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Inadequate tissue blood supply (e.g., in a wound or a poorly vascularised graft) can result in tissue ischemia and necrosis. As revascularization is a slow process relative to the proliferation of bacteria and the onset and spread of tissue necrosis, extensive tissue damage and loss can occur. Necrosis can spread rapidly, and treatment options are limited such that loss of tissue in ischemic tissue following necrosis onset is considered unavoidable and irreversible.Oxygen delivery from biomaterials exploiting aqueous decomposition of peroxy-compounds has shown some potential in overcoming the supply limitations caused by quite short oxygen diffusion distances in tissues by creating higher concentration gradients than can be attained by air saturated solutions or by distributing oxygen supply throughout a scaffold or construct by using particulate formulations. These have found application in tissue preservation, bioinks, creation of 3D tissue analogues etc. In preclinical models among the more exciting reports was a single study demonstrating reduction of ischemic skin necrosis albeit only short term using short term sub dermal delivery of oxygen below ischemic skin flaps. To explore this effect further, we developed an implantable solid peroxide-biomaterial based system with reduced hydrogen peroxide release by virtue of incorporation of minerals to catalytically decompose it in a much longer flap than examined previously. Blood flow in this flap reduced from essentially normal to essentially zero, along its 9cm length. Without treatment ∼50% of the total flap was necrotic in 2-4 days. In both groups, complete necrosis in the distal third of the flap with no observable flood flow was observed. But in the middle low blood flow region of the flap, treatment did prevent necrosis. This study indicated that subdermal oxygen delivery alone cannot completely mitigate dermal necrosis if no blood flow is present, but it could improve the survival of partially tissue at least in the short term which could find application to augment conventional treatments or to gain time until surgical intervention.

Melanoma is an immunogenic cancer with a high response rate to immune checkpoint inhibitors (ICIs). It harbors a high mutation burden compared with other cancers and, as a result, has abundant tumor-infiltrating lymphocytes (TILs) within its microenvironment. However, understanding the complex interplay between the stroma, tumor cells, and distinct TIL subsets remains a substantial challenge in immune oncology. To properly study this interplay, quantifying spatial relationships of multiple cell types within the tumor microenvironment is crucial. To address this, we used cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) to simultaneously quantify the expression of 35 protein markers, characterizing the microenvironment of 5 benign nevi and 67 melanomas. We profiled more than 220,000 individual cells to identify melanoma, lymphocyte subsets, macrophage/monocyte, and stromal cell populations, allowing for in-depth spatial quantification of the melanoma microenvironment. We found that within pretreatment melanomas, the abundance of proliferating antigen-experienced cytotoxic T cells (CD8 + CD45RO + Ki67 + ) and the proximity of antigen-experienced cytotoxic T cells to melanoma cells were associated with positive response to ICIs. Our study highlights the potential of multiplexed single-cell technology to quantify spatial cell-cell interactions within the tumor microenvironment to understand immune therapy responses.

Endoglin is a transmembrane protein that binds transforming growth factor b (TGF-b) with high affinity. It is thought to modulate TGF-b signaling and responses through interactions on cell surfaces with TGF-b receptors. It is highly expressed on endothelial cells of tissues undergoing angiogenesis. Since ischemia-induced changes such as angiogenesis are in part regulated by TGF-b, it is important to elucidate the precise mechanism by which they occur if we are to influence the effects of ischemia on tissue. Since endoglin is one of the receptors involved in regulating TGF-b signaling, we tested whether endoglin expression will increase in response to ischemic injury. A pig skin flap model was developed and used in our laboratory to study the effect of ischemia on the expression of endoglin and its ligand TGF-b1 using immunohistochemistry. We observed an increased expression of endoglin and TGF-b1 in the epidermal layer, blood vessels, and fibroblasts in ischemic skin flaps as compared to non-ischemic control skin flaps. Given the role of TGF-b and endoglin in angiogenesis, this may represent a mechanism by which ischemia stimulates angiogenesis. Much work remains to be done to delineate the exact mechanisms by which TGF-b acts and the exact role of endoglin in TGF-b signaling. Understanding how to regulate the actions of TGF-b by manipulating the expression of endoglin may provide a therapeutic avenue given the importance of TGF-b in tumour angiogenesis.

Discoid or chronic lupus erythematosus is an autoimmune disease that produces skin lesions on the face and scalp. Rarely do lesions present with linear configuration, but when they do, the lesions often follow the lines of embryologic migration. A 24-year-old man presented with a slowly progressing asymptomatic violaceous linear patch running from the root of his frontal scalp to the nasal tip. A Doppler ultrasound and skin biopsy were performed and the histological findings demonstrated characteristic findings of discoid lupus erythematosus. A full physical examination, review of systems and laboratory investigations showed no indication of systemic lupus. High potency topical steroids and calcineurin inhibitors were prescribed along with photoprotection. At 4-month follow-up, all his lesions had mostly cleared. We report here the first case, to our knowledge, of discoid lupus erythematosus with en coup de saber presentation mimicking morphea.

This is a 40-year-old woman with sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay syndrome, who has genital and extragenital lichen sclerosus on the abdomen and the upper back that have become erythematous and painful during febrile episodes. This report summarizes the published cases of sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay and highlights associated mucocutaneous features.

The high background tumor mutation burden in cutaneous melanoma limits the ability to identify significantly mutated genes (SMGs) that drive this cancer. To address this, we performed a mutation significance study of over 1,000 melanoma exomes, combined with a multi-omic analysis of 470 cases from The Cancer Genome Atlas. We discovered several SMGs with co-occurring loss-of-heterozygosity and loss-of-function mutations, including PBRM1, PLXNC1 and PRKAR1A, which encodes a protein kinase A holoenzyme subunit. Deconvolution of bulk tumor transcriptomes into cancer, immune and stromal components revealed a melanoma-intrinsic oxidative phosphorylation signature associated with protein kinase A pathway alterations. We also identified SMGs on the X chromosome, including the RNA helicase DDX3X, whose loss-of-function mutations were exclusively observed in males. Finally, we found that tumor mutation burden and immune infiltration contain complementary information on survival of patients with melanoma. In summary, our multi-omic analysis provides insights into melanoma etiology and supports contribution of specific mutations to the sex bias observed in this cancer. Alkallas et al. uncover new significantly mutated genes in a large cohort of cutaneous melanoma, including the RNA helicase DDX3X, through integrated analysis of genomic, transcriptomic and DNA methylation data.

Raymarching signed distance fields is a technique used by graphics experts and demoscene enthusiasts to construct scenes with features unusual in traditional polygonal workflows-blending shapes, kaleidoscopic patterns, reflections, and infinite fractal detail all become possible and are represented in compact representations that live mostly on the graphics card. Until now these scenes have had to be constructed in shaders by hand, but the Raymarching Toolkit for Unity is an extension that combines Unity's highly visual scene editor with the power of raymarched visuals by automatically generating the raymarching shader for the scene an artist is creating, live.

Background: Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new classification is based on genetic variants with mutations in keratin KRT6A, KRT6B, KRT6C, KRT16, KRT17, and an unknown mutation. Here, we present a case of PC with unusual clinical and histological features and a favorable response to oral acitretin. Case: A 49-year-old male presented with diffuse and striate palmoplantar keratoderma, thickened nails, knuckle pads, and pseudoainhum. Histology showed compact hyperkeratosis, prominent irregular acanthosis, and extensive epidermolytic hyperkeratosis, suggestive of Vörner's palmoplantar keratoderma. However, keratin 9 and 1 were not mutated, and full exome sequencing showed heterozygous missense mutation in type I keratin K16. Conclusion: To our knowledge, epidermolytic hyperkeratosis has not been previously described with PC. Our patient had an excellent response, maintained over the last 5 years, to a low dose of acitretin. We wish to emphasize the crucial role of whole exome sequencing in establishing the correct diagnosis.

Background Familial hypercholesterolemia is a genetic lipoprotein disorder characterized by elevated plasma low-density lipoprotein cholesterol level, (tendinous xanthomas, xanthelasmas, and premature arcus corneus) and early onset atherosclerotic cardiovascular disease. Familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 genes. Rare mutations in low-density lipoprotein receptor adapter protein 1, APOE p.Leu167del or lysosomal acid lipase genes can mimic FH. The prevalence of heterozygous familial hypercholesterolemia is estimated to be 1/250 worldwide, although some populations with founder effects show a higher prevalence. The rare homozygous form has an estimated prevalence of 0.000004 or 1/250,000 and is characterized by markedly elevated low-density lipoprotein cholesterol, skin manifestations (planar xanthomas, tendinous xanthomas) in childhood and extremely premature atherosclerotic cardiovascular disease. While tendinous xanthomas are considered pathognomonic for familial hypercholesterolemia, they can also be found in rare diseases, including sitosterolemia. Here, we report a case of severe tendinous xanthomatosis with heterozygous familial hypercholesterolemia due to the low-density lipoprotein receptor del >15 kb mutation. The phenotypic expression of the disease is out of proportion with the genetic diagnosis or biochemical measurements. Case report We report the case of 51-year-old woman of French-Canadian origin diagnosed with heterozygous familial hypercholesterolemia since age 12. She presented with hypercholesterolemia with total cholesterol 7.6 mmol/L, with an imputed low-density lipoprotein cholesterol level of 6.5 mmol/L. She had extensive tendinous xanthomas of the Achilles tendons, knees, elbows and metacarpophalangeal joints. Because of cosmetic disfigurement, she had multiple excisions of Achilles, knee and elbow xanthomas, albeit with rapid recurrence. Our patient has a significant family history of lung cancer and other autoimmune diseases associated with familial hypercholesterolemia and xanthoma. Lipid-lowering therapy was started, at age 12; which included initially cholestyramine, then changed to statin and ezetimibe. Eventually, evolocumab was added. Despite trying different lipid-lowering therapy, there has been no noticeable decrease in the size of the xanthomas. Conclusion Our patient has severe xanthomatosis out of proportion with the genetic diagnosis or biochemical measurements. Her xanthomatosis did not improve by pharmacological therapy consisting of statins and evolocumab despite a 50% reduction in low-density lipoprotein cholesterol. It is likely that the patient presented here has a second genetic disorder that leads to extensive xanthomatosis.

We present a rare case of a 61-year-old woman presenting with a widespread erosive eruption on her torso and extremities. Although the lesions were histologically compatible with toxic epidermal necrolysis, clinically the patient was hemodynamically stable, had no mucosal involvement and had no relevant medical history or potentially incriminating medications. Further investigations uncovered a new diagnosis of systemic lupus erythematosus, with this toxic epidermal necrolysis–like eruption being the first presentation of the disease. This case highlights the importance of broadening the differential diagnosis in patients presenting with acute widespread cleavage of the epidermis, using the spectrum of acute syndrome of apoptotic pan-epidermolysis as a reference.

QinetiQ has been the primary engineering support contractor to the RAAF airworthiness section (ASI-DGTA) since 1996. Over that 16 year time period many airworthiness investigations and assessments of structural integrity have been performed on a wide variety of RAAF aircraft types and Army rotary wing aircraft. A complete capability has been developed to manage structural fatigue in accordance with airworthiness standards, and indeed to transition the management of an aircraft from a design standard to a preferred RAAF management standard in response to capability requirements. Many important lessons have been learnt and have reinforced the capability. This paper describes some of the major programs that QinetiQ has undertaken for the RAAF, and the lessons learnt from them.

Topical application of collagen has been suggested to enhance wound healing; however, its long-term effect on wounds has not been studied in a rat model.Topical application of collagen type I will not facilitate incision healing or cosmesis in rats up to 28 days postwounding.The effects of bovine collagen type I (6 mg/mL) on the rat surgical paired skin incision model were examined. Each rat served as its own control in which topical collagen was applied to one incision while normal saline (0.9%) was applied to the other incision. Rats were euthanized three (n=6), seven (n=6) and 28 (n=5) days after wounding. Tissue harvested from each time point was examined for maximal breaking strength, and for biochemical and histological analysis.There were no statistically significant differences (ie, P0.05) in maximum wound breaking strength between the collagen- and saline-treated wounds at all time points. Histological analysis revealed a similar infiltration of inflammatory cells and fibroblasts in the wound edges of all incisions when matched with time of wounding. Western blot analysis revealed no differences in fibronectin or collagen I content in all wounds in each rat.The topical application of collagen did not facilitate wound healing from three to 28 days in the rat wound model.L’application topique de collagène améliorerait la guérison des plaies. Cependant, on n’a pas étudié son effet à long terme sur les plaies d’un modèle de rat.L’application topique de collagène de type I ne facilitera pas la cicatrisation ou l’esthétique d’une incision chez les rats jusqu’à 28 jours après la formation de plaies.Les auteurs ont examiné les effets du collagène bovin de type I (6 mg/mL) sur un modèle de double incision cutanée chez des rats. Chaque rat était son propre sujet témoin, car du collagène topique était appliqué sur une incision, et une solution physiologique normale (0,9 %), sur l’autre. Les rats étaient euthanasiés trois (n=6), sept (n=6) et 28 (n=5) jours après la création des plaies. Les auteurs ont prélevé des tissus à chacun de ces moments et les ont examinés pour établir leur résistance maximale à la rupture et pour procéder à une analyse biochimique et histologique.Il n’y a pas de différence statistiquement significative (c’est-à-dire P0,05) quant à la résistance maximale à la rupture des plaies traitées au collagène et de celles traitées au moyen d’une solution physiologique à l’un de ces trois moments. L’analyse histologique a révélé une infiltration similaire des cellules inflammatoires et des fibroblastes dans les lèvres de la plaie de chacune des incisions par rapport au moment de création de la plaie. Le transfert de Western n’a révélé aucune différence dans le contenu en fibronectine ou en collagène I des plaies de chaque rat.L’application topique de collagène ne facilite pas la cicatrisation des plaies au bout de trois à 28 jours dans un modèle de plaies chez les rats.

Bullous systemic lupus erythematosus (BSLE) is a rare autoimmune subepidermal blistering disease with a female predominance characterized as an acute vesicobullous eruption in patients with systemic lupus erythematosus (SLE). Here we report a case of BSLE in a 16-year-old boy that does not adhere to the criteria originally established and suggest a new outlook on this condition.

e15071Background: Therapeutics targeting inhibitory immune checkpoints have revolutionized the treatment of advanced and metastatic melanoma. Clinical trials of dual treatment with anti-CTLA4 and a...

To date, more than 200 cases of nephrogenic systemic fibrosis have been documented worldwide. All patients have had renal failure, most of them requiring dialysis. We herein describe the course of a hemodialyzed patient who developed nephrogenic systemic fibrosis in the months following magnetic resonance angiography of the lower extremities. The disease is characterized by skin thickening and tendon fibrosis leading to joint contractures that can quickly confine the patient to a wheelchair. Systemic involvement may occur, leading to cardiomyopathy, pulmonary fibrosis, pulmonary hypertension or even death. No consistently effective therapy has been reported. An association between gadolinium exposure and the development of the disease has been found, although no causal link has yet been proven. In a patient with renal failure, magnetic resonance imaging with gadolinium enhancement should be done only after having seriously considered the risk/benefit ratio. Implications concerning the choice of imaging methods when searching for ischemic nephropathy or aorto-iliac disease before renal transplantation are discussed.

Background Classic Kaposi's sarcoma (KS) is predominantly a disease of eastern Mediterranean and Ashkenazi Jewish elderly men. Nevertheless, the disease has been reported to occur in people from various other ethnic and regional backgrounds. Objective We report, for the first time, the occurrence of classic KS in five Inuit people living in northern Quebec, Canada. Methods and results We describe the case of a 69-year-old Inuit man with classic KS, and report four other cases of KS in the Inuit population, identified by a review of our hospital's dermatopathology records. Conclusion The discovery of classic KS in the Inuit population of northern Quebec brings with it new questions as to the origins of the KS-associated herpes virus in this population. It is our belief that the answers to these questions are in the genotype of the virus that is present in this community.

Background. Complements C3 and C5 have independently been shown to augment and increase wound healing and strength. Our goal was to investigate the combinatorial effect of complements C3 and C5 on wound healing. Methods. Each rat served as its own control where topical collagen was applied to one incision and 100 nM of C3 and C5 in collagen vehicle was applied to the other incision (n=6). To compare between systemic effects, a sham group of rats (n=6) was treated with collagen alone on one wound and saline on the other. At day 3, the tissue was examined for maximal breaking strength (MBS) and sectioned for histological examination. Results. There was a statistically significant 88% increase in MBS with the topical application of C3C5 when compared to sham wounds (n<0.05). This was correlated with increased fibroblast and collagen deposition in the treated wounds. Furthermore, there appeared to be an additive hemostatic effect with the C3C5 combination. Conclusions. The combination of complements C3 and C5 as a topical application drug to skin wounds significantly increased wound healing maximum breaking strength as early as 3 days.

We describe a patient with Grave's discase who developed purpura fulminans and who was found to have anticardiolipin antibodies after being started on propylthiouracil (PTU). We discuss the potential role of the antiphospholipid antibody in this woman's presentation, and its association to both PTU and autoimmune thyroid disease.

The complement system is composed of bactericidal and hemolytic proteins that increase capillary leakage and inflammatory cell migration. The role of complement C3 to augment wound healing has not yet been studied.We examined the effects of topical complement C3 formulation at two concentrations (10 and 100 nM) on the rat surgical skin incision model. Skin was examined for maximal breaking strength and sectioned for histological examination. Fibronectin and collagen I content were measured using western blot analysis.There was a statistically significant 74% increase in maximum wound strength with the topical application of 100 nM of C3 at day 3 (850 ± 138 g) when compared to the control rats (490 ± 57 g). Histological correlation was seen with an increased inflammatory cell and fibroblast infiltration in treated wounds as compared to control rats as early as 3 days post-wounding. Western blots revealed increased fibronectin and collagen I levels in C3 treated wounds.Topical application of complement C3 in collagen formulation to skin wounds significantly increases wound healing as early as 3 days after wounding. This is correlated with increased inflammatory cell recruitment and the subsequent early fibroblast migration and increased collagen deposition and organization in wounds.

Ovarian carcinomas exhibit extensive heterogeneity, and their etiology remains unknown. Histological and genetic evidence has led to the proposal that low grade ovarian serous carcinomas (LGOSC) have a different etiology than high grade carcinomas (HGOSC), arising from serous tumours of low malignant potential (LMP). Common regions of chromosome (chr) 3 loss have been observed in all types of serous ovarian tumours, including benign, suggesting that these regions contain genes important in the development of all ovarian serous carcinomas. A high-density genome-wide genotyping bead array technology, which assayed >600,000 markers, was applied to a panel of serous benign and LMP tumours and a small set of LGOSC, to characterize somatic events associated with the most indolent forms of ovarian disease. The genomic patterns inferred were related to TP53, KRAS and BRAF mutations. An increasing frequency of genomic anomalies was observed with pathology of disease: 3/22 (13.6%) benign cases, 40/53 (75.5%) LMP cases and 10/11 (90.9%) LGOSC cases. Low frequencies of chr3 anomalies occurred in all tumour types. Runs of homozygosity were most commonly observed on chr3, with the 3p12-p11 candidate tumour suppressor region the most frequently homozygous region in the genome. An LMP harboured a homozygous deletion on chr6 which created a GOPC-ROS1 fusion gene, previously reported as oncogenic in other cancer types. Somatic TP53, KRAS and BRAF mutations were not observed in benign tumours. KRAS-mutation positive LMP cases displayed significantly more chromosomal aberrations than BRAF-mutation positive or KRAS and BRAF mutation negative cases. Gain of 12p, which harbours the KRAS gene, was particularly evident. A pathology review reclassified all TP53-mutation positive LGOSC cases, some of which acquired a HGOSC status. Taken together, our results support the view that LGOSC could arise from serous benign and LMP tumours, but does not exclude the possibility that HGOSC may derive from LMP tumours.

Teaching awards are commonly regarded as an incentive to encourage pedagogic excellence. Inasmuch as their effectiveness depends on how they are perceived by faculty, the authors investigated the impact of a teaching award in the Faculty of Medicine (Faculty Honor List for Educational Excellence) on the attitudes of award recipients and departmental chairs. A questionnaire was designed to sample opinion on the extent to which the Honor List program was publicized, whether the award contributed to recognition and/or stature in the academic unit, and whether it was personally valued by recipients. The questionnaire was sent to all 23 departmental chairs and to all 43 faculty members who had received the award between 1998 and 2002; 78% of the chairs and 77% of the recipients responded. The results revealed marked discrepancies between the perceptions of chairs and recipients. Chairs, although uncertain of the effect on quality of teaching, largely regarded the award as prestigious and well publicized within their departments. A notably smaller percentage of award recipients shared these views. Nonetheless, 93% of recipients valued the award highly, and 45% of recipients indicated that the award inspired them to enhance the quality of their teaching.

To date, more than 200 cases of nephrogenic systemic fibrosis have been documented worldwide. All patients have had renal failure, most of them requiring dialysis. We herein describe the course of a hemodialyzed patient who developed nephrogenic systemic fibrosis in the months following magnetic resonance angiography of the lower extremities. The disease is characterized by skin thickening and tendon fibrosis leading to joint contractures that can quickly confine the patient to a wheelchair. Systemic involvement may occur, leading to cardiomyopathy, pulmonary fibrosis, pulmonary hypertension or even death. No consistently effective therapy has been reported. An association between gadolinium exposure and the development of the disease has been found, although no causal link has yet been proven. In a patient with renal failure, magnetic resonance imaging with gadolinium enhancement should be done only after having seriously considered the risk/benefit ratio. Implications concerning the choice of imaging methods when searching for ischemic nephropathy or aorto-iliac disease before renal transplantation are discussed.

Bronchiolitis obliterans and organizing pneumonia (BOOP) is an inflammatory, fibrotic disorder of the small airways, alveoli and pulmonary intersitium. Often idiopathic and usually benign, this condition may cause dyspnea and influenza-like symptoms. Polyarteritis nodosa (PAN) is a small and medium vessel vasculitis, which usually involves the kidney and other viscera but rarely results in vasculitis of the lungs. This is the second case of BOOP associated with PAN reported in the literature. Knowledge of this association is likely to be of value because an undiagnosed vasculitis can rapidly become fatal.

A 75 year-old uncircumcised man presented with a 1.1mm thick malignant melanoma on the ventral aspect of the glans penis. He underwent isosulfan blue and technetium 99m guided sentinel lymph node (SLN) biopsy and distal penectomy with 2 cm margins. This is the third reported case of penile melanoma using both markers for SLN mapping. While frozen sections and HE stains were negative, S-100 and HMB-45 immunohistochemistry revealed micrometastasis in one of the sentinel nodes. This case illustrates that any discussion with the patient about management and prognosis should await immunohistochemistry results.

A 47-year-old black woman of Haitian descent presented with a 20-year history of a persistent nonpruritic rash involving her trunk and the proximal aspect of her legs. Prior lesions had also involved her buttocks and breasts. She had tried several courses of topical steroids, with no improvement. Her medical history was remarkable for Crohn disease, which was in remission. There was no family history of similar skin lesions. Physical examination revealed well-demarcated, circular, scaly, hyperpigmented plaques with an atrophic cigarette paper texture on the trunk, thighs, and buttocks (Figure 1 and Figure 2). The findings of laboratory investigations, including a complete blood cell count, liver function tests, thyroid-stimulating hormone, albumin, and a basic metabolic panel, were normal. A chest x-ray film showed no abnormalities. The results of a potassium hydroxide preparation and a fungal culture were negative. A skin biopsy specimen was obtained from a plaque on the trunk (Figure 3). What is your diagnosis?

A 50-year-old man with a 4-year history of non-Hodgkin's lymphoma presented to the dermatology clinic with painful violaceous plaques in his peri-inguinal area that had slowly enlarged over 3 weeks. A year before presentation the patient had undergone allogeneic stem-cell transplantation and was

• Abnormalities of pigmentation are a well-known side effect of antimalarial therapy. Quinidine, an antiarrhythmic agent, is structurally related to the common antimalarials but, to our knowledge, has not been associated with pigmentary abnormalities. We report a case of localized blue-gray pigmentation, clinically and histologically identical to antimalarial-induced pigmentation, in a patient receiving quinidine therapy. ( Arch Dermatol 1986;122:1062-1064)