Changes in Inflammatory Markers in Patients Treated for Buruli Ulcer and Their Ability to Predict Paradoxical Reactions.

Mycobacterium ulcerans causes Buruli ulcer, the third most frequent mycobacterial disease after tuberculosis and leprosy. Transient clinical deteriorations, known as paradoxical reactions (PRs), occur in some patients during or after antibiotic treatment. We investigated the clinical and biological features of PRs in a prospective cohort of 41 patients with Buruli ulcer from Benin. Neutrophil counts decreased from baseline to day 90, and interleukin 6 (IL-6), granulocyte colony-stimulating factor, and vascular endothelial growth factor were the cytokines displaying a significant monthly decrease relative to baseline. PRs occurred in 10 (24%) patients. The baseline biological and clinical characteristics of the patients presenting with PRs did not differ significantly from those of the other patients. However, the patients with PRs had significantly higher IL-6 and tumor necrosis factor alpha (TNF-α) concentrations on days 30, 60, and 90 after the start of antibiotic treatment. The absence of a decrease in IL-6 and TNF-α levels during treatment should alert clinicians to the possibility of PR onset.

Histological changes in facial melasma after treatment with triple combination cream with or without oral tranexamic acid and/or microneedling: A randomised clinical trial.

Background Melasma is an acquired dyschromia with several histologic alterations in the epidermis, basement membrane and upper dermis. The treatment of melasma is challenging due to the irregular response and chronicity of the disease. To date, there are no curative strategies, largely due to the limited understanding of the intrinsic effects of each treatment. Objectives The objective of the study was to evaluate the histological changes promoted by triple combination cream, with or without complementary treatment with microneedling and oral tranexamic acid, in the treatment of melasma. Methods A factorial, randomised, controlled and evaluator-blinded clinical trial was performed involving 64 women with facial melasma, divided in four groups, who underwent 60 days of treatment with triple combination cream alone (control group) or combined with two monthly microneedling sessions (microneedling group), TA 250 mg twice daily (tranexamic acid group), or both tranexamic acid group and microneedling group. The participants underwent biopsy of the area with melasma at inclusion (D1) and D60. The primary outcomes were the variation (D1 × D60) between the variables: Thickness of the epidermis and stratum corneum, stratum corneum compaction and solar elastosis; melanin density in the epidermis and upper dermis; proportion between the extension of the nonintact and intact basement membrane zone; mast cell count in the upper dermis; melanocyte count in the basal layer, pendulum melanocyte count and melanocyte area; immunostaining density of vascular endothelial growth factor; stem cell factor and keratinocyte growth factor. Results One participant in the TG discontinued tranexamic acid due persistent headache; and herpes simplex occurred in three patients after microneedling. The groups showed a 24% (CI95%: 17-35%; P < 0.01) reduction in epidermal melanin density. There was no change in dermal melanin density or the area of melanocytes after treatment. There was an overall 25% (CI95%: 7-42%; P < 0.01) reduction in the number of pendulum melanocytes, especially in the microneedling and tranexamic acid group, that presented a 41% (CI95%: 7-73%; P < 0.01) reduction. The extension of the nonintact basal membrane relative to the intact basal membrane decreased after treatment, especially in microneedling group and microneedling and tranexamic acid group. There was an increase of 13% (CI95%: 5-21%; P = 0.02) in epidermal thickness and 6% (CI95%: 0-22%; P = 0.04) thinning of the stratum corneum in the groups. All groups showed stratum corneum compaction. Solar elastosis improved only in the microneedling group and microneedling and tranexamic acid group. Vascular endothelial growth factor immunostaining increased 14% (CI95%: 4-24%; P = 0.03) in the groups; and stem cell factor increased only in microneedling group. There was no change in the number of mast cells, CD34 and keratinocyte growth factor immunostaining. Limitations The site of biopsy may not represent all of the facial melasma and the immunohistochemical sensitivity of the cytokines does not have a stoichiometric relationship with proteins. Conclusion A greater thickness of the epidermis is associated with melasma bleaching. Dermal melanin seems to have no impact on melasma prognosis. Damage to the skin barrier and stimulus of angiogenesis should be avoided in the treatment of melasma. Microneedling complements the topical treatment of melasma by improving patterns of skin photoaging. Oral tranexamic acid complements the topical treatment of melasma by inhibiting the stem cell factor.

Cyclooxygenase 2 and vascular endothelial growth factor-potential targets to manage lepra reactions: A case-control study.

Reactions in leprosy have an immune mediated pathogenesis. While type 1 reactions are delayed hypersensitivity phenomenon, type 2 reactions are immune complex mediated. Key molecules which mediate the immune insult in lepra reactions require evaluation in order to tailor their therapy and prevent disability. The objective of the study was to evaluate expressions of Cyclooxygenase 2 and Vascular Endothelial Growth Factor in skin biopsies from leprosy patients and correlate their expression with presence of either type 1 or type 2 lepra reactions. This was a case control study. Cyclooxygenase 2 and Vascular Endothelial Growth Factor expression in dermal macrophages and vascular endothelium was assessed immunohistochemically. Biopsies from patients with Non-reactive leprosy and healthy controls were used for comparison. SPSS software was used for statistical analysis. A total of 147 skin biopsies were evaluated, including 18 with Type 1 reaction, 39 Type 2 reaction, 81 non-reactive leprosy and 9 healthy controls. Both Cyclooxygenase 2 and Vascular Endothelial Growth Factor expression were significantly higher in type 1 followed by type 2 reaction as compared to controls. These results may guide us regarding use of Cyclooxygenase 2 and Vascular Endothelial Growth Factor inhibitor drugs which may be a major step in treating reactive leprosy patients and preventing nerve damage and disability.

A study of serum vascular endothelial growth factor in infantile hemangiomas.

BACKGROUND: Though infantile hemangiomas are the most common benign tumor of infancy, their etiopathogenesis is not fully understood. Some studies report a diagnostic role for vascular endothelial growth factor (VEGF), but such studies are lacking from India. AIMS: To study the clinicoepidemiological profile of infantile hemangiomas, to estimate and compare the serum levels of VEGF in infantile hemangiomas and controls, and to determine correlations between serum levels of VEGF and growth characteristics of infantile hemangiomas. METHODS: A hospital-based, cross-sectional study was carried out on 30 clinically diagnosed cases of infantile hemangioma and 30 controls presenting with other disorders. VEGF levels were recorded for both cases and controls by the sandwich enzyme-linked immunosorbent assay (ELISA) technique. Results were analyzed using SPSS version 20.0, and their significance determined using appropriate tests. RESULTS: Mean serum VEGF level in the cases was 216.8 ± 49.2 pg/ml while in the control group it was 115.1 ± 43.1 pg/ml (P < 0.0001). There were no statistically significant correlations between serum VEGF levels and sex or size, phase of growth, morphological variants or ulceration of lesions. LIMITATIONS: Our sample was not large enough to draw clinically applicable conclusions. An adequate sample size could not be achieved because of low incidence of the disease, and resource and time constraints. CONCLUSIONS: The mean value of serum VEGF in the study group was significantly higher than that in the control group, suggesting that serum VEGF can serve as a diagnostic marker of infantile hemangiomas. Mean serum VEGF was higher in proliferative lesions than in involuting lesions, indicating that it may also be useful as a prognostic serological marker in cases of infantile hemangioma.

Inflammatory choroidal neovascularization in Indian eyes: Etiology, clinical features, and outcomes to anti-vascular endothelial growth factor.

BACKGROUND AND OBJECTIVES: The aim was to study the clinical profile of inflammatory choroidal neovascularization (CNV) and its treatment response to intravitreal bevacizumab or ranibizumab on pro re nata (PRN) basis in Indian eyes. MATERIALS AND METHODS: This was a retrospective case series of consecutive patients with inflammatory CNV treated with anti-vascular endothelial growth factor (anti-VEGF) in a tertiary eye care center in Eastern India between 2009 and 2014. The data about clinical features, investigations, treatment, and outcomes were obtained from the medical records. We included patients with active inflammatory CNV but with no evidence of inflammation and were treated with anti-VEGF alone, with a minimum follow-up of 6 months. Main outcome measures were a clinical and etiological profile of inflammatory CNV in Indian eyes and their response to treatment. RESULTS: Thirty eyes of 28 patients were included in the study. The mean follow-up was 17.93 ± 14.28 months (range 6-53 months). In our cohort, seven (23.33%) eyes had inflammatory CNV secondary to idiopathic choroiditis, four (13.33%) eyes had toxoplasmosis, idiopathic panuveitis, and Vogt Koyanaki Harada's disease each. Three (10%) eyes had geographic helicoid peripapillary choroidopathy and tubercular choroiditis each. Remaining two (6.66%) eyes had punctate inner choroidopathy, while multifocal choroiditis with panuveitis, resolved endogenous endophthalmitis and Hansen's diseases were the etiology in one (3.33%) case of inflammatory CNV each. The mean number of injections were 2.76 (range 1-5). Among thirty eyes of inflammatory CNV, 16 (53.3%) eyes showed improvement, eight (26.6%) maintained the same vision, whereas six (20%) eyes showed deterioration of vision. Interpretations and Conclusion: Idiopathic choroiditis was the most common cause of inflammatory CNV and PRN intravitreal anti-VEGF (ranibizumab or bevacizumab) appears to have effective treatment response.

The involvement of endothelial mediators in leprosy.

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

The involvement of endothelial mediators in leprosy

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

The involvement of endotelial mediators in leprosy

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

Cyclooxygenase 2 expression in vessels and nerves in reversal reaction leprosy.

Tissue expression of cyclooxygenase (COX)2, an inducible enzyme synthesizing eicosanoids in inflammation, was studied in reversal reaction (RR) leprosy in comparison with nonreactionary leprosy. COX2 was consistently expressed in cells of the mononuclear-macrophage lineage across the leprosy spectrum. Only in RR, the following two additional sites showed COX2 expression in the dermis and subcutis: 1) microvessels and 2) nerve bundles and isolated nerve fibers. The same sites also express vascular endothelial growth factor (VEGF). This is in keeping with experimental models relating VEGF to COX2 expression, with VEGF enhancing prostaglandin production through COX2 stimulation and prostaglandin synthase expression. We postulate that selective COX2 inhibitors, which are currently used in several inflammatory conditions, could be considered for RR treatment to reduce acute symptoms caused by tissue edema and possibly prevent long-term nerve damage, the main complication of RR.

Short report: Cyclooxygenase 2 expression in vessels and nerves in reversal reaction leprosy

Tissue expression of cyclooxygenase (COX)2, an inducible enzyme synthesizing eicosanoids in inflammation, was studied in reversal reaction (RR) leprosy in comparison with nonreactionary leprosy. COX2 was consistently expressed in cells of the mononuclear-macrophage lineage across the leprosy spectrum. Only in RR, the following two additional sites showed COX2 expression in the dermis and subcutis: 1) microvessels and 2) nerve bundles and isolated nerve fibers. The same sites also express vascular endothelial growth factor (VEGF). This is in keeping with experimental models relating VEGF to COX2 expression, with VEGF enhancing prostaglandin production through COX2 stimulation and prostaglandin synthase expression. We postulate that selective COX2 inhibitors, which are currently used in several inflammatory conditions, could be considered for RR treatment to reduce acute symptoms caused by tissue edema and possibly prevent long-term nerve damage, the main complication of RR.

Overexpression of vascular endothelial growth factor and its endothelial cell receptor KDR in type 1 leprosy reaction.

The sites of expression of vascular endothelial growth factor (VEGF) and of KDR, its endothelial cell receptor, were investigated in leprosy reaction Type 1, or reversal reaction (RR), by immunohistochemistry and in situ hybridization. In comparison with nonreactional leprosy, overexpression of both VEGF and KDR was seen in granuloma cells, especially epithelioid and foreign body-type giant cells, the epithelium and the vascular endothelium of RR specimens. In granuloma cells, hybridization for VEGF was stronger than immunostaining, a finding that may reflect the rapid turnover of VEGF in an immunologically dynamic situation such as RR. In the epidermis, double immunohistochemistry revealed VEGF overexpression in CDla-positive dendritic cells. The VEGF may not only be relevant for hyperpermeability and mononuclear cell differentiation (the key morphologic features in the acute, clinically evident phase of RR), but it could also be implicated in RR onset, when dendritic cells are activated in response to antigen stimulation.