.

5Department of Cardiology, Herlev and Gentofte Hospital, Gentofte, Kildegårdsvej 28, 2900 Hellerup, Denmark.

Background: To investigate the incidence and the mortality-rates of systemic sclerosis (SSc), its primary causes of death, and the temporal trends in events in Denmark during the last decades.

Methods: Using the Danish National Patient Registry, we identified all persons aged ≥18 years with a first-time diagnosis of SSc (ICD-10 code M34, excluding M34.2) between 1995 and 2015.

Results: A total of 2778 incident SSc cases were identified. The mean age at time of SSc diagnosis was 56 (standard deviation 15) years and 76% were women. The overall incidence rate (per 1,000,000 person-years) of diagnosed SSc was 24.4 (95% confidence interval 23.6-25.4), with a slight increase over the study period, age- and sex-adjusted incidence rate ratio 1.02 (95% confidence interval 1.01-1.02) per 1-year increase. The 1-year all-cause mortality rate per 100 person-years decreased from 6.1 (3.1-12.2) in 1995 to 5.3 (2.5-11.1) in 2015, sex- and age-adjusted hazard ratio 0.96 (95% CI 0.94-0.98) per 1-year increase. Over the period, the average age at SSc diagnosis increased and the proportion of women decreased, whereas the burden of comorbidities increased. One fifth of all deaths were attributable to cardiovascular causes, a fourth to pulmonary diseases, and 15% were due to cancer.

Conclusions: Within the last few decades, the incidence of SSc has increased and the 1-year mortality rate has decreased slightly in Denmark. Almost half of all deaths were attributable to cardiopulmonary causes.
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http://dx.doi.org/10.1186/s41927-018-0043-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390621PMC
December 2018

Potential of contrast agents to enhance in vivo confocal microscopy and optical coherence tomography in dermatology: A review.

J Biophotonics 2019 06 14;12(6):e201800462. Epub 2019 Apr 14.

Department of Dermatology, Bispebjerg Hospital, Nielsine Nielsens Vej 9, 2400 København NV, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Distinction between normal skin and pathology can be a diagnostic challenge. This systematic review summarizes how various contrast agents, either topically delivered or injected into the skin, affect distinction between skin disease and normal skin when imaged by optical coherence tomography (OCT) and confocal microscopy (CM). A systematic review of in vivo OCT and CM studies using exogenous contrast agents on healthy human skin or skin disease was performed. In total, nine CM studies and one OCT study were eligible. Four contrast agents aluminum chloride (AlCl) n = 2, indocyanine green (ICG) n = 3, sodium fluorescein n = 3 and acetic acid n = 1 applied to CM in variety of skin diseases. ICG, acetic acid and AlCl showed promise to increase contrast of tumor nests in keratinocyte carcinomas. Fluorescein and ICG enhanced contrast of keratinocytes and adnexal structures. In OCT of healthy skin gold nanoshells, increased contrast of natural skin openings. Contrast agents may improve delineation and diagnosis of skin cancers; ICG, acetic acid and AlCl have potential in CM and gold nanoshells facilitate visualization of adnexal skin structures in OCT. However, as utility of bedside optical imaging increases, further studies with robust methodological quality are necessary to implement contrast agents into routine dermatological practice.
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http://dx.doi.org/10.1002/jbio.201800462DOI Listing
June 2019

Transfollicular delivery of gold microparticles in healthy skin and acne vulgaris, assessed by in vivo reflectance confocal microscopy and optical coherence tomography.

Lasers Surg Med 2019 Mar 5. Epub 2019 Mar 5.

Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, DK-2400, Copenhagen, Denmark.

Introduction: Topical application of gold microparticles (GMPs) for selective photothermolysis is a recently FDA-cleared therapy for acne vulgaris. Current evidence indicates the potential of optical imaging to non-invasively visualize GMPs and describe photothermal tissue effects.

Objectives: To qualitatively and quantitatively describe GMP delivery in vivo and visualize laser-mediated thermal effects of GMPs in facial skin of acne patients and healthy participants, using reflectance confocal microscopy (RCM) and optical coherence tomography (OCT).

Methods: Patients with facial acne (n = 14), and healthy participants (n = 7) were included. RCM and OCT images were acquired at baseline, after GMP application, and after diode laser exposure. All images were evaluated qualitatively and quantitatively with regards to GMP delivery in skin layers and morphological thermal effects. Lastly, skin biopsies were obtained to compare RCM and OCT findings to histology.

Results: GMPs were delivered equally in healthy participants and acne patients, and in lesional and non-lesional acne skin. In RCM images, GMPs appeared as hyperreflective aggregates inside hair follicles and eccrine ducts, corresponding to natural skin openings (NSOs). The fraction of NSOs with hyperreflective content increased significantly after GMP application compared to baseline (50-75% increase, P = 8.88 × 10 ). Similarly, in OCT images, GMPs appeared as hyperreflective columns inside hair follicles and were not detected in surrounding skin. GMPs reached a maximum depth of 920 μm (median 300 μm). After laser exposure, RCM and histology revealed selective perifollicular tissue changes around NSOs.

Conclusion: Optical imaging visualizes GMP delivery and thermal tissue response following laser exposure and enables bedside monitoring of transfollicular microparticle delivery. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23076DOI Listing
March 2019

Association of metabolites reflecting type III and VI collagen formation with modified Rodnan skin score in systemic sclerosis - a cross-sectional study.

Biomarkers 2019 Jun 19;24(4):373-378. Epub 2019 Mar 19.

a Nordic Bioscience , Biomarker and Research , Herlev , Denmark.

The objective was to investigate blood-based biomarkers of type I (PRO-C1), III (PRO-C3) and VI (PRO-C6) collagen formation in systemic sclerosis (SSc) patients and examine their correlation to modified Rodnan skin score (mRSS). Limited (lSSc,  = 76) and diffuse SSc (dSSc,  = 41) fulfilling the ACR/EULAR 1980 and 2013 classification criteria for SSc and asymptomatic controls ( = 9) were included. PRO-C1, PRO-C3 and PRO-C6 were measured in serum. LSSc compared to dSSc were significantly older, had longer disease duration and lower mRSS. PRO-C3 was higher in early dSSc compared to early lSSc (mean [95 percentile], 27.4 [13.1-39.1] ng/mL vs 14.9 [8.2-28.8] ng/mL,  = 0.006). PRO-C6 levels were higher in early dSSc compared to early lSSc and late dSSc (early dSSc: 28.2 [10.4-92.3] ng/ml vs early lSSc: 11.0 [6.9-28.5] ng/ml;  = 0.006 and late dSSc: 12.6 [6.5-25.3] ng/mL,  = 0.04). No difference was observed with PRO-C1. PRO-C3 and PRO-C6 were moderately correlated with mRSS with R-partials of 0.36 ( < 0.001) and 0.29 ( = 0.002), respectively Measures of type III and VI collagen formation are potential objective biomarkers of fibrosis in systemic sclerosis. These biomarkers could be useful in monitoring the disease and efficacy of treatment.
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http://dx.doi.org/10.1080/1354750X.2019.1587509DOI Listing
June 2019

Validity of first-time diagnoses of congenital epidermolysis bullosa in the Danish National Patient Registry and the Danish Pathology Registry.

Clin Epidemiol 2019 17;11:115-124. Epub 2019 Jan 17.

Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark,

Purpose: Congenital epidermolysis bullosa (CEB) is a group of rare monogenic genodermatoses. Phenotypically, the diseases vary in both severity and dissemination, which complicates studies of their epidemiology. To investigate the potential of using the Danish National Patient Registry (DNPR) for epidemiological research on CEB, we examined the positive predictive value (PPV) of a first-time diagnosis of CEB.

Methods: We identified patients with a record of CEB in DNPR and the Danish Pathology Registry (DPR) during January 1, 1977, until December 31, 2015. We restricted diagnoses from two dermatological departments and one regional hospital. Diagnoses in the DNPR are coded by the eighth and tenth revisions of the ICD (ICD-8 and ICD-10) and in the DPR by the Systematized Nomenclature of Medicine (SNOMED). We used clinical description in medical records, family history, histological findings, and molecular genetic investigations to validate diagnoses and classified them as rejected and confirmed. We estimated PPVs for any diagnosis, according to coding systems used, and for additional subdivisions of ICD-10 codes.

Results: We identified 116 cases from the hospital departments investigated and evaluated 96 medical records for validity. The overall PPV for probable CEB was 62.5% (95% CI: 52.5-71.5). For ICD-8, ICD-10, and SNOMED codes, the PPVs were 30.8% (95% CI: 11.4-57.7), 76.7% (95% CI: 65.8-84.9), and 0.0% (95% CI: 0.0-21.7), respectively. For the ICD-10 codes, we found the highest PPVs for diagnoses arising from the dermatological departments. For subdivisions of ICD-10 codes, PPVs were high for epidermolysis bullosa simplex and dystrophica.

Conclusion: The PPVs for first-time diagnoses of CEB registered in the two Danish nationwide registries investigated, DNPR and DPR, ranged from low to average. We therefore recommend that these data be used with caution and restricted to ICD-10 diagnoses from specialized dermatological departments.
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http://dx.doi.org/10.2147/CLEP.S184742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340365PMC
January 2019

Acne vulgaris severity graded by in vivo reflectance confocal microscopy and optical coherence tomography.

Lasers Surg Med 2019 01 2;51(1):104-113. Epub 2018 Aug 2.

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

Introduction: Acne is an inflammatory disease of the pilosebaceous unit, which can be investigated in vivo using reflectance confocal microscopy (RCM) and optical coherence tomography (OCT).

Objectives: By means of RCM and OCT to identify morphological characteristics of acne that may be associated with clinical acne severity.

Methods: Patients with mild to moderate facial acne (n = 14, Investigators Global Assessment scale, IGA 1-3), and healthy participants (n = 7, IGA 0) were included in this explorative study. A total of 108 RCM image blocks and 54 OCT scans (each RCM and OCT image measuring 6 × 6 mm) were captured from lesional-, perilesional, and lesion-free skin areas. Acne lesions, infundibular regions of follicles and inflammation degree were compared in acne patients and healthy participants.

Results: Combined use of RCM and OCT demonstrated infundibular morphology, acne lesions, and blood flow. RCM images of perilesional- and lesion-free skin in acne patients revealed follicle infundibula with hyperkeratinized borders and abundant keratin plugs, contrasting skin of healthy participants. Higher acne severity related to increased number of follicles with hyperkeratotic borders (P = 0.04) and keratin plugs (P = 0.006), increased infundibulum diameter (P < 0.001), increased density of inflammatory cells (P < 0.001), and blood flow (P = 0.03). Acne lesion morphology was not associated with acne severity.

Conclusion: Combined use of RCM and OCT elucidated distinctive follicle infundibulum characteristics and inflammation degree that were associated with acne severity. Future trials may apply imaging techniques to support clinical acne grading, and monitor treatment efficacy. Lasers Surg. Med. 51:104-113, 2019. © 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23008DOI Listing
January 2019

The β3-integrin endothelial adhesome regulates microtubule-dependent cell migration.

EMBO Rep 2018 07 24;19(7). Epub 2018 May 24.

School of Biological Sciences, Norwich Research Park, University of East Anglia, Norwich, UK

Integrin β3 is seen as a key anti-angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro- or anti-angiogenic depends on the context in which it is expressed. To understand precisely β3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the β3-dependent adhesome. We show that depletion of β3-integrin in this cell type leads to changes in microtubule behaviour that control cell migration. β3-integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2-driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both and , are more sensitive to microtubule targeting agents when β3-integrin levels are reduced.
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http://dx.doi.org/10.15252/embr.201744578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030693PMC
July 2018

The value of ultrahigh resolution OCT in dermatology - delineating the dermo-epidermal junction, capillaries in the dermal papillae and vellus hairs.

Biomed Opt Express 2018 May 19;9(5):2240-2265. Epub 2018 Apr 19.

Technical University of Denmark, DTU Fotonik, Kongens Lyngby, 2800, Denmark.

Optical coherence tomography (OCT) imaging of the skin is gaining recognition and is increasingly applied to dermatological research. A key dermatological parameter inferred from an OCT image is the epidermal (Ep) thickness as a thickened Ep can be an indicator of a skin disease. Agreement in the literature on the signal characters of Ep and the subjacent skin layer, the dermis (D), is evident. Ambiguities of the OCT signal interpretation in the literature is however seen for the transition region between the Ep and D, which from histology is known as the dermo-epidermal junction (DEJ); a distinct junction comprised of the lower surface of a single cell layer in epidermis (the stratum basale) connected to an even thinner membrane (the basement membrane). The basement membrane is attached to the underlying dermis. In this work we investigate the impact of an improved axial and lateral resolution on the applicability of OCT for imaging of the skin. To this goal, OCT images are compared produced by a commercial OCT system (Vivosight from Michaelson Diagnostics) and by an in-house built ultrahigh resolution (UHR-) OCT system for dermatology. In 11 healthy volunteers, we investigate the DEJ signal characteristics. We perform a detailed analysis of the dark (low) signal band clearly seen for UHR-OCT in the DEJ region where we, by using a transition function, find the signal transition of axial sub-resolution character, which can be directly attributed to the exact location of DEJ, both in normal (thin/hairy) and glabrous (thick) skin. To our knowledge no detailed delineating of the DEJ in the UHR-OCT image has previously been reported, despite many publications within this field. For selected healthy volunteers, we investigate the dermal papillae and the vellus hairs and identify distinct features that only UHR-OCT can resolve. Differences are seen in tracing hairs of diameter below 20 μm, and in imaging the dermal papillae where, when utilising the UHR-OCT, capillary structures are identified in the hand palm, not previously reported in OCT studies and specifically for skin not reported in any other optical imaging studies.
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http://dx.doi.org/10.1364/BOE.9.002240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946785PMC
May 2018

Two optical coherence tomography systems detect topical gold nanoshells in hair follicles, sweat ducts and measure epidermis.

J Biophotonics 2018 09 19;11(9):e201700348. Epub 2018 Jun 19.

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

Optical coherence tomography (OCT) is an established imaging technology for in vivo skin investigation. Topical application of gold nanoshells (GNS) provides contrast enhancement in OCT by generating a strong hyperreflective signal from hair follicles and sweat glands, which are the natural skin openings. This study explores the utility of 150 nm diameter GNS as contrast agent for OCT imaging. GNS was massaged into skin and examined in four skin areas of 11 healthy volunteers. A commercial OCT system and a prototype with 3 μm resolution (UHR-OCT) were employed to detect potential benefits of increased resolution and variability in intensity generated by the GNS. In both OCT-systems GNS enhanced contrast from hair follicles and sweat ducts. Highest average penetration depth of GNS was in armpit 0.64 mm ± SD 0.17, maximum penetration depth was 1.20 mm in hair follicles and 15 to 40 μm in sweat ducts. Pixel intensity generated from GNS in hair follicles was significantly higher in UHR-OCT images (P = .002) and epidermal thickness significantly lower 0.14 vs 0.16 mm (P = .027). This study suggests that GNSs are interesting candidates for increasing sensitivity in OCT diagnosis of hair and sweat gland disorders and demonstrates that choice of OCT systems influences results.
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http://dx.doi.org/10.1002/jbio.201700348DOI Listing
September 2018

Noninvasive measurement of reepithelialization and microvascularity of suction-blister wounds with benchmarking to histology.

Wound Repair Regen 2017 11 16;25(6):984-993. Epub 2018 Feb 16.

Department of Dermatology and Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

We explored use of the suction-blister wound model in the assessment of not only epidermal regeneration but also pain, the microvascular response and bacteriology. The effects of topical zinc sulfate were studied to articulate the methodologies in this double-blind trial. One epidermal suction blister (10 mm) was induced on each buttock in 30 healthy volunteers (15 females:15 males) and deroofed on day 0. The wounds were randomized to daily treatment with 1.4% zinc sulfate shower gel (n = 20), placebo (n = 20) or control (n = 20). Digital photography coupled with planimetry, transepidermal water loss (TEWL) measurement and optical coherence tomography (OCT) was benchmarked to the gold standard of histology of 60 full-thickness wound biopsies on day 4. Pain increased after application of the shower gels. Microvessel density, determined from OCT images, increased from day 0 to day 2 in the three groups but increased more with the placebo than with the zinc shower gel (p = 0.003) or the control treatment (p = 0.002) and correlated (r  = 0.313, p = 0.015) with the inflammatory response on day 4, as determined by histology. Coagulase-negative staphylococci were more common in wounds compared with skin (p = 0.002) and was reduced (p = 0.030) with zinc sulfate treatment. Planimetric analysis of digital wound images was not biased (p = 0.234) compared with histology, and TEWL measurements showed no correlation (r  = 0.052, p = 0.691) with epithelialization. Neoepidermal formation, determined by histology, did not differ (p = 0.290) among the groups. Zinc sulfate reduced (p = 0.031) the release of lactate dehydrogenase from cultured gel-treated keratinocytes isolated from the blister roofs. Therefore, combination of the standardized suction-blister wound model with noninvasive planimetry and OCT is a useful tool for assessing wound therapies. Zinc sulfate transiently dampened inflammation and reduced bacterial growth.
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http://dx.doi.org/10.1111/wrr.12605DOI Listing
November 2017

Immuno-fluorescent Labeling of Microtubules and Centrosomal Proteins in Ex Vivo Intestinal Tissue and 3D In Vitro Intestinal Organoids.

J Vis Exp 2017 12 13(130). Epub 2017 Dec 13.

School of Biological Sciences, University of East Anglia;

The advent of 3D in vitro organoids that mimic the in vivo tissue architecture and morphogenesis has greatly advanced the ability to study key biological questions in cell and developmental biology. In addition, organoids together with recent technical advances in gene editing and viral gene delivery promises to advance medical research and development of new drugs for treatment of diseases. Organoids grown in vitro in basement matrix provide powerful model systems for studying the behavior and function of various proteins and are well suited for live-imaging of fluorescent-tagged proteins. However, establishing the expression and localization of the endogenous proteins in ex vivo tissue and in in vitro organoids is important to verify the behavior of the tagged proteins. To this end we have developed and modified tissue isolation, fixation, and immuno-labeling protocols for localization of microtubules, centrosomal, and associated proteins in ex vivo intestinal tissue and in in vitro intestinal organoids. The aim was for the fixative to preserve the 3D architecture of the organoids/tissue while also preserving antibody antigenicity and enabling good penetration and clearance of fixative and antibodies. Exposure to cold depolymerizes all but stable microtubules and this was a key factor when modifying the various protocols. We found that increasing the ethylenediaminetetraacetic acid (EDTA) concentration from 3 mM to 30 mM gave efficient detachment of villi and crypts in the small intestine while 3 mM EDTA was sufficient for colonic crypts. The developed formaldehyde/methanol fixation protocol gave very good structural preservation while also preserving antigenicity for effective labeling of microtubules, actin, and the end-binding (EB) proteins. It also worked for the centrosomal protein ninein although the methanol protocol worked more consistently. We further established that fixation and immuno-labeling of microtubules and associated proteins could be achieved with organoids isolated from or remaining within the basement matrix.
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http://dx.doi.org/10.3791/56662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755565PMC
December 2017

Vehicle type affects filling of fractional laser-ablated channels imaged by optical coherence tomography.

Lasers Med Sci 2017 Apr 17;32(3):679-684. Epub 2017 Feb 17.

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, DK-2400, Copenhagen, NV, Denmark.

Ablative fractional laser (AFXL) is an emerging method that enhances topical drug delivery. Penetrating the skin in microscopic, vertical channels, termed microscopic treatment zones (MTZs), the fractional technique circumvents the skin barrier and allows increased uptake of topically applied drugs. This study aims to elucidate the impact of vehicle type on the filling of MTZs from application of liquid, gel, and cream vehicles. Ex vivo pig skin was exposed to 10,600 nm fractional CO laser at 5% density, 120 μm beam diameter, and fluences of 40 and 80 mJ/microbeam (mJ/mb). Six repetitions were performed for each of six interventions (2 fluences and 3 vehicle types, n = 36). MTZ dimensions and filling by vehicle type were evaluated by optical coherence tomography, using blue tissue dye as a contrast-enhancing agent. Outcome measure was degree of MTZ filling assessed as percentages of empty, partially filled, and completely filled MTZs (108-127 MTZs/intervention analyzed) and evaluated statistically using Kruskal-Wallis and Dunn's tests. MTZs reached mid-dermal levels of 225 μm (40 mJ/mb) and 375 μm (80 mJ/mb) penetration depths (p < 0.0001). Filling of MTZs depended on type of applied vehicle. At 80 mJ/mb, liquid (67% completely filled, p < 0.01) and gel (60%, p < 0.05) formulations filled MTZs significantly better than cream formulation (31%). At 40 mJ/mb, liquid and gel formulations filled 90% (p < 0.05) and 77% (p > 0.05) of MTZs completely versus 55% for cream formulation. Thus, filling was overall greater for more superficial MTZs. In conclusion, vehicle type affects filling of MTZs, which may be of importance for AFXL-assisted drug delivery.
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http://dx.doi.org/10.1007/s10103-017-2168-zDOI Listing
April 2017

Ninein is essential for apico-basal microtubule formation and CLIP-170 facilitates its redeployment to non-centrosomal microtubule organizing centres.

Open Biol 2017 02;7(2)

School of Biological Sciences, University of East Anglia, Norwich, UK

Differentiation of columnar epithelial cells involves a dramatic reorganization of the microtubules (MTs) and centrosomal components into an apico-basal array no longer anchored at the centrosome. Instead, the minus-ends of the MTs become anchored at apical non-centrosomal microtubule organizing centres (n-MTOCs). Formation of n-MTOCs is critical as they determine the spatial organization of MTs, which in turn influences cell shape and function. However, how they are formed is poorly understood. We have previously shown that the centrosomal anchoring protein ninein is released from the centrosome, moves in a microtubule-dependent manner and accumulates at n-MTOCs during epithelial differentiation. Here, we report using depletion and knockout (KO) approaches that ninein expression is essential for apico-basal array formation and epithelial elongation and that CLIP-170 is required for its redeployment to n-MTOCs. Functional inhibition also revealed that IQGAP1 and active Rac1 coordinate with CLIP-170 to facilitate microtubule plus-end cortical targeting and ninein redeployment. Intestinal tissue and organoids from the double KO mouse with deletions in the genes encoding CLIP-170 and CLIP-115, respectively, confirmed requirement of CLIP-170 for ninein recruitment to n-MTOCs, with possible compensation by other anchoring factors such as p150 and CAMSAP2 ensuring apico-basal microtubule formation despite loss of ninein at n-MTOCs.
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http://dx.doi.org/10.1098/rsob.160274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356440PMC
February 2017

Fractional laser-assisted drug uptake: Impact of time-related topical application to achieve enhanced delivery.

Lasers Surg Med 2017 04 25;49(4):348-354. Epub 2016 Nov 25.

Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark.

Background And Objective: Ablative fractional laser (AFXL) is acknowledged to increase uptake of topically applied agents in skin. AFXL channels gradually close over time, which may impair this capability. The time frame for applying a drug after AFXL exposure remains to be established. The aim of this study, was to investigate the importance of time-related topical application after AFXL exposure and to relate resultant uptake in skin with AFXL channel morphology and skin integrity.

Study Design/materials And Methods: Buttock skin of healthy volunteers (n = 11) was exposed to 10,600 nm fractional CO laser using 5% density, 120 μm beam diameter, 15 mJ pulse energy. Sodium fluorescein (NaF) a small, hydrophilic molecule (370 MW, log P =  -1.52) was applied under standardized conditions at specific time points after laser exposure (0, 2, 5, 10, 30, 60, 90 minute, 6, 24, and 48 hours). Fluorescence photography collected fluorescence images up to 180 minute after NaF application. Optical coherence tomography (OCT) assessed AFXL channel dimensions and transepidermal water loss (TEWL) estimated loss of skin integrity.

Results: Fluorescence intensities (FI) were significantly elevated when NaF was applied up to 6 hours after laser exposure compared to non-laser-processed skin (median FI 1947 arbitrary units [interquartile range 1,246-3,560] versus 1,004 [350-1,538], P < 0.02). The highest FI occurred when NaF was applied within 30 minute after laser exposure and similar FI were reached for applications at 0, 2, 5, 10, and 30 minute after AFXL exposure (0 minute: 3,866 [3,526-4,575], 30 minute: 3,775 AU [3,070-4,484], P > 0.1). NaF application later than 30 minute after AFXL exposure resulted in gradually decreasing FI, becoming similar to intact skin when applied at 24-48 hours after AFXL exposure (P > 0.2). OCT images demonstrated that AFXL channels closed over time (100% [100-100%] open up to 30 minute, 75% [4-86%] at 6 hours and 3% [0-15%] at 24-48 hours after AFXL exposure). TEWL measurements proved loss of skin integrity up to 6 hours after AFXL exposure, while integrity was similar in laser-exposed and non-laser-exposed skin at 24-48 hours.

Conclusions: The time frame to maintain enhanced drug delivery sustained for several hours after AFXL exposure, corresponding to channel morphology and loss of skin integrity. Lasers Surg. Med. 49:348-354, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.22610DOI Listing
April 2017

Dynamic Optical Coherence Tomography Capillaroscopy: A New Imaging Tool in Autoimmune Connective Tissue Disease.

JAMA Dermatol 2016 10;152(10)

Department of Dermatology, Bispebjerg Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Importance: Vasculopathy characterized by functional and structural abnormalities of the microcirculation plays an important role in systemic sclerosis and dermatomyositis. Although there are several advantages in using capillaroscopy, the method does not offer insight on the skin architecture, flow status, or morphology of the deeper dermal vessels. Dynamic optical coherence tomography (D-OCT) is a recently developed OCT technique that enables detection of high-speed changes in back-scattered light caused by moving cells in vessels. The high resolution of OCT enables the detection of the papillary loops.

Objective: To explore the potential for OCT capillaroscopy of the nailfolds using D-OCT.

Design, Setting, And Participants: In this case series study of 4 participants, the nailfolds in 2 patients with systemic sclerosis, 1 patient with dermatomyositis, and a healthy volunteer were scanned using D-OCT. The included patients were all outpatients from the department of dermatology at Bispebjerg Hospital. Data were analyzed from November 2015 to February 2016.

Main Outcomes And Measures: Dynamic OCT capillaroscopy revealed a potential for imaging of the capillary morphology, the surrounding skin architecture, and flow status of the capillaries in the nailfold. Moreover, D-OCT quantified evident changes of the blood flow in normal nailfold capillaries after application of nitroglycerine and brimonidine.

Results: This case series included 4 adult women. The quantitative measurements of the blood flow in the D-OCT images of the healthy participant showed significant quantitative differences in blood flow before and after application of nitroglycerine (mean difference, 0.035; 95% CI, 0.008-0.061; P = .02) and brimonidine (mean difference, -0.015; 95% CI, -0.082 to -0.039; P < .001). In the dermatomyositis patient, the en face D-OCT images showed a striking detailed Y-shaped dilated capillary correlating with the clinical finding. In the 2 patients with systemic sclerosis, D-OCT depicted megacapillaries, as well as loss of capillaries. Moreover, cross-sectional OCT images demonstrated a characteristic loss of distinct dermo-epidermal junction and more compact dermis with loss of adnexal structures.

Conclusions And Relevance: Compared with conventional capillaroscopy, D-OCT offers second-to-none information on nailfold capillary morphology, overall skin architecture, as well as quantitative data on vascular abnormalities and blood flow in the nailfold in a single scan.
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http://dx.doi.org/10.1001/jamadermatol.2016.2027DOI Listing
October 2016

Spatiotemporal closure of fractional laser-ablated channels imaged by optical coherence tomography and reflectance confocal microscopy.

Lasers Surg Med 2016 Feb 12;48(2):157-65. Epub 2015 Aug 12.

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

Background And Objective: Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) offer high-resolution optical imaging of the skin, which may provide benefit in the context of laser-assisted drug delivery. We aimed to characterize postoperative healing of ablative fractional laser (AFXL)-induced channels and dynamics in their spatiotemporal closure using in vivo OCT and RCM techniques.

Study Design/materials And Methods: The inner forearm of healthy subjects (n = 6) was exposed to 10,600 nm fractional CO2 laser using 5 and 25% densities, 120 μm beam diameter, 5, 15, and 25 mJ/microbeam. Treatment sites were scanned with OCT to evaluate closure of AFXL-channels and RCM to evaluate subsequent re-epithelialization.

Results: OCT and RCM identified laser channels in epidermis and upper dermis as black, ablated tissue defects surrounded by characteristic hyper-and hyporeflective zones. OCT imaged individual laser channels of the entire laser grid, and RCM imaged epidermal cellular and structural changes around a single laser channel to the depth of the dermoepidermal junction (DEJ) and upper papillary dermis. OCT images visualized a heterogeneous material in the lower part of open laser channels, indicating tissue fluid. By OCT the median percentage of open channels was evaluated at several time points within the first 24 hours and laser channels were found to gradually close, depending on the used energy level. Thus, at 5 mJ/microbeam, 87% (range 73-100%) of channels were open one hour after laser exposure, which declined to 27% (range 20-100%) and 20% (range 7-93%) at 12 and 24 hours after laser exposure, respectively. At 25 mJ/microbeam, 100% (range 100-100%) of channels were open 1 hour after laser exposure while 53% (range 33-100%) and 40% (range 0-100%) remained open at 12 and 24 hours after exposure. Median depth and width of open channels decreased over time depending of applied energy. RCM verified initial re-epithelialization from day 2 for all energy levels used. Morphology of ablation defects by OCT and RCM corresponded to histological assessments.

Conclusions: OCT and RCM enabled imaging of AFXL-channels and their spatiotemporal closure. Laser channels remained open up to 24 hours post laser, which may be important for the time perspective to deliver topical substances through AFXL channels.
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http://dx.doi.org/10.1002/lsm.22386DOI Listing
February 2016

Foot-and-mouth disease virus 3C protease induces fragmentation of the Golgi compartment and blocks intra-Golgi transport.

J Virol 2013 Nov 28;87(21):11721-9. Epub 2013 Aug 28.

Norwich Medical School, Faculty of Medicine and Health, University of East Anglia, Norwich, United Kingdom.

Picornavirus infection can cause Golgi fragmentation and impose a block in the secretory pathway which reduces expression of major histocompatibility antigens at the plasma membrane and slows secretion of proinflammatory cytokines. In this study, we show that Golgi fragmentation and a block in secretion are induced by expression of foot-and-mouth disease virus (FMDV) 3C(pro) and that this requires the protease activity of 3C(pro). 3C(pro) caused fragmentation of early, medial, and late Golgi compartments, but the most marked effect was on early Golgi compartments, indicated by redistribution of ERGIC53 and membrin. Golgi fragments were dispersed in the cytoplasm and were able to receive a model membrane protein exported from the endoplasmic reticulum (ER). Golgi fragments were, however, unable to transfer the protein to the plasma membrane, indicating a block in intra-Golgi transport. Golgi fragmentation was coincident with a loss of microtubule organization resulting from an inhibition of microtubule regrowth from the centrosome. Inhibition of microtubule regrowth also required 3C(pro) protease activity. The loss of microtubule organization induced by 3C(pro) caused Golgi fragmentation, but loss of microtubule organization does not block intra-Golgi transport. It is likely that the block of intra-Golgi transport is imposed by separate actions of 3C(pro), possibly through degradation of proteins required for intra-Golgi transport.
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http://dx.doi.org/10.1128/JVI.01355-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807340PMC
November 2013
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