Development Of Skin Ulcers Research Articles

Therapeutic Lymphangiogenesis Is a Promising Strategy for Secondary Lymphedema.

Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, as well as the development of skin ulcers, recurrent pain, and infection. Currently, countermeasures against lymphedema are mainly physical therapy such as lymphatic massage, elastic stockings, and skin care, and there is no effective and fundamental treatment with a highly recommended grade. Therefore, there is a need for the development of a fundamental novel treatment for intractable lymphedema. Therapeutic lymphangiogenesis, which has been attracting attention in recent years, is a treatment concept that reconstructs the fragmented lymphatic network to recover lymphatic vessel function and is revolutionary to be a fundamental cure. This review focuses on the translational research of therapeutic lymphangiogenesis for lymphedema and outlines the current status and prospects in the development of therapeutic applications.

Detection of TNF Alpha Level as Biomarker in Different Stages of Cutaneous Leishmaniasis Infection

Leishmaniasis is a global illness that is endemic in many countries, including Iraq. The characteristic of cutaneous leishmaniasis (CL) is the development of skin ulcers that are controlled by the immune system. Tumor necrosis factor-alpha (TNF-α), a cytokine generated by the innate immune response to CL infection, can influence disease clearance in the human host. The effect of this pro-inflammatory cytokine in CL ulcer development during the infection is not well established. In this study TNF-α level was detected in the patients who suffered from cutaneous leishmaniasis. This level was also assessed in the newly diagnosed patients and others who were undergoing different stages of pentostam treatment. Notably the results revealed a significant increment in TNF-α serum levels in the test groups of newly infected patients, as well as, in the patients enduring second and third trials of pentostam treatment, which was (1125.49, 838.75, 1264.26) ng/ml accordingly, in comparison with healthy control group which was 235.35 ng/ml. Furthermore, there was no significant observation in TNF-α among the three patient groups. The perceived rise of TNF-α serum levels may give insights into this pro-inflammatory cytokine as a biomarker in the prognosis and tracking the disease progression.

347 IL-33 deficiency protects skin from ulcer formation in ischemia-reperfusion-induced decubitus mouse model

Decubitus ulcers are serious problems in elderly long-term bedridden patients. Currently, there are no evidence-based treatment in the early phase decubitus to prevent the development of skin ulcers, except for reducing body weight load, by changing position or using cushions. Ischemia- reperfusion (I/R) injury is characterized by the reperfusion of blood to previously ischemic tissue, which induces cellular injury. I/R injury is associated with vascular infarction or vasospasm in various organs such as the brain, heart, liver, and kidneys, and there is also increasing evidence that cutaneous I/R injury is also associated with the development of decubitus. Interleukin-33 (IL- 33) is a member of IL-1 cytokine family that enhance Th2 immune reaction. IL-33 is one of danger signals to elicit inflammation upon tissue damage. We speculated that abundant IL-33 would be released in decubitus ulcer formation (I/R injury), thus we sought to determine if IL-33 acted an important role in the decubitus ulcer formation following I/R and investigate the mechanism. Ulcer area was reduced in IL-33KO mice and sST2 Tg mice compared to WT mice. Anti-IL-33 or anti-ST2L neutralizing antibody reduced the I/R-induced ulceration in WT mice. The number of infiltrating M2 macrophages was larger in IL-33KO mice at day8 I/R ulceration but that of mast cells and neutrophils was less. Real time (RT)-PCR results showed that expression of IL-1β was suppressed, but that of CCL17, related to M2 macrophage differentiation, was upregulated in IL-33KO mice compared to WT mice. In vitro study showed that macrophages from IL-33KO mice was able to produce IL-1β with IL-33 stimulation. These results indicate that blocking of IL-33 signaling would prevent or reduce the decubitus ulcer formation, by reducing mast cells and neutrophil infiltration and increasing M2 macrophage infiltration. We propose that blocking of IL-33 signal would have a great potential in prevention and treatment of early phase decubitus ulcer, which would tremendously contribute to clinical medicine.

INFLUENCE OF PATHOGENS, FISH-RELATED CHARACTERISTICS, AND ENVIRONMENTAL FACTORS ON THE DEVELOPMENT OF SKIN ULCERATIONS IN WILD COMMON DAB (LIMANDA LIMANDA) FROM THE NORTH SEA.

Environmental changes or stressors can result in the development of diseases. Through regular fish disease surveys in the Belgian part of the North Sea, attention was drawn to a sudden increase of skin ulceration prevalence between 2011 and 2014 in common dab (Limanda limanda). Information on prevalence, ulceration, bacteriology, fish-related (e.g., length, age, and sex) and (spatial and temporal) environmental factors, and fishing intensity were gathered. This detailed investigation was framed within a long-term monitoring program, executed every spring-autumn from 2000 to present. Ulcerations were observed in 1.3% of fish (n=3,999). Spatial and temporal differences were evident, and highest prevalence was found in summer. Vibrio was the dominant cultivated bacterial genus present in the lesions. Skin ulcerations appeared to be correlated with length and body condition of the fish, as well as with temperature and pH of the seawater and fishing vessel density. Our research suggested the involvement of multiple factors in the development of skin ulcerations in common dab and endorsed the effects of changing environment and human influence on the marine ecosystem through activities such as fishing.

Tenacibaculum piscium sp. nov., isolated from skin ulcers of sea-farmed fish, and description of Tenacibaculum finnmarkense sp. nov. with subdivision into genomovars finnmarkense and ulcerans

Results of previous multilocus sequence and whole-genome-based analyses have suggested that a homogeneous group of isolates belonging to the genus Tenacibaculum, represented by strain TNO020T and associated with skin ulcer development in sea-farmed fish, represents an as-yet-undescribed species. Comparative whole-genome analysis performed in the present study clustered five isolates, including TNO020T, in a distinct lineage within the genus Tenacibaculum. Phenotypic differences, high intra-cluster average nucleotide identity (ANI) values and low ANI values with other Tenacibaculum species support the proposal of a novel species, for which we propose the name Tenacibaculum piscium sp. nov. with strain TNO020T (=CCUG 73833T=NCIMB 15240T) as the type strain. Further, large-scale genome analyses confirmed the existence of two different phylogenetic lineages within 'T. finnmarkense', a species effectively but not validly published previously. ANI values just above the species delineation threshold of 95-96 % confirmed that both lineages belong to the same species. This result was also supported by DNA-DNA hybridization values. Phenotypically, the two conspecific lineages are distinguishable by differences in growth temperature range and ability to degrade l-proline. For the group of isolates already commonly known as 'T. finnmarkense', we propose the name Tenacibaculum finnmarkense sp. nov., with strain TNO006T (=CCUG 73831T=NCIMB 15238T) as the type strain. We further propose the subdivision of T. finnmarkense sp. nov. into two genomovars, T. finnmarkense genomovar finnmarkense with strain TNO006T (=CCUG 73831T=NCIMB 15238T) as the type strain and T. finnmarkense genomovar ulcerans with strain TNO010T (=CCUG 73832T=NCIMB 15239T) as the type strain.

Pinpointing the role of Aeromonas salmonicida in the development of skin ulcerations in common dab (Limanda limanda).

Aeromonas salmonicida was isolated from ulcerations in common dab (Limanda limanda). An experiment was performed to pinpoint its role in ulceration development, considering the importance of the skin barrier and the pigmented and non-pigmented sides. The skin of dab was treated in three zones, one where scales and epidermis were removed, one where mucus was discarded and one non-treated zone. Fish were tagged to allow individual identification and challenged with A.salmonicida. Mortality and severity of the developing lesions were recorded for 21days post-inoculation. Starting 12days post-inoculation, mortality occurred gradually in challenged fish; however, no direct cause could be established. Both control fish and challenged fish developed ulcerations containing A.salmonicida. Sequencing of vapA gene revealed that isolates retrieved from both groups were distinct, suggesting the presence of A.salmonicida prior to the trial. Most ulcerations developed in zones where skin was removed, suggesting that abrasion might be a predisposing factor in ulceration development. Ulcerations were also observed at the insertion site of the tag, where exposed muscle tissue might have favoured the development of ulcerations. In conclusion, A.salmonicida seems to be involved in the development of skin ulcerations in dab, although the exact pathogenesis needs to be elucidated.

Transmission experiment in Atlantic salmon (Salmo salar) with an Atlantic Canadian isolate of Moritella viscosa

In Atlantic Canada, Moritella viscosa is often cultured from Atlantic salmon skin ulcers in the summer and autumn months when water temperature is > 10 °C. The objectives of our study were to: 1) describe the development of skin ulcers associated with an Atlantic Canadian M. viscosa isolate; and 2) determine if this isolate could be transmitted horizontally between fish via water under laboratory conditions. Atlantic salmon in salt water were bath-immersed with M. viscosa (5.6 × 106 cfu ml-1) at 10.9 ± 0.2 °C. After observing skin lesions, water from each bath-challenge tank was diverted to a “delayed-challenge” tank with previously unexposed fish. The initial bath-challenge fish expressed clinical signs of skin ulcers within four days of exposure. Fish that were not sacrificed during our trial fully recovered by 26 days post-challenge. No clinical signs of disease were observed in fish from the delayed-challenge tanks. Our results suggest skin lesions induced by an M. viscosa isolate from Atlantic Canada have similar pathology to winter ulcer disease described in Europe. Most bath-challenged fish were not systemically infected until the development of visible skin ulcerations. None of the delayed-challenge fish were infected with M. viscosa, which suggests horizontal transmission via the water was not sufficient to cause disease in our study.

Scrutinizing the triad of Vibrio tapetis, the skin barrier and pigmentation as determining factors in the development of skin ulcerations in wild common dab (Limanda limanda)

Recently, Vibrio tapetis was isolated for the first time from skin ulcerations in wild-caught common dab (Limanda limanda). To further examine its role in the development of these skin lesions, an in vivo experiment was performed. The significance of the skin barrier and in addition the difference between pigmented and non-pigmented side were investigated. Hence, the skin of common dab was treated in three different ways on both the pigmented and non-pigmented side. On a first “treatment zone”, the scales and overlying epidermal tissue were removed whereas in a second zone only the mucus was discarded. The third zone served as a non-treated zone. Thereafter, fish were challenged with V. tapetis. The control group was sham treated. Mortality, clinical signs, severity and size of the developing lesions were recorded. All animals were sacrificed and sampled 21 days post-inoculation. Significantly more fish of the group challenged with V. tapetis died compared to the control group with the highest incidence occurring 4 days post-inoculation. Fish challenged with V. tapetis developed more severe skin ulcerations. In zones where scales and epidermal tissue were removed, the ulcerations were more severe compared to zones where only mucus was eliminated. Ulcerations occurred more frequently, were more severe and larger on the pigmented side. Our data represents prove of V. tapetis as causative agent of ulcerative skin lesions although prior damage of the skin seems to be a major contributing factor. Furthermore, the pigmented side seemed predisposed to the development of skin ulcerations.

Dermatological Toxicity of Hydroxycarbamide

Hydroxycarbamide is an antitumor agent mainly used for treatment of Ph-negative myeloproliferative disorders and sickle cell disease. The development of skin ulcers is a rare but serious adverse event in long-term antitumor therapy. Hydroxycarbamide-induced ulcers are often multiple and bilateral, and usually occur in the lower legs, although they can occur in other regions of the body. The ulcers are smallsized and shallow with sharp margins and yellow fibrine-covered base. They cause constant severe, difficult to treat pain which is a characteristic sign. The drug withdrawal usually leads to spontaneous healing of ulcers. Regular dermatologic screening must be obligatory for all the patients receiving hydroxycarbamide. The present paper provides a literature review on dermatological toxicity of hydroxycarbamide and a clinical case description.

IL-1β Production by Intermediate Monocytes Is Associated with Immunopathology in Cutaneous Leishmaniasis

Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease in which skin ulcer development is associated with mononuclear cell infiltrate and high levels of inflammatory cytokine production. Recently, NLRP3 inflammasome activation and IL-1β production have been associated with increased pathology in murine cutaneous leishmaniasis. We hypothesized that cutaneous leishmaniasis patients have increased expression of NLRP3, leading to high levels of IL-1β production. In this article we show high production of IL-1β in biopsy samples and Leishmania antigen-stimulated peripheral blood mononuclear cells from patients infected with L.braziliensis and reduced IL-1β levels after cure. IL-1β production positively correlated with the area of necrosis in lesions and duration of the lesions. The main source of IL-1β was intermediate monocytes (CD14++CD16+). Furthermore, our murine experiments show that IL-1β production in response to L.braziliensis was dependent on NLRP3, caspase-1, and caspase-recruiting domain (ASC). Additionally, we observed an increased expression of the NLRP3 gene in macrophages and the NLRP3 protein in intermediate monocytes from cutaneous leishmaniasis patients. These results identify an important role for human intermediate monocytes in the production of IL-1β, which contributes to the immunopathology observed in cutaneous leishmaniasis patients.

First isolation of Vibrio tapetis and an atypical strain of Aeromonas salmonicida from skin ulcerations in common dab (Limanda limanda) in the North Sea.

Skin ulcerations rank amongst the most prevalent lesions affecting wild common dab (Limanda limanda) with an increase in prevalence of up to 3.5% in the Belgian part of the North Sea. A complex aetiology of these ulcerations is suspected, and many questions remain on the exact factors contributing to these lesions. To construct the aetiological spectrum of skin ulcerations in flatfish, a one-day monitoring campaign was undertaken in the North Sea. Fifteen fish presented with one or more ulcerations on the pigmented and/or non-pigmented side. Pathological features revealed various stages of ulcerations with loss of epidermal and dermal tissue, inflammatory infiltrates and degeneration of the myofibers bordering the ulceration, albeit in varying degrees. Upon bacteriological examination, pure cultures of Vibrio tapetis were retrieved in high numbers from five fish and of Aeromonas salmonicida in one fish. The V.tapetis isolates showed cross-reactivity with the sera against the representative strain of serotype O2 originating form a carpet-shell clam (Ruditapes descussatus). Moreover, the A.salmonicida isolates displayed a previously undescribed vapA gene sequence (A-layer type) with possible specificity towards common dab. Further research is necessary to pinpoint the exact role of these agents in the development of skin ulcerations in common dab.

Cytotoxic activity in cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a chronic disease caused by species of the protozoan Leishmania and characterised by the presence of ulcerated skin lesions. Both parasite and host factors affect the clinical presentation of the disease. The development of skin ulcers in CL is associated with an inflammatory response mediated by cells that control parasite growth but also contribute to pathogenesis. CD8+ T cells contribute to deleterious inflammatory responses in patients with CL through cytotoxic mechanisms. In addition, natural killer cells also limit Leishmania infections by production of interferon-γ and cytotoxicity. In this review, we focus on studies of cytotoxicity in CL and its contribution to the pathogenesis of this disease.

Multilocus sequence analysis reveals extensive genetic variety within Tenacibaculum spp. associated with ulcers in sea-farmed fish in Norway

Skin ulcer development in sea-reared salmonids, commonly associated with Tenacibaculum spp., is a significant fish welfare- and economical problem in Norwegian aquaculture. A collection of 89 Tenacibaculum isolates was subjected to multilocus sequence analysis (MLSA). The isolates were retrieved from outbreaks of clinical disease in farms spread along the Norwegian coast line from seven different fish species over a period of 19 years. MLSA analysis reveals considerable genetic diversity, but allows identification of four main clades. One clade encompasses isolates belonging to the species T. dicentrarchi, whereas three clades encompass bacteria that likely represent novel, as yet undescribed species. The study identified T. maritimum in lumpsucker, T. ovolyticum in halibut, and has extended the host and geographic range for T. soleae, isolated from wrasse. The overall lack of clonality and host specificity, with some indication of geographical range restriction argue for local epidemics involving multiple strains. The diversity of Tenacibaculum isolates from fish displaying ulcerative disease may complicate vaccine development.

Atlantic salmon winter-ulcer disease: Combining mortality and skin ulcer development as clinical efficacy criteria against Moritella viscosa infection

The bacterium Moritella viscosa causes classical winter-ulcer disease in seawater-farmed salmonids. Despite widespread vaccination with multi-component vaccines containing the M. viscosa-antigen, disease outbreaks continue to be reported in Norway. In trials reported here, commercially available vaccines containing M. viscosa-components were used to vaccinate groups of Atlantic salmon (Salmo salar L.). In two well-controlled experimental studies, bath challenge with M. viscosa was carried out after 600, 1000, or 1500degree days (dd) post immunization. A field study was also carried out comparing four commercial vaccines to evaluate protection against M. viscosa under commercial farming conditions. In order to increase the resolution of the clinical outcome of these M. viscosa infections studies, we used mortality and expanded the phenotypic parameters to also include skin ulceration status of survivors. The experimental laboratory challenge studies showed that immunization is effective at 600dd and significantly protects against the clinical consequences (both mortality and skin ulceration) of M. viscosa infection, with relative protection reaching 91% compared to saline controls and 65% compared to a vaccine formulation lacking M. viscosa antigen. M. viscosa challenge was confirmed but induced only minor clinical consequences to the vaccinated groups in the field trial. The results demonstrate that the experimental bath challenge model discriminates between non-specific and specific vaccine protection against M. viscosa. The model was further successful in documenting protection utilizing cutaneous ulcer development, the most prevalent clinical manifestation of M. viscosa infection. Although the degree of protection is significantly different between the vaccines on test, immunization constitutes an important management tool providing protection against M. viscosa infections in marine farmed Atlantic salmon.

Role of Vibrio tapetis in the development of skin ulceration in common dab (Limanda Limanda)

Role of Vibrio tapetis in the development of skin ulceration in common dab (Limanda Limanda)

A Potential Role for Mononuclear Phagocytes in Cutaneous Ulcer Development in Human Immunodeficiency Virus–Leishmania braziliensis Coinfection

Skin ulcer development in cutaneous leishmaniasis due to Leishmania braziliensis infection is associated with a mononuclear cell infiltrate and high levels of tumor necrosis factor (TNF). Herein, we show that despite the absence of Leishmania-driven TNF, a cutaneous leishmaniasis patient with acquired immunodeficiency syndrome developed a skin ulcer. The presence of mononuclear phagocytes and high levels of TNF, chemokine (C-C motif) ligand 2 (CCL2), and metalloproteinase-9 in tissue are identified as potential contributors to immunopathology observed in L. braziliensis-infected patients.

Species‐specific effects of subdaily temperature fluctuations on consumption, growth and stress responses in two physiologically similar fish species

AbstractFluctuations in water temperature can have important physiological consequences for fishes. Effects of daily thermal cycles are well studied and can be beneficial, increasing prey consumption and growth rates when mean and maximum temperatures of the fluctuations are at or below the species’ optimum temperature. While less studied, subdaily temperature fluctuations are also common in many aquatic habitats and can be caused by both natural and anthropogenic processes. We performed laboratory experiments to examine how two fish species (yellow perch, Perca flavescens, and walleye, Sander vitreus) with similar thermal preferences respond to chronic exposure to subdaily temperature variability. We selected temperature treatments that reflected observed thermal variation after examining water temperature data from multiple aquatic systems. We then separately exposed yellow perch and walleye to a stable 23 °C treatment and 12‐h cycles of 23 ± 2 °C or 23 ± 4 °C for 45 days. Adult yellow perch exposed to fluctuations of 23 ± 4 °C over 12 h expressed higher consumption, growth and food conversion efficiency than fish experiencing stable 23 °C. Temperature fluctuations, though, resulted in mortalities and the development of skin ulcers in yellow perch that did not occur under stable temperatures. In contrast, the same 12‐h temperature fluctuations did not result in mortalities or stress responses in juvenile walleye. Moreover, unlike yellow perch, growth rates of walleye were lower under 12‐h temperature fluctuations compared with the stable 23 °C treatment. Our results indicate that species with similar thermal preferences can respond differently to the same subdaily temperature fluctuations.

A canine model of experimental infection with Leishmania (L.) mexicana.

BackgroundCutaneous leishmaniasis is a tropical disease affecting over one million patients annually and Leishmania (L.) mexicana is one of the major etiological agents in the Americas. Here we established the first experimental infection of L. (L.) mexicana in canids.MethodsBeagle dogs were infected intradermally with culture-derived L. (L.) mexicana. We followed skin ulcer development, histopathological signs, parasite burden and the immune status of the infected dogs.ResultsAll infected dogs developed uniform oval-craterform ulcers similar to those observed in humans, associated with mixed T helper 1/T helper 2 immune responses. Parasites were detected in the healed lesions 15 weeks post-infection. Higher anti-Leishmania IgG levels correlated with larger lesions and high IgG1/IgG2 ratio was associated with some level of splenomegaly.ConclusionsThe canine model described in this work will be of use for further understanding of L. (L.) mexicana immunopathogenensis, and for drug and vaccine development.

Capillaroscopic skin ulcer risk index: A new prognostic tool for digital skin ulcer development in systemic sclerosis patients

Digital ulcerations are one of the most frequent manifestations of microangiopathy in patients with systemic sclerosis (SSc; scleroderma). The early detection of SSc patients who are at high risk to develop digital ulcers could allow a preventive treatment of these complications with reduction of morbidity and social costs. The aim of our study was to develop a capillaroscopic skin ulcer risk index (CSURI) that can predict the onset of new digital ulcers by using nailfold videocapillaroscopy (NVC) in patients with SSc. We performed NVC in 120 consecutive unselected patients with SSc (13 men, 107 women, mean +/- SD age 56.1 +/- 13.4 years, mean +/- SD SSc duration 44.7 +/- 60.7 months) to assess the total number of capillaries in the distal row (N), maximum loop diameter (D), number of megacapillaries (M), and the M:N ratio. Within 3 months since NVC examination, 35 of 120 patients experienced digital ulcers. A significant association between ischemic lesions and the M:N ratio, N, and D was observed; the combination of these parameters allowed us to develop the CSURI, which is characterized by the formula D x M:N(2). A receiver operating characteristic curve analysis showed an area under the curve of 0.926 for ulcer appearance, with specificity and sensitivity of 85.9% and 94.3%, respectively, at the cutoff value of 2.94. Interestingly, 33 of 35 patients with new skin ulcers had a CSURI >2.94, but only 2 of 35 had a CSURI < or =2.94. The proposed CSURI may represent a novel tool with the ability to predict the development of digital ulcers in patients with scleroderma.

Effect of oral immunization with liposome‐entrapped bacterial antigen on protection against experimentalaeromonas hydrophila

Abstract Liposome‐entrapped atypical Aeromonas hydrophila antigen was prepared to investigate the potential protective efficacy for A. hydrophila infection. Carp (Cyprinus carpio) were immunized orally with liposome‐entrapped A. hydrophila antigen. After immunization, significantly more antigen‐specific antibodies were detected in serum, intestinal mucus and bile than non‐immunized control group. The immunized carp were then challenged by immersion with 1 × 106 cfu/ml of A. hyrdophila for 60 min. Of the eight non‐immunized carp, three carp died (62.5% survival), whereas five out of six (83.5%) of the immunized survived. Furthermore, development of skin ulcers was significantly inhibited in carp immunized with liposomes containing A. hydrophila antigen. These results suggest that liposomes containing A. hydrophila antigen have a potential for induction of protective immune responses against atypical A. hydrophila infection and also suggest the possibility of developing a vaccine that may ultimately be used...