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Biomedical subjects

M Bhushan

Publications and source records attributed to M Bhushan.

At least 19 recordsLinked to original sources
PubMed2005

Solar angioedema: an uncommonly recognized condition?

Solar urticaria is a well defined although uncommon photosensitivity disorder, and is said to be the underlying cause of chronic urticaria in approximately 0.5% cases. In contrast, solar angioedema is seldom reported. We describe two patients with postulated solar angioedema, associated with clinical and/or phototest features of solar urticaria. Recognition of solar provocation of angioedema has important consequences for patient management.

Angioedema↗
PubMed2003

IL-1beta-induced Langerhans' cell migration and TNF-alpha production in human skin: regulation by lactoferrin.

In mice, the roles of cytokines in the initiation of epidermal Langerhans' cell (LC) migration are well documented; however, the mechanism of this response in humans is less well defined. The purpose of the present investigation was to examine the contribution of interleukin (IL)-1beta to human epidermal LC migration and to define further the mechanisms of this response. We demonstrate here that homologous recombinant IL-1beta administered intradermally to healthy human volunteers provides a stimulus for LC migration, with significant (P < 0.01) reductions in LC densities being observed at both 2 h and 4 h following treatment. At the later time-point of 4 h, injection of IL-1beta was also accompanied by activation of those LC remaining in the epidermis. Analysis of fluid aspirated from suction blisters formed at injection sites revealed significant (P < 0.01) tumour necrosis factor (TNF)-alpha production (2.99 +/- 1.18 pg TNF-alpha/mg protein; mean +/- s.d. of n = 10) in response to IL-1beta treatment compared with saline control injections (0.90 +/- 1.05 pg TNF-alpha/mg protein). Prior topical application of human recombinant lactoferrin (LF), an iron-binding protein found in exocrine secretions and skin, inhibited IL-1beta-mediated LC migration and also compromised the production of TNF-alpha protein as measured in suction blister fluids derived from each of the treatment sites. Taken together, these data demonstrate that IL-1beta is associated with both the stimulation of human epidermal LC migration and local TNF-alpha production. Topical treatment with LF compromises both these responses. These data suggest that topical LF may potentially represent a novel therapeutic in the treatment of skin inflammation where TNF-alpha is an important mediator.

Adult↗
PubMed2002

Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing.

BACKGROUND: Langerhans cells (LCs) play essential roles in the initiation and regulation of cutaneous immune responses mediated through their successful migration from the epidermis to draining lymph nodes while carrying antigen. Tumour necrosis factor (TNF)-alpha, a keratinocyte-derived cytokine, has recently been shown to play an important role in the mobilization of LCs from human epidermis. Although it is known that with age the immune system changes, the influence of increasing age on the function of human LCs has not been defined clearly. OBJECTIVES: To examine the influence of age on the ability of TNF-alpha to induce LC migration. METHODS: Ten elderly (six men, four women; mean age 76 years, range 72-79) and 10 young (six men, four women; mean age 23 years, range 18-35) volunteers received intradermal injections of 200 U of human recombinant TNF-alpha diluted in sterile saline, and control injections of sterile saline alone, at each of two paired sites identified on photoprotected buttock skin. Two hours later, paired injection sites were excised by punch biopsy. One set of paired biopsies was processed for assessment of the frequency and morphology of epidermal LCs, following preparation of epidermal sheets and immunofluorescence staining for the LC marker CD1a. The remaining paired biopsies were processed in formalin and the inflammatory response to TNF-alpha was assessed by standard histological examination. RESULTS: Mean +/- SEM baseline values for LC frequency within epidermal sheets were significantly different between young (1156.3 +/- 38.5 cells mm(-2)) and elderly subjects (835.7 +/- 48.2 cells mm(-2); P < 0.01). Intradermal injections of 200 U of TNF-alpha caused a significant reduction in the frequency of LCs in both elderly and young subjects (P < 0.01). However, the extent of TNF-alpha-induced LC migration was substantially different between the two groups, with a mean 9% reduction in LC frequency in elderly volunteers compared with a mean 23% decrease in young subjects. Exposure to TNF-alpha was associated with a perivascular polymorphonuclear infiltrate at 2 h in all young subjects; in contrast, only 50% of the elderly individuals showed evidence of such a response. CONCLUSIONS: There are significant differences between young and old skin with respect to both resting LC numbers and their response to TNF-alpha. These age-related changes in LC frequency and function may contribute to the altered cutaneous immune function observed in the elderly.

Adolescent↗
PubMed2002

Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.

BACKGROUND: Skin-homing, memory T lymphocytes play an important role in the pathogenesis of psoriasis by interacting with the vascular addressin, E-selectin and trafficking into lesional skin. Thus an attractive option for targeted therapy of the disease would be blockade of skin-homing T cells with an antibody directed at E-selectin. OBJECTIVE: We performed a multicentre, randomized, placebo-controlled trial to investigate the clinical efficacy and side-effect profile of a humanized monoclonal antibody to E-selectin, CDP850, in the treatment of moderate to severe chronic plaque psoriasis. METHODS: Patients with moderate/severe chronic plaque psoriasis were selected for study. Nine male subjects (mean age 37 years, range 25-47) were given 20 mg kg-1 CDP850 intravenously as a single dose and four subjects (three males, one female; mean age 40 years, range 23-50) received placebo infusion. Clinical response to treatment was assessed using the psoriasis area and severity index (PASI). Skin biopsies were taken for immunohistochemical analysis at the baseline, pretreatment, visit and also at day 2 and weeks 1 and 4 postinfusion. RESULTS: The treatment was well-tolerated with a minimal side-effect profile. Plasma E-selectin levels were significantly decreased in those subjects who received CDP850 compared with those who had placebo for the entire study period. At the end of study (8 weeks postinfusion), there was no significant reduction in PASI from baseline for either the CDP850 or placebo-treated groups. Immunohistochemical analysis of biopsies taken from lesional psoriatic skin showed that 2 days after dosing with CDP850, staining for E-selectin was decreased, although not absent, on dermal vascular endothelial cells when compared with baseline (P < 0.01). This decrease in E-selectin expression was maintained 4 weeks after infusion (P < 0.05). It was not, however, accompanied by a significant reduction in numbers of neutrophils or lymphocytes in the dermis. There was a statistically significant increase in CD1a-positive epidermal Langerhans cells compared with pre-dose levels at week 1 (P < 0.05). CONCLUSIONS: This clinicopathological study shows that anti-E-selectin (CDP850), although a well-tolerated, logical and safe therapy, does not appear to possess a therapeutic role in the treatment of chronic plaque psoriasis.

Adult↗
PubMed2002

Recent advances in cutaneous angiogenesis.

An understanding of the molecular basis of angiogenesis is key to the appreciation of many of the advances made in the field of neovascularization over the past two decades. The sequence of events involved in angiogenesis includes: (i) increased vascular permeability and leakage; (ii) degradation of basement membrane; (iii) endothelial cell proliferation and migration through the surrounding extracellular matrix; and (iv) maturation and stabilization of the newly formed vessel bed. This review provides an update on the molecular basis of such pathways in the skin, with particular emphasis on the endothelial cell-specific vascular endothelial growth factor and angiopoietins as modulators of angiogenesis that can be targeted in therapy of cutaneous disease.

Angiogenesis Inducing Agents↗
PubMed2002

Lactoferrin: influences on Langerhans cells, epidermal cytokines, and cutaneous inflammation.

It has been suggested previously that, in addition to other biological roles, lactoferrin (LF) may display antiinflammatory properties secondary to the regulation of cytokine expression. To explore this concept further, we have here examined in human volunteers the influence of recombinant homologous LF on the migration of epidermal Langerhans cells (LC), a process that is known to be dependent upon the local availability of certain proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). In common with previous studies in mice, it was found that topical administration of LF prior to exposure at the same site to the contact sensitizer diphenylcyclopropenone resulted in a significant reduction of allergen-induced LC migration from the epidermis (measured as a function of the frequency of CD1a+ or HLA-DR+ LC found in epidermal sheets prepared from punch biopsies of the treated skin sites). However, under the same conditions of exposure, LF was unable to influence migration of LC induced by the intradermal administration of TNF-alpha data consistent with the hypothesis that one action of LF in the skin is to regulate the local production of this cytokine. Further support for this hypothesis was derived from experiments conducted with IL-1beta. This cytokine is also able to induce the mobilization of LC following intradermal injection, although in this case, migration is known to be dependent upon the de novo production of TNF-alpha. We observed that prior exposure to LF resulted in a substantial inhibition of IL-1beta-induced LC migration, data again consistent with the regulation of TNF-alpha production by LF. Collectively, these results support the view that LF is able to influence cutaneous immune and inflammatory processes secondary to regulation of the production of TNF-alpha and possibly other cytokines.

Administration, Topical↗
PubMed2001

Acute oedema blisters: a report of 13 cases.

BACKGROUND: The development of bullae accompanying acute oedema is a commonly observed clinical sign but has been rarely reported in the literature. OBJECTIVES: To document the clinical features and increase awareness of this entity. METHODS: Retrospective case note review of 13 inpatient consultation cases seen in two dermatology departments. RESULTS: Oedema blisters appear to be related to the speed of development rather than the degree of oedema, and respond rapidly to the reduction of the underlying oedema. CONCLUSIONS: Recognition of oedema blisters is important as they respond quickly and completely to treatment of the underlying oedema.

Acute Disease↗
PubMed2001

Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Palmoplantar pustular psoriasis (PPP) is a chronic, relapsing condition often recalcitrant to therapy. Synthetic retinoids have been found to be efficacious in the treatment of PPP, but their use is limited by side-effects. Liarozole is an imidazole-like compound that inhibits the retinoic acid (RA) 4-hydroxylase-mediated breakdown of all-trans RA, causing elevation of plasma and cutaneous levels of RA. Thus liarozole acts as a retinoid-mimetic drug. Liarozole has already been found to be effective in the treatment of retinoid-responsive conditions such as chronic plaque psoriasis and ichthyoses. OBJECTIVES: To assess the efficacy and side-effect profile of liarozole in the treatment of PPP. METHODS: We performed a double-blind, randomized, placebo-controlled trial of oral liarozole 75 mg twice daily for 12 weeks in the treatment of PPP. The trial was conducted at two centres and involved 15 patients. RESULTS: Using the PPP Area and Severity Index we found a statistically significant (P = 0.02) improvement in PPP in subjects on liarozole (median 3, range 1.8-14.1) as compared with placebo (median 12.1, range 5-18) by the end of the treatment phase. There was also a statistically significant difference (P = 0.006) in the number of fresh pustules after treatment for the two study groups (liarozole median 2, range 0-18; placebo median 38, range 2-75). The severity of disease (on a scale of 0-8) between the two groups was significantly different at the end of treatment (liarozole median 1, range 1-5; placebo median 3, range 2-6; P = 0.04). No patients withdrew from the trial because of adverse events. The most commonly reported side-effects were pruritus, cheilitis and xerosis but these were rarely severe and resolved rapidly on discontinuation of treatment. Laboratory results, including haematology, liver function tests and serum cholesterol and triglycerides were not significantly different between the liarozole and placebo groups. CONCLUSIONS: The results of this pilot study suggest that liarozole 75 mg twice daily is an effective and well-tolerated therapy for PPP. In addition, the pharmacokinetics of liarozole may help to circumvent side-effects associated with synthetic retinoids and allow its use in premenopausal women.

Administration, Oral↗
PubMed2000

Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization.

Langerhans cells (LC) are members of the wider family of dendritic cells. LC reside in the epidermis where they serve as sentinels of the immune system, their responsibilities being to sample the external environment for changes and challenges and to deliver information (antigen) to responsive T lymphocytes within skin draining lymph nodes. The ability of LC to migrate from the epidermis to regional lymph nodes is therefore of pivotal importance to the induction of cutaneous immune responses. The journey that LC have to make from the skin has a number of requirements. Initially it is necessary that LC disassociate themselves from surrounding keratinocytes and are liberated from other influences that encourage their retention in the epidermis. Subsequently, migrating LC must successfully traverse the basement membrane of the dermal-epidermal junction and make their way, via afferent lymphatics, to draining lymph nodes. Effective entry into lymph nodes is necessary, as is correct positioning of cells within the paracortex. There is increasing evidence that both cytokines and chemokines, and their interaction with appropriate receptors expressed by LC, orchestrate the mobilization and movement of these cells. We here consider the parts played by these molecules, and how collectively they induce and direct LC migration.

Animals↗
PubMed2000

The Salford Psoriasis Index: an holistic measure of psoriasis severity.

We have developed, tested and validated a new scoring system for psoriasis: the Salford Psoriasis Index (SPI). The SPI incorporates the current clinical extent of psoriasis based on the Psoriasis Area and Severity Index (PASI), a score indicating psychosocial disability, and past severity based on treatment history. The resultant three-figure SPI (signs, psychosocial disability, interventions) is a similar paradigm to the TNM (tumour, nodes, metastasis) classification used for cancer staging. The first figure transforms the PASI into a number from 0 to 10 reflecting extent of psoriasis. The second assesses the psychosocial impact of psoriasis on each patient using a 0-10 visual analogue scale. The third figure reflects historical severity of disease as judged by the need for systemic treatment, admission to hospital and number of episodes of erythroderma. The SPI was prospectively employed in assessing 150 consecutive patients with psoriasis. Furthermore, in a separate cohort of 100 patients we tested the Psychosocial Impact Score against a recognized self-report psoriasis-specific measure, the Psoriasis Disability Index. There was a strong correlation between the two (r = 0.59, P < 0.001). However, the Psychosocial Impact Score correlated poorly with clinical extent scores such as the PASI (r = 0.28, P < 0.05) and the Self-administered PASI in 72 patients tested (r = 0.19, P = 0.1). There was a high correlation between all six observers in 20 patients for both PASI (r = 0.71; 95% confidence interval, CI 0.51-0.86) and the Extent Score (r = 0.70; 95% CI 0. 56-0.89). We believe that the SPI will be more relevant to real-life categorization of psoriasis severity in that it takes an holistic approach based not only on physician assessment but also psychological disability and treatment resistance.

Adolescent↗
PubMed2000

Lymphoepithelioid cell lymphoma (Lennert's lymphoma) presenting as atypical granuloma annulare.

We describe a case presenting as atypical granuloma annulare where the underlying diagnosis, confirmed by lymph node biopsy, was lymphoepithelioid cell lymphoma (Lennert's lymphoma). Lennert's lymphoma is a peripheral T-cell lymphoma which may follow a variable course and transform into an aggressive phase. Cutaneous manifestations of this condition have only rarely been reported in the literature. The presence of granulomas in the skin may have either obscured the lymphoma infiltrate or may have reflected a more generalized immune response to the underlying malignancy.

Diagnosis, Differential↗
PubMed2000

Nailfold video capillaroscopy in psoriasis.

Changes in the microvasculature are considered to play an important part in the pathogenesis of psoriasis and its associated arthritis. The novel method of nailfold video capillaroscopy is an extension of the technique of widefield nailfold microscopy which has been of diagnostic and predictive use in the in vivo study of the microcirculation in systemic sclerosis and other connective tissue disorders. However, similar studies in patients with psoriasis and psoriatic arthritis and/or nail changes have produced conflicting results. We tested the hypothesis that any abnormalities in nailfold capillaries of either a quantitative or qualitative nature might be observed more readily in subjects with pathology adjacent to the nailfold, i.e. distal interphalangeal (DIP) joint changes and/or nail dystrophy, when using this technique. Forty-four patients with psoriasis were recruited (21 males, 23 females). Twelve patients had psoriasis alone, 13 had psoriasis and nail changes, six had DIP joint involvement with changes of psoriasis elsewhere, and 13 had psoriasis, DIP arthritis and nail changes. Capillary density and standard capillary dimensions were studied and compared with those of 44 age- and sex-matched control subjects. There was a significant (P < 0.05) decrease in capillary loop density in patients with either psoriasis plus nail disease (14.5 +/- 5.7 capillaries per 3 mm field) or psoriasis plus nail and DIP joint disease (14.3 +/- 5. 0) when compared with controls (19.2 +/- 3.8). In patients with psoriatic arthritis affecting the DIP joints, there was a statistically significant (P < 0.05) decrease in arterial and venous capillary limb diameters, and this was also seen in those with arthritis associated with nail changes. However, there was no difference in capillary dimensions between patients with psoriasis and/or nail changes when compared with normal controls. Morphological abnormalities previously described in the literature were not noted in any of our four patient groups. Our findings of diminution in both nailfold capillary bed density and dimensions of the arterial and venous capillary limbs suggest that vascular injury, previously noted in ultrastructural studies, may play a part in the pathogenesis of psoriatic arthritis. However, in contrast to previous studies, we found no specific pattern of a morphological nature of nailfold capillaries in patients with psoriasis with or without nail changes, when compared with normal controls.

Adult↗
PubMed2000

'Brooke of Manchester'.

We present a brief account of the life and times of Dr Henry Grundy Brooke, a Manchester dermatologist and key figure in British dermatology in the nineteenth century. Our report highlights the achievements of a man whose contributions to dermatology continue to be of relevance in the new millennium.

Dermatology↗