Dermal Vessels Research Articles

Dermal microvessel density and maturity is closely associated with atherogenic dyslipidemia and accumulation of advanced glycation end products in adult patients with type 1 diabetes

In patients with diabetes, functional changes in microcirculation and subclinical vascular pathology precede clinical manifestation of microangiopathic complications. The objective of this study was to evaluate the association between established vascular risk factors and density, maturity, and reactivity of dermal blood vessels in adults with type 1 diabetes (DM1). We included 148 DM1 patients (87 men) with a median (IQR) age of 40.5 (30.5–49) years and a median diabetes duration of 21 (17–29.5) years. The control group consisted of 13 healthy volunteers (6 men) with a median (IQR) age of 36 (31–43). Accumulation of advanced glycation end products (AGEs) was assessed using the AGE-Reader device. In the immunohistochemical (IHC) analyses, anti-CD133, anti-CD34, anti-CD31, and anti-vWF autoantibodies were used. Microvessel density (MVD) in the skin was calculated using the “hot spots technique”. Microvascular function was examined by single-point laser-Doppler flowmetry (LDF). Median MVD, calculated for both papillary and reticular dermis, for CD31 antigen expression was 38 (19–56) per 1 mm2. The median CD34+ blood vessel density was 121 (100–155) per 1 mm2, CD133+ was 79 (63–92) per 1 mm2, and vWF+ was 50 (40–69) per 1 mm2. The average CD34/CD31 index was 2.78, the vWF/CD31 ratio was 1.32 and the CD133/CD31 ratio was 1.75. The CD34/CD31 index was positively associated with serum triglyceride concentration (Beta: 0.26, p = 0.012) and negatively associated with serum HDL cholesterol concentration (Beta: −0.22, p = 0.027), both independently from age, sex, diabetes duration, BMI, HbA1c value, presence of hypertension, and eGFR. We found a negative correlation between MVD assessed by CD31 and skin AF (r = −0.21, p = 0.016). In LDF, the area under the blood flow/time curve (AUC) correlated positively with CD31+ MVD (r = 0.21, p = 0.011) and negatively with CD34+ MVD (r = −0.20, p = 0.017). The MVD did not differ between participants with diabetes and healthy controls, and it did not differ according to the presence of retinopathy among the participants with diabetes. Atherogenic dyslipidemia is associated with increased formation of new blood vessels, characterized by high expression of CD34 and low reactivity in LDF. Conversely, chronic hyperglycemia and excessive formation of AGEs may result in decreased vascularity.

Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds.

Endothelial cells line blood and lymphatic vessels and form intercellular junctions, which preserve vessel structure and integrity. The vascular endothelial cadherin, VE-cadherin, mediates endothelial adhesion and is indispensible for blood vessel development and permeability regulation. However, its requirement for lymphatic vessels has not been addressed. During development, VE-cadherin deletion in lymphatic endothelial cells resulted in abortive lymphangiogenesis, edema, and prenatal death. Unexpectedly, inducible postnatal or adult deletion elicited vessel bed-specific responses. Mature dermal lymph vessels resisted VE-cadherin loss and maintained button junctions, which was associated with an upregulation of junctional molecules. Very different, mesenteric lymphatic collectors deteriorated and formed a strongly hyperplastic layer of lymphatic endothelial cells on the mesothelium. This massive hyperproliferation may have been favored by high mesenteric VEGF-C expression and was associated with VEGFR-3 phosphorylation and upregulation of the transcriptional activator TAZ Finally, intestinal lacteals fragmented into cysts or became highly distended possibly as a consequence of the mesenteric defects. Taken together, we demonstrate here the importance of VE-cadherin for lymphatic vessel development and maintenance, which is however remarkably vessel bed-specific.

A Case of Henoch-Schönlein Purpura on Endoscopy

Vasculitis of Gastrointestinal (GI) tract presents with abdominal pain, nausea, vomiting, and bleeding. It is difficult to diagnose vasculitis through endoscopy due to low diagnostic yield of endoscopic biopsies and therefore it is important to consider clinical feature. We present a case of IgA vasculitis involving GI tract, emphasizing role of multidisciplinary approach. A 77 years old man with medical history of Grave's disease, atrial fibrillation, osteoarthritis, gout, and hypertension presented to Emergency Room due to worsening abdominal pain, nausea, vomiting, and blood in stool. Patient reported abdominal pain for 3 weeks, diffuse and dull and becoming periumbilical and reproducible without any relieving or exacerbating factors. He reported early satiety without weight loss. Complete metabolic panel (CMP) and complete blood count (CBC), and Lactic Acid were normal however patient had 2gram urine protein. He had periumbilical tenderness and bilateral lower extremities pitting edema with purpuric patches. Abdomen and Pelvic CT scan showed nonspecific wall thickening of distal esophagus, stomach, cecum, distal ileum, and small segment of jejunum. On Enteroscopy nodular appearing fundic mucosa with ulcerations was seen, biopsy showed ischemic gastropathy. Second portion of Duodenum showed nodular appearing mucosa while Third portion showed an ulcerated duodenal lesion which was biopsied and showed ulcer with acute duodenitis. Proximal Jejunum was normal however ulceration with surrounding erythema was noted distally and biopsy showed ulcerative jejunitis. Colonoscopy showed scattered areas of ulceration and erythema extending from rectum to terminal ileum which was biopsied and showed features of resolving acute ischemia. Rheumatology was consulted and punch biopsy from lower extremity showed granular deposit of IgA surrounding superficial dermal vessel compatible with Henoch-Schönlein Purpura. Renal biopsy showed focal mesangial proliferation with segmental inflammatory glomerulopathy with sclerosis consistent with IgA nephropathy. Patient was started on high dose steroids 80mg/day. Renal function was followed and was stable therefore steroids were tapered off. Patient underwent repeat Colonoscopy and Enteroscopy after 1 year of being off of steroids which showed normal mucosa. Our case highlights difficulty in diagnosing vasculitis through endoscopy and shows clinical course of vasculitis of GI tract through follow-up endoscopy.

An unusual presentation of eosinophilic granulomatosis with polyangiitis with a good response to rituximab

IntroductionEosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis that belongs to the anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides. It usually presents with late onset asthma in association with ear, nose and throat, cardiac, lung and gastrointestinal involvement. Aim of the workTo present a case of EGPA man with an unusual presentation. Case reportA 24 years old patient with EGPA presented with deep vein thrombosis and nerve palsy without a history of asthma or other usual manifestations of the disease. The left leg showed a skin rash and associated deep vein thrombosis as well as a small ulcer over the pulp of the right thumb. The total leucocyte count was 14.5 × 109/L (41% eosinophils), erythrocyte sedimentation rate was 30 mm/1st hour and C-reactive protein 12.2 mg/L. Hepatitis B and C serology, antinuclear antibody (ANA) and antiphospholipid antibodies were all negative. ANCA was positive: myeloperoxidase (MPO) 36.9 U/ml and proteinase-3 (PR3) 15.9 U/ml and urinalysis was normal. The dermal and subcutaneous blood vessels displayed fibrinoid deposits, necrosis, and neutrophilic infiltrates in keeping with vasculitis. The patient showed a prompt and good response to corticosteroid and rituximab therapy with resolution of his symptoms. ConclusionThere is a necessity to keep an open eye for the diagnosis of EGPA in patients with eosinophilia even in the absence of asthma or other usual manifestations, as prompt therapy may be organ and life-saving. B cell therapy should be considered in patients resistant to conventional therapy and those in whom preservation of fertility is desired.

Is the humoral immunity dispensable for the pathogenesis of psoriasis?

Imbalances of T-cell subsets are hallmarks of disease-specific inflammation in psoriasis. However, the relevance of B cells for psoriasis remains poorly investigated. To analyse the role of B cells and immunoglobulins for the disease-specific immunology of psoriasis. We characterized B-cell subsets and immunoglobulin levels in untreated psoriasis patients (n=37) and compared them to healthy controls (n=20) as well as to psoriasis patients under disease-controlling systemic treatment (n=28). B-cell subsets were analysed following the flow cytometric gating strategy based on the surface markers CD24, CD38 and CD138. Moreover, immunofluorescence stainings were used to detect IgA in psoriatic skin. We found significantly increased levels of IgA in the serum of treatment-naïve psoriasis patients correlating with disease score. However, IgA was only observed in dermal vessels of skin sections. Concerning B-cell subsets, we only found a moderately positive correlation of CD138+ plasma cells with IgA levels and disease score in treatment-naïve psoriasis patients. Confirming our hypothesis that psoriasis can develop in the absence of functional humoral immunity, we investigated a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (CVID) characterized by a lack of B cells and immunoglobulins. We detected variants in three of the 13 described genes of CVID and a so far undescribed variant in the ligand of the TNFRSF13B receptor leading to disturbed B-cell maturation and antibody production. However, this patient showed typical psoriasis regarding clinical presentation, histology or T-cell infiltrate. Finally, in a group of psoriasis patients under systemic treatment, neither did IgA levels drop nor did plasma cells correlate with IgA levels and disease score. B-cell alterations might rather be an epiphenomenal finding in psoriasis with a clear dominance of T cells over shifts in B-cell subsets.

PROX1 is a transcriptional regulator of MMP14

The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

Amyloid Beta Peptide Is Released during Thrombosis in the Skin

While it is known that amyloid beta (Aβ) deposits are found in different tissues of both Alzheimer’s disease (AD) patients and healthy individuals, there remain questions about the physiological role of these deposits, the origin of the Aβ peptide, and the mechanisms of its localization to the tissues. Using immunostaining with specific antibodies, as well as enzyme-linked immunosorbent assay, this study demonstrated Aβ40 peptide accumulation in the skin during local experimental photothrombosis in mice. Specifically, Aβ peptide accumulation was concentrated near the dermal blood vessels in thrombotic skin. It was also studied whether the released peptide affects microorganisms. Application of Aβ40 (4 µM) to the external membrane of yeast cells significantly increased membrane conductance with no visible effect on mouse host cells. The results suggest that Aβ release in the skin is related to skin injury and thrombosis, and occurs along with clotting whenever skin is damaged. These results support the proposition that Aβ release during thrombosis serves as part of a natural defense against infection.

Dermoscopic patterns of early-stage mycosis fungoides in a Chinese population.

Early-stage mycosis fungoides (eMF) is a clinical diagnostic challenge because it can mimic inflammatory diseases. Dermoscopy has been reported to be useful in evaluation of eMF in Caucasian patients; however, dermoscopic features of eMF in the Chinese population are lacking. To determine the validity of dermoscopy in the diagnosis and differential diagnosis of eMF in a Chinese population. This was a retrospective study that included a total of 101 patients with eMF (n = 31), chronic dermatitis (CD; n = 36) or plaque psoriasis (PP; n = 34) who were examined dermoscopically, histopathologically and immunohistochemically. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for predefined dermoscopic criteria in relation to the diagnosis of eMF. In addition, CD34 immunohistochemistry was used to visualize dermal vessels to correlate dermoscopic features with histological changes. Linear vessels (sensitivity 90.3%, specificity 92.9%), characteristic vascular structures resembling spermatozoa (sensitivity 74.2%, specificity 100%) and orange-yellowish patchy areas (sensitivity 90.3%, specificity 91.4%) were highly predictive for the diagnosis of eMF compared with CD and PP. Dermoscopy shows great value in the diagnosis and differential diagnosis of eMF in a Chinese population.

Abstract 288: Nitric Oxide Mediates Active Downregulation of Tissue Factor Expression in Human Pericytes

Tissue Factor (TF) is a transmembrane protein that not only expresses pro-coagulant enzymatic activity, but also mediates signal transduction by several second messenger pathways. It plays an obvious role in hemostasis and thrombosis, as well as modulating angiogenesis, inflammation, immune responses and progression of malignancy and metastasis. TF is normally expressed by a limited subset of cell types. It can also be induced on other cells by a plethora of mediators, mostly linked to inflammation and immune responses. By contrast, TF has only been shown to be actively downregulated in a single circumstance: we have reported that constitutive expression of TF by pericytes around dermal vessels disappears during angiogenesis associated with wound healing. This suggests that downregulation of pericyte TF may play a functional role in the process of angiogenesis. We previously reported that TF protein in cultured human pericytes is significantly reduced 8 hours after treatment with phorbol 12-myristate 13-acetate (PMA) (94.71% reduction + 2.18%, p<0.001). This loss of TF protein is facilitated by reduction of TF mRNA. Downregulation of TF protein and mRNA depends on Protein Kinase C. The goal of the current study was to identify a physiologic mediator of pericyte TF downregulation. Treatment of human pericytes with growth factors and cytokines involved in wound healing did not change TF expression. Co-culture of human pericytes with human microvascular endothelial cells in transwells in the presence of basic fibroblast growth factor (bFGF) resulted in downregulation of pericyte TF. However, conditioned media from endothelial cells grown in the presence of bFGF did not trigger a decrease of TF in pericytes. bFGF has been shown to stimulate NO production, and both bFGF and NO have been linked to angiogenesis. This led us to consider nitric oxide (NO) as a potential labile mediator of TF downregulation. TF protein was reduced 8 hours after treatment with DETA/NO (44% reduction + 6.1%, p<0.01). However, expression of TF mRNA was not reduced at this time, as it is during culture with PMA. Our working hypothesis is that TF downregulation in pericytes is partially mediated by endothelial cell-derived NO, but is also mediated by additional PKC-dependent pathways.

The spectrum of fibroelastolytic papulosis: a retrospective case series.

Introduction: There is an overlap between clinical and pathological features of the entities known as pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-PDE) and white fibrous papulosis of the neck (WFPN). Although the term fibroelastolytic papulosis has been used to encompass both entities as spectrum variants of a one and only disease, many authors still differentiate the two.Methods: Cases of fibroelastolytic papulosis confirmed by histopathologic examination were retrospectively reviewed within a time frame of 2.5 years.Results: Five cases of fibroelastolytic papulosis were identified. All patients were females aged between 63 and 78 years, presenting with an asymptomatic eruption of isolated or coalescing white to yellow papules on the neck. Two of the patients also had involvement of other anatomical areas. In all cases histology demonstrated a significantly decreased or absent papillary dermal elastic plexus, a mild superficial perivascular lymphocytic infiltrate and sparse melanophages in the papillary dermis, without interface changes. A decrease in upper reticular dermal elastic fibers was noted in four cases and thickening of dermal collagen bundles in three cases. Dilated superficial dermal vessels were present in 3 cases and mild epidermal atrophy in one case.Conclusion: We find the differentiation of PXE-PDE and WFPN to be somewhat theoretical, often confusing, and based on non-significant subtle histological and clinical differences. In our opinion, we should not continue to use these terms, but favor the common term of fibroelastolytic papulosis.

Age-Related Changes in Serine-Arginine Protein Kinase 1 (SRPK1) Content in the Human Dermis

The goal of the present study was to analyze the content of serine-arginine protein kinase 1 (SRPK1) in the human dermis at different ages (from gestational week 20 to 85 years of age). Indirect immunohistochemical detection was used to visualize SRPK1, proliferating cell nuclear antigen (PCNA), and CD 31, an endothelial cell marker, in skin sections. The results showed that the SRPK1 content in the dermal fibroblasts is increased between the antenatal period and 20 years of age and decreased uniformly afterwards (until 61–85 years of age). The SRPK1 content in microcirculation blood vessels of the dermis is increased uniformly between the antenatal period and the age of 61–85 years. Dermis vascularization and the numbers and proliferative activity of fibroblasts was or were decreased steadily between the antenatal period and the age of 61–85 years. The decrease in the SRPK1 content in dermal fibroblasts after 20 years of age occurs concomitantly with the decrease of fibroblast number and proliferative activity. The age-related increase in the SRPK1 content in dermal blood vessels occurs concomitantly with a decrease in vascularization. Therefore, one can assume that SRPK1 exerts dissimilar effects on the proliferation of different dermal components during aging.

Cutaneous collagenous vasculopathy: development after coronary artery bypass surgery

Cutaneous collagenous vasculopathy (CCV) is a rare benign microangiopathy of the superficial dermal vessels. Clinically, it is characterized by widespread, asymptomatic development of cutaneous telangiectasia in the absence of systemic symptoms. Morphologically, it most resembles generalized essential telangiectasia and other telangiectatic syndromes such as telangiectasia macularis eruptiva perstans (TMEP), ataxia telangiectasia, and hereditary hemorrhagic telangiectasia. It is distinctive in its histology, showing characteristic dilated thick-walled blood vessels in the superficial dermis. The thickened walls of these superficial dermal blood vessels demonstrate reduplication of the basement membrane on PAS staining. We report a 63-year-old man with CCV with this condition for 20 years, starting in 1996. He was diagnosed in the past as having essential telangiectasia. The development of the telangectasias occurred after coronary artery bypass grafting, also performed in 1996. This case not only demonstrates the characteristic clinical and histologic findings, but also suggests a possible mechanism. Moreover, it illustrates that cases of generalized essential telangiectasia may in fact be CCV that are misclassified.

Histopathological evaluation of skin in cirrhotic patients with pruritus

Background: Cirrhosis often is a silent disease Clinical symptoms at presentation may include jaundice of the eyes or skin, pruritus, gastrointestinal bleeding, coagulopathy, increasing abdominal girth, and mental status changes. Pruritus may be the presenting symptom, arising years before any other classic clinical and laboratory markers of hepatic dysfunction. This study examines the clinical, laboratory and histopathological changes in the skins of cirrhotic patients with pruritus in comparison with cirrhotic patients without pruritus and healthy control skins . Patients and Methods: To evaluate clinical, laboratory and histopathological changes in cirrhotic patients with pruritus, cirrhotic patients without pruritus and corresponding healthy (control). skin biopsies (20 specimens each) using hematoxylin and eosin stain and to study mast cell density using gimesa stain. Results: In the skin biopsy specimens of the cirrhotic patients with pruritus we found several histological changes including: epidermal hyperplasia (acanthosis) ,vascular ectasia(dilated dermal blood vessels), hypertrophied dermal nerve endings, mixed inflammatory cellular infilterate and lymphocytic vasculopathy (swelling of the endothelial cell lining of the blood vessels without fibrinoid necrosis, leucocytoclasia or extravasation of red blood cells). Evaluation of mast cell count in Gimesa stained skin sections revealed an increased numbers of these cells in the group of cirrhotic patients with pruritus ( N=5-10). The cells noted in perivascular, perineural and interstitial distribution (between collagen bundles). Conclusions: We report, for the first time, some histopathologial changes in the skins of cirrhotic patients with pruritus in comparison with cirrhotic patients without pruritus and healthy control skins .

Histological and Morphological Characterization of Developing Dermal Lymphatic Vessels.

The capacity to visualize the lymphatic vasculature in three-dimensions has revolutionized our understanding of the morphogenetic mechanisms important for constructing the lymphatic vascular network during development. Two complementary approaches are commonly employed to assess the function of genes and signaling pathways important for development of the dermal lymphatic vasculature in the mouse embryo. The first of these is whole-mount immunostaining of embryonic skin to analyze dermal lymphatic vessel network patterning and morphology in two and three dimensions. The second is immunostaining of thin tissue sections to examine lymphatic vessel identity, lumen formation and protein localization within discrete lymphatic endothelial cells in a two-dimensional setting. Here we present detailed protocols for multicolor immunofluorescent immunostaining of embryonic dorsal skin and thin tissue cryosections. Each of these methods generates high-resolution images of the dermal lymphatic vasculature, yielding information integral to in-depth characterization of lymphatic vessel phenotypes in the developing mouse embryo.

Regulation of T helper cell responses during antigen presentation by norepinephrine-exposed endothelial cells.

Dermal blood vessels and regional lymph nodes are innervated by sympathetic nerves and, under stress, sympathetic nerves release norepinephrine (NE). Exposure of primary murine dermal microvascular endothelial cells (pDMECs) to NE followed by co-culture with Langerhans cells (LCs), responsive CD4+ T-cells and antigen resulted in modulation of CD4+ T-cell responses. NE-treatment of pDMECs induced increased production of interleukin (IL)-6 and IL-17A while down-regulating interferon (IFN)-γ and IL-22 release. This effect did not require contact between pDMECs and LCs or T-cells and depended upon pDMEC production of IL-6. The presence of NE-treated pDMECs increased the proportion of CD4+ T-cells expressing intracellular IL-17A and increased IL-17A mRNA while decreasing the proportion of IFN-γ- or IL-22-expressing CD4+ T-cells and mRNA levels for those cytokines. Retinoic acid receptor-related orphan receptor gamma (ROR-γt) mRNA was significantly increased in CD4+ T-cells while T-box transcription factor (T-bet) mRNA was decreased. Intradermal administration of NE prior to hapten immunization at the injection site produced a similar bias in draining lymph node CD4+ T-cells towards IL-17A and away from IFN-γ and IL-22 production. Under stress, release of NE may have significant regulatory effects on the outcome of antigen presentation through actions on ECs with enhancement of inflammatory skin disorders involving IL-17/T helper type 17 (Th17) cells.

Histopathology of Calciphylaxis: Cohort Study With Clinical Correlations.

Calciphylaxis is a rare, painful, and life-threatening condition with a high mortality rate. Although the etiology of calciphylaxis is not well understood, it has been proposed that calcium deposition within and around subcutaneous vessels restricts blood flow chronically, thereby predisposing the patient to acute pannicular and dermal thrombosis. Given increasing recognition of the role of hypercoagulability in calciphylaxis, this retrospective cohort study sought to evaluate the presence of thromboses and dermal angioplasia in calciphylaxis. Moreover, we aimed to validate previous observations about the histopathology of calciphylaxis compared with skin biopsies from patients with end-stage renal disease but without calciphylaxis. After a meticulous clinical chart review, we assessed the corresponding skin biopsies for the presence of vessel calcification, thromboses, and dermal angioplasia in skin biopsies from patients with calciphylaxis (n = 57) and compared with those from patients with end-stage renal disease but without calciphylaxis (n = 26). Histopathologic findings were correlated with clinical features such as chronic kidney disease, diabetes, or associated malignancy. Our results validated a prior observation that calciphylaxis was significantly more likely to show calcification of dermal vessels and diffuse dermal thrombi. This study reports the frequent finding of dermal angioplasia, a potential marker of chronic low-grade ischemia, as another frequent microscopic finding in calciphylaxis. Among cases of calciphylaxis, histopathologic changes in patients with chronic kidney disease were indistinguishable from those in patients without chronic kidney disease, thereby implying a final common pathogenic pathway in both uremic and nonuremic calciphylaxis. In future, larger, prospective studies may be useful in validating these findings.

Immunohistochemical analysis on aquaporin-1 and aquaporin-3 in skin wounds from the aspects of wound age determination.

Immunohistochemical investigation of aquaporin (AQP)1 and AQP3 was performed in human skin wounds obtained from forensic autopsy cases. A total of 55 human skin wounds of different postinfliction intervals were collected as follows: group I, 0-3days (n=16); II, 4-7days (n=11); III, 9-14days (n=16); and IV, 17-21days (n=12). In uninjured skin samples, AQP1 and AQP3 could be slightly detected in dermal vessels and keratinocytes, respectively. The percentage of AQP1+ vessels and the number of AQP3+ keratinocytes were apparently elevated in accordance with wound ages. The number of AQP3+ keratinocytes was distinctly evident in groups II and III. Morphometrically, both AQP1+ vessel area and AQP3+ cell number were markedly increased in group II, compared with other three groups. With regard to forensic safety, AQP1+ vessel area of over 5% would imply wound ages of 4-12days. Moreover, the positive area of >15% would suggest wound age of 7-10days. Especially, most samples of skin wounds aged 5-10days except for only one sample (a 10-day-old wound) showed AQP3+ cell number of >300, and the remaining other samples had that of <300. Thus, the AQP3+ cell number of >300 would indicate wound ages of 5-10days. Collectively, immunohistochemical analyses of AQP1 and AQP3 in human skin wounds would support the objective accuracy of wound age determination.

Up-regulation of α1-adrenoceptors in burn and keloid scars

Stimulation of α1-adrenoceptors evokes inflammatory cytokine production, boosts neurogenic inflammation and pain, and influences cellular migration and proliferation. Hence, these receptors may play a role both in normal and abnormal wound healing. To investigate this, the distribution of α1-adrenoceptors in skin biopsies of burn scars (N=17), keloid scars (N=12) and unscarred skin (N=17) was assessed using immunohistochemistry. Staining intensity was greater on vascular smooth muscle in burn scars than in unscarred tissue, consistent with heightened expression of α1-adrenoceptors. In addition, expression of α1-adrenoceptors was greater on dermal nerve fibres, blood vessels and fibroblasts in keloid scars than in either burn scars or unscarred skin. These findings suggest that increased vascular expression of α1-adrenoceptors could alter circulatory dynamics both in burn and keloid scars. In addition, the augmented expression of α1-adrenoceptors in keloid tissue may contribute to processes that produce or maintain keloid scars, and might be a source of the uncomfortable sensations often associated with these scars.

A possible implication of reduced levels of LIF, LIFR, and gp130 in vasculopathy related to systemic sclerosis.

Leukemia inhibitory factor (LIF) is a member of IL-6 family, which serves as a potent chemoattractant for neutrophils as well as a potent angiostatic factor. LIF has been implicated in various autoimmune inflammatory diseases, but its role still remains elusive in systemic sclerosis (SSc). Therefore, we investigated the potential role of LIF in the development of SSc by evaluating the clinical correlation of serum LIF levels, the expression of LIF and its receptors in skin samples, and in vitro experiments with human dermal microvascular endothelial cells. Serum LIF levels were significantly decreased in patients with SSc, especially in those with disease duration of<1year compared with healthy controls. As for clinical correlation, SSc patients with digital ulcers exhibited serum LIF levels significantly lower than those without. In immunohistochemistry, the expression of LIF and its receptors, LIF receptor and gp130, was remarkably decreased in dermal blood vessels of SSc lesional skin relative to those of healthy control skin. Furthermore, gene silencing of transcription factor Fli1, whose deficiency is involved in the development of SSc vasculopathy, suppressed the expression of LIF, LIF receptor, and gp130 and Fli1 bound to the promoters of those genes in human dermal microvascular endothelial cells. Collectively, these results suggest that decreased serum LIF levels may be associated with vasculopathy in SSc and that Fli1 deficiency may contribute to the inhibition of LIF-dependent biological effects on SSc endothelial cells by suppressing the expression of LIF, LIF receptor, and gp130.

A Rare Case of Sulfasalazine-Induced DRESS Syndrome With Acute Liver Injury

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening, drug-induced hypersensitivity syndrome, characterized by rash, fever, lymphadenopathy, eosinophilia, and internal organ involvement. Most cases of DRESS involve the liver with transaminitis less than 10 times the upper limit of normal, however, severe disease can also rarely be seen - as presented in this case. A 39-year-old woman with psoriatic arthritis (PsA) presents with progressive whole body pruritic rash for one week. Ten months prior to admission, she started apremilast and then one month prior to presentation also started sulfasalazine for her PsA. One week prior to presentation, she noticed an erythematous, pruritic maculopapular rash on her face, chest, arms, legs, and with associated fever. At that time, her rheumatologist discontinued all PsA medications, and she was treated with penicillin for suspected scarlet fever. Her rash worsened, developing facial edema and confluent blistering of her arms and legs. She also developed painful cervical lymphadenopathy. Upon admission, she had a new transaminitis (AST and ALT > 1000 IU/L), elevated INR (1. 4), leukocytosis (30 x103/uL) with eosinophilia (3300 cells/uL), positive HHV-6, and negative viral and autoimmune hepatitis serologies. She had no infectious or neurologic evidence of symptomatic HHV-6 infection. Dermatology, gastroenterology and infectious disease were consulted. A skin biopsy showed a robust lymphomatoid cellular immune reaction with dermal infiltration of eosinophils, consistent with DRESS syndrome. She was started on intravenous and topical steroids and transitioned to a long oral steroid taper, with subsequent resolution of her rash, leukocytosis, and acute liver injury. DRESS syndrome is associated with a range of drugs, including anticonvulsants (phenytoin), sulphonamides, and rarely sulfasalazine. As seen in our case, the onset of the disease is delayed, and ranges from 2 to 6 weeks after the initiation of the therapy. While most cases of DRESS involve only a mild hepatoxicity, severe disease can rarely induce severe transaminitis (AST and ALT >1000 IU/L), hepatomegaly and fulminant liver failure. Treatment involves withdrawal of the causative drug, systemic high dose corticosteroids, and in rare cases with fulminant liver failure even liver transplantation. DRESS syndrome has a mortality rate of 10%, most commonly due to liver failure, making liver involvement a poor prognostic marker.Figure: Trend of Laboratory Values During Hospital Course.Figure: All samples were stained with Hematoxylin-eosin. The biopsy revealed a striking interface dermatitis with marked papillary edema leading to focal areas of epidermaldermal separation (A, B). The supervening epidermis showed spongiosis and eczematous changes (C, D). Many dermal vessels were surrounded by a dense lymphocytic infiltrate containing scattered transformed immunoblastic elements as well as eosinophils (E). There was vascular mural fibrin deposition with mural edema and concomitant endothelial cell swelling, consistent with a lymphomatoid vasculitis (F). ((A) 4x; (B) 10x; (C) 20x; (D) 40x; (E) 100x; (F) 100x).