Biomedical subjects
Publications and source records attributed to A R Ahmed.
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Cicatricial pemphigoid (CP) is an autoimmune mucocutaneous blistering disease associated with scarring. Heat shock protein 47 (HSP47) is thought to play an important role in fibrogenesis, but its role in skin lesions of cicatricial pemphigoid is not yet known. In the present study, we examined the role of HSP47 in dermal fibrosis in cutaneous lesions of a CP patient. Skin biopsies from a patient with CP, and from normal subjects were studied for the expression of HSP47, and interstitial collagens (type I and type III collagens) by immunohistochemistry. Dermal fibroblasts isolated from skin of normal individuals and from fibrotic skin of a CP patient were used to study the expression of HSP47, transforming growth factor beta 1 (TGF-beta 1), type I and type III collagens. Compared to the control skin sections, an increased expression of HSP47 was associated with an increased deposition of interstitial collagens in the fibrotic skin section of the CP patient. Similarly, in contrast to control dermal fibroblasts, the fibroblasts isolated and cultured from fibrotic skin of the CP patient, and grown in vitro, exhibited increased expression of HSP47, type I and type III collagens. Furthermore, compared to the normal control fibroblasts, an increased expression of TGF-beta 1 was detected in the dermal fibroblasts isolated from fibrotic skin of the CP patient. When dermal fibroblasts were treated with various concentrations of TGF-beta 1 (6.25, 12.5, 25, 50 and 100 ng/ml for 24 h), it induced the expression of both type I collagen and HSP47, as determined by quantitative real-time PCR. In conclusion, the expression of TGF-beta 1, HSP47, type I collagen and type III collagen was up-regulated in the fibrotic skin of CP patient, and a complex interaction of these molecules may initiate and propagate the fibrotic cascade in the skin of CP patients.
Addition of wheat bran to sorghum flour (Dabar cultivar) at two extraction rates 72% and 80% resulted in lowering reducing sugars. The percent decrease was 75.6% compared with the control at the end of fermentation period. There was a highly significant (p < or = 0.05) increase in crude fiber content as a result of addition of wheat bran. The increase was from 0.8 to 5.2 and from 0.5 to 5.3% for the 80% S/WB and 72% S/WB blends, respectively. Sorghum bread containing wheat bran was lower in reducing sugars and showed a significant increase (p < 0.05) in starch content. Sorghum bread containing wheat bran resulted in a lower in vitro protein and starch digestibilities.
SUMMARY: Oral pemphigoid (OP) is a chronic autoimmune disease, involving the oral cavity, characterized by a homogenous linear deposition of immunoglobulins, complement, or both along the basement membrane zone (BMZ) and a subepithelial blister formation. The alpha6/beta4 heterodimer is an integrin family of adhesion receptors, which mediates basal cell to matrix interactions. Recent evidence suggests a pathophysiologic role for antibodies against human alpha6 integrin in blister formation in OP, in organ culture studies. Fifty percent of OP patients have been reported to experience disease progression to involve other mucosal tissues, including the eye and larynx. To prevent this extension of disease, systemic therapy with systemic corticosteroids, dapsone, and immunosuppressive agents has been recommended. The use of intravenous immunoglobulin (IVIg) in the treatment of pemphigoid has been recently described. In this study, we present the use of IVIg, in a group of seven patients, with severe OP, in whom systemic conventional treatment was contraindicated. To determine the influence of treatment on antibodies to human alpha6 integrin in OP, seven patients with OP treated with IVIg therapy and a comparable control group of seven patients with OP, treated with conventional therapy, were evaluated at monthly intervals, for a 12 consecutive month treatment period. An effective clinical response was observed in all seven patients treated with IVIg therapy, after a mean treatment period of 4.5 months. IVIg therapy induced a prolonged and sustained clinical remission in all seven patients after a mean treatment period of 26.9 months. A statistically significant difference was observed in the quality of life pre- and post-IVIg therapy (P < 0.001). Both the study and the control groups had a very similar initial serological response to treatment. A statistically significant reduction in the antibody titres was observed after four months of treatment, in both groups (P = 0.015). Thereafter, patients treated with IVIg therapy had a faster rate of decline in the antibody titres, and the difference in the rate of decline between the study and control groups became statistically significant after six months of treatment (P = 0.03). The use of IVIg therapy resulted in reduction of antialpha6 antibody titres and in inducing and maintaining both a sustained, clinical and serological remission.
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Interleukin (IL-)1 is an important mediator of inflammatory responses and plays an important role in the pathogenesis of various autoimmune diseases. Cicatricial pemphigoid (CP) is a multisystem autoimmune inflammatory disease. We have studied the role of IL-1 in its pathogenesis. We have investigated the serum levels of IL-1 components (IL-1alpha, IL-1beta, and IL-1Ra), and determined the role of intravenous immunoglobulin (IVIg) therapy in patients with CP. Serum levels of IL-1alpha and beta were significantly higher in untreated patients with active disease compared to levels in patients in prolonged clinical remission and normal human controls (P<0.0001). The serum levels of IL-1Ra were higher in patients in prolonged clinical remission compared to patients with active disease (P=0.002). Hence elevated levels of IL-1alpha and beta and low levels of IL-1Ra correlate with disease activity. The levels of IL-1alpha and beta were statistically significantly higher in sera of CP patients with active disease pre-IVIg therapy compared to post-IVIg therapy (P<0.0001). Statistically significantly higher levels of IL-1Ra were present in post-IVIg treatment serum samples when compared to levels in pre-IVIg treatment (P<0.0001). In the in vitro experiments, the levels of IL-1alpha and beta produced by the peripheral blood mononuclear cells (PBMC) isolated from patients before IVIg therapy were significantly higher when compared to the PBMC isolated from post-IVIg patients (P<0.0001). Significantly higher levels of IL-1Ra were observed in the supernatants of PBMC collected from pre-IVIg patients and cultured with exogenously added IVIg, when compared to the levels of PBMC to which IVIg was not added (P<0.0001). IL-1 may be an important cytokine involved in the pathogenesis of CP. The regulation of IL-1 could be one of the mechanisms, amongst others, by which IVIg may exert its beneficial effect in the treatment of CP.
CONTEXT: Mucous membrane pemphigoid has a wide clinical spectrum. The clinical context was to determine whether pemphigoid disease that initiates in the oral cavity progresses to involve other mucosae and to determine the influence of systemic therapy on such progression. OBJECTIVE: To determine the clinical outcomes and disease progression in patients with oral pemphigoid for whom dapsone therapy was impossible. DESIGN: Retrospective analysis of a cohort of 20 patients with immunopathologic-proven oral pemphigoid studied between September 1, 1994, and October 31, 2000. Twelve patients received conventional therapy that consisted of a combination of oral prednisone with an immunosuppressive agent. Eight patients in whom such therapy was contraindicated received intravenous immunoglobulin therapy. Patients were followed up for 33 to 62 months (mean follow-up, 47.5 months). SETTING: Patients were treated in an ambulatory tertiary medical care facility of a university-affiliated hospital. PATIENTS: The 20 patients had pemphigoid disease limited to the oral cavity only at the initial clinical presentation and when enrolled in the study. MAIN OUTCOME MEASURES: The following variables were compared between the 2 groups of patients: (1) duration of treatment, (2) frequency of relapses, (3) induction of remission, (4) adverse effects of therapy, (5) extra oral involvement, and (6) quality of life. RESULTS: Using the aforementioned factors, the group treated with intravenous immunoglobulin had statistically significant shorter treatment duration, fewer relapses, higher remission rate, fewer adverse effects, no extraoral involvement, and a better quality of life compared with the group who received conventional therapy. CONCLUSIONS: Intravenous immunoglobulin is a safe and effective modality to treat mucous membrane pemphigoid. It seems to be a good option for patients who cannot be treated with dapsone and in whom conventional therapy is contraindicated or results in the development of serious adverse effects. In patients with progressive mucous membrane pemphigoid, intravenous immunoglobulin therapy may arrest disease progression.
Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, is a rare vesiculobullous disease of mucosal tissues, which involves the oral, ocular, and other mucous membranes. We have studied a group of patients with histologically and immunopathologically proven pemphigoid disease involving predominantly the conjunctiva and oral mucosa in addition to other mucosae. The purpose of our study was to (i) demonstrate the specific binding of autoantibodies present in the sera of patients with MMP to normal human oral mucosa by indirect immunofluorescence (IIF) and (ii) to study the role of these autoantibodies in the pathogenesis of subepithelial blister formation using normal human buccal mucosa in organ culture. Serum and IgG fractions from MMP patients showed homogeneous smooth linear binding along the basement membrane zone (BMZ) of the normal buccal mucosa on IIF. Serum from pemphigus vulgaris patients showed intercellular or keratinocyte cell surface staining. BMZ separation developed at 48 h after incubation of normal human buccal mucosa in organ culture, with serum or IgG from patients with MMP but not after addition of normal human serum. Addition of pemphigus vulgaris serum to the in vitro culture of normal human buccal mucosa showed acantholysis. This preliminary report suggests that circulating autoantibodies may have an important role in the pathogenesis of MMP. This in vitro organ culture model will facilitate enhancing our understanding of various molecular events during the process of blister formation in MMP and in the study of other mucosal diseases.
Intravenous immunoglobulin (IVIG) is increasingly being used for the treatment of autoimmune diseases. In the present report, the role of IVIG on in vivo and in vitro production of IL-1 and IL-1 receptor antagonist (Ra) was studied in patients with pemphigus vulgaris (PV). Serum samples from 20 untreated patients with active PV prior to initiation of systemic therapy, 20 patients receiving IVIG treatment, 20 patients in clinical remission after conventional therapy, and 20 normal human controls were studied to determine the serum levels of IL-1alpha, IL-1beta, and IL-1Ra. The in vitro production of these cytokines was measured in the culture supernatant of peripheral blood mononuclear cells (PBMC) from 10 PV patients immediately before and after IVIG therapy and from age and sex-matched 10 healthy donors simultaneously. Elevated levels of IL-1alpha and IL-1beta were detected (i) in the serum of untreated PV patients with active disease prior to systemic therapy and (ii) before IVIG infusions in patients receiving IVIG therapy. These increased levels are statistically significant when compared to the levels in healthy controls (P < 0.01). A marked reduction of IL-1alpha and IL-1beta was detected (i) in the serum of patients in prolonged clinical remission and (ii) immediately after IVIG infusion in those patients on IVIG therapy. Increased level of IL-1Ra was detected in PV patients in prolonged clinical remission and after IVIG infusion in those receiving IVIG therapy. These differences were statistically significant when compared to the levels in normal controls and to the levels in the sera of patients with active disease (P < 0.01) or just before the beginning of IVIG infusion (P < 0.01). Similar differences in the levels of IL-1alpha, IL-1beta, and IL-1Ra were found in the culture supernatant of PBMC isolated from the PV patients pre and post IVIG therapy. These observations suggests that, compared to normal controls, patients with active PV have reversed levels of IL-1alpha, IL-1beta, and IL-1Ra. IVIG therapy may down-regulate production of IL-1alpha and IL-1beta and enhance production of IL-1Ra, in vivo and in vitro. This might be one of the important mechanisms by which IVIG produces its early therapeutic effects in pemphigus vulgaris.
There are several reports in the literature describing the coexistence of features of pemphigus vulgaris and pemphigoid in the same patient. We describe 15 patients with clinical, histological, and immunopathological features of mucous membrane (cicatricial) pemphigoid at the time of initial diagnosis. All 15 patients failed to respond clinically to conventional systemic agents over a mean period of 7.2 years. Hence, IVIg therapy was used. Prior to initiating IVIg therapy, features of mucous membrane pemphigoid and pemphigus vulgaris were demonstrated by various serological tests. Different assays were performed to identify molecular characteristics of these two autoantibodies. Twenty-five healthy normal individuals, 22 patients with mucous membrane pemphigoid, 17 patients with pemphigus vulgaris, and 12 patients with pemphigus foliaceus served as controls for comparison of serological studies. On indirect immunofluorescence, using monkey esophagous as substrate, sera of all 15 patients had demonstrable levels of anti-intercellular cement substance (ICS) or anti-keratinocyte cell surface antibody. Sera of 14 patients on salt split skin bound to the epidermal side of the split, which was consistent with mucous membrane pemphigoid. Sera of all 15 patients demonstrated binding to a 205-kDa protein (human B4 integrin) and a 130-kDa protein (desmoglein 3) on immunoblot. In a sample of sera from each of the 6 patients with mucous membrane pemphigoid and pemphigus vulgaris, the anti-ICS antibody was of the IgG4 subclass. The IgG4 subclass is a characteristic feature associated with pathogenic autoantibodies in pemphigus vulgaris. Hence, in such patients, a dual diagnosis should be considered and confirmed by various serological assays. It is possible that the presence of two pathogenic autoantibodies in these patients could have contributed to the lack of response to conventional immunosuppressive therapy.
The aim of this study was to determine the relative utility of various preoperative diagnostic imaging modalities for the evaluation of benign schwannoma, including positron emission tomography (PET) utilising fluorine-18 fluoro-2-deoxy-D-glucose (FDG) and fluorine- 18 alpha-methyl tyrosine (FMT). computed tomography (CT), magnetic resonance imaging (MRI) and digital subtraction angiography (DSA). We retrospectively reviewed imaging findings in 22 patients with 25 histopathologically documented benign schwannomas of the extremities. Pre-operative imaging included: FDG-PET (n=22), FMT-PET (n=17), MRI (n=25), CT (n=16) and DSA (n=17). All 22 lesions examined by PET with FDG and/or FMT showed accumulation. The standardised uptake values (SUVs) for FDG-PET for the 22 examined tumours ranged from 0.33 to 3.7, and eight of them (36.4%) were assessed as malignant on the basis of their uptake. The SUVs for FMT ranged from 0.44 to 1.47, and 15 out of the 17 evaluated (88.2%) showed values indicating the tumour to be benign. CT demonstrated variable attenuation and contrast enhancement. MRI signal characteristics were relatively consistent: iso-signal or darker than skeletal muscle on T1-weighted and isosignal or brighter than subcutaneous fat on T2-weighted images. The venous tumour staining depicted on DSA was found to be significantly correlated with FDG accumulation. All tumours but one were treated by surgical enucleation. One tumour suspected to be malignant on the basis of imaging findings was treated with primary wide resection. Although CT, MRI and PET studies are all useful for the detection and localisation of schwannoma, our findings suggest that, among the imaging modalities studied, FMT-PET may be the most reliable technique for the differentiation of benign schwannoma from malignancy.
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PURPOSE: To evaluate the efficacy of tacrolimus (FK 506) therapy in patients with ocular cicatricial pemphigoid (OCP). METHODS: In a cohort study, six patients with OCP, in whom the disease was not controlled by conventional immunosuppressive agents administered in high doses for an appropriate period of time, were treated with FK 506. The FK 506 was administered orally at the daily dose of 8 mg. Final clinical response to FK 506 was divided into three categories based on the difference between severity of conjunctival inflammation before and after FK 506 therapy. "Total control" of disease activity was defined as residual inflammatory activity of 0.5 or less in the final examination and an inflammation decrement of at least 0.5 between initial and final examination. "Partial control" was defined as final disease activity 1.0 or 1.5 and at least 0.5 decrement of disease activity between initial and final examination. "Uncontrolled inflammation" was defined as final disease activity above 1.5 or no improvement between initial and final activity. RESULTS: The average age of the patients was 67.5 years (range 50-75 years). Male to female ratio was 1:1. The average duration of OCP prior to beginning of FK 506 treatment was 6.25 years (range 3-12.5 years). The average duration of treatment with FK 506 was 11 months (range 5-18 months). The average disease activity prior to the administration of FK 506 was 2.6 (range 2.0-3.0). The average disease activity at the time when FK 506 was stopped was 2.0 (range 1.0-2.5). In four patients (67%) FK 506 failed to control activity of OCP, and in two patients (33%) the activity was controlled partially. CONCLUSIONS: Although FK 506 was not used in a prospective randomized trial and although we used the drug only in patients with OCP refractory to conventional immunosuppressive agents, it is likely that FK 506 is incapable of controlling the activity of OCP and inducing a remission.
We prospectively followed 32 patients with soft-tissue malignant fibrous histiocytoma (MFH). Parameters were age; sex; tumor size, location, and depth; operative method; chemotherapy; radiotherapy; and histology. Patients with recurrence or metastases due to MFH within 6 months after the initial operation were separated from those without these characteristics by discriminant analysis with statistically significant difference. The order of influential functions was histology, depth of tumor, operative method, and sex. Male patients with deep-seated storiform-pleomorphic type MFH, receiving less comprehensive surgery, had the greatest risk of local recurrence or early metastases. We have to pay particular attention to patients with these factors and perform adequate surgery, because local recurrence and metastases were found to be closely related, and to have a great influence on the prognosis of this disease. Discriminant analysis to separate patients with MFH recurrence or metastases within 6 months after the initial operation from those without these characteristics is worthwhile for prognostic assessment.
Cicatricial pemphigoid is a heterogeneous group of autoimmune subepidermal blistering diseases associated most commonly with autoantibodies to bullous pemphigoid (BP)180 and less frequently with those to laminin 5 or type VII collagen. In addition, a few cases have been described with autoantibodies to the beta4 subunit of alpha6beta4 integrin. We describe a patient with extensive disease of ocular, oral, pharyngeal, laryngeal and genital mucous membranes that healed with scarring of conjunctivae. IgG autoantibodies bound to the dermal-epidermal junction on direct immunofluorescence (IF) microscopy and to the epidermal side of 1 mol L(-1) NaCl-split skin on indirect IF microscopy. Our patient's circulating IgG recognized a 205-kDa protein in extracts of 293T cells transfected with the beta4 subunit of alpha6beta4 integrin and in the cell extract of DJM-1 cells. Our patient's IgG and IgA autoantibodies also reacted with full-length BP180 derived from epidermal extracts and the ectodomain of BP180 (LAD-1) derived from culture supernatant of keratinocytes. In addition, a weak IgG reaction with BP230 was noted. The disease rapidly responded to dexamethasone-cyclophosphamide pulse therapy, and immunoblot reactivity to both beta4 integrin and BP180 decreased according to disease activity.
There are several studies that describe the simultaneous presence and conversion of pemphigus foliaceus into pemphigus vulgaris and vice versa. We describe eight patients with clinical, histological and immunopathological features of pemphigus foliaceus, at the time of the initial diagnosis. After a mean period of 2.5 years, additional serological features of pemphigus vulgaris were observed. During a long-term follow-up, systemic therapies, their durations and treatment outcomes were recorded. These patients did not respond to conventional systemic therapy and developed multiple side-effects from these drugs. Hence, they were treated with intravenous immunoglobulin therapy (IVIg). Prior to the initiation of IVIg therapy, different assays were performed to detect the presence of autoantibodies, including indirect immunofluorescence (IIF), immunoblot assay using bovine gingival lysate, and ELISA. Twenty-five healthy normal individuals, 12 patients with pemphigus vulgaris, and eight patients with pemphigus foliaceus served as controls for comparison of serological studies. At the time of initial diagnosis, the sera of all eight study patients also demonstrated binding on an immunoblot assay to a 160-kDa protein (desmoglein 1) only. This is typically observed in pemphigus foliaceus. Prior to staring IVIg therapy, binding was observed to both the 160 kDa and 130 kDa (desmoglein 3) proteins on an immunoblot assay which was characteristic of pemphigus vulgaris. The antidesmogleins, 1 and 3 autoantibodies, were predominantly of the IgG4 subclass in all eight patients studied. IVIg therapy induced remission in four patients and control in four of the eight patients. The total follow-up period ranged from 2.6 to 9.5 years (mean 5.3 years). It is difficult to determine the exact time at which these patients with pemphigus foliaceus developed pemphigus vulgaris. It is possible that the disease was nonresponsive to conventional immunosuppressive therapy owing to the simultaneous presence of two autoantibodies.
We describe 27 cases of bone tumours or tumour-like lesions where there was spontaneous regression. The follow-up period was 2.8-16.7 years (average, 7.0 years). Fourteen of these cases were no longer visible on plain radiographs. Histological diagnosis included exostosis, eosinophilic granuloma, fibrous dysplasia, fibrous cortical defect, non-ossifying fibroma, osteoid osteoma and bone island. Most cases began to reduce in adolescence or earlier, although sclerotic type lesions showed their regression in older patients. All lesions thought to be eosinophilic granuloma began to regress after periods of less than 3 months, while the duration of the other lesions showed wide variation (1-74 months). As resolution of the lesions took between 2 and 79 months (mean, 25.0 +/- 20.3 months) we consider that the most likely mechanism was recovery of normal skeletal growth control. In exostosis with fracture, alteration of vascular supply may contribute to growth arrest, but not to subsequent remodelling stage. In inflammatory-related lesions such as eosinophilic granuloma, cessation of inflammation may be the mechanism of growth arrest, whilst temporary inflammation may stimulate osteogenic cells engaged in remodeling. In the sclerotic type, growth arrest is a less probable mechanism. Necrosis within the tumour and/or local changes in hormonal control, plus remodelling of the sclerotic area takes longer. Knowledge of the potential for spontaneous resolution may help in management of these tumour and tumour-like lesions of bone.
BACKGROUND: Conventional therapy of severe bullous pemphigoid (BP) relies on the use of high-dose systemic corticosteroids with or without adjuvants, notably immunosuppressive agents. This approach can result in debilitating and potentially fatal side effects, hence the need to explore alternative therapies. Intravenous immunoglobulin (IVIg) therapy is emerging as one possibility. OBJECTIVE: Our purpose was to determine whether any preliminary conclusion can be drawn about the potential for the use of IVIg to treat patients with severe BP. METHODS: A literature search was done to identify reports, in English-language peer-reviewed journals, on the use of IVIg to treat patients with BP. Reports were examined for information on disease duration, severity, therapies used before and after IVIg, dose and frequency of IVIg administration, and its immediate and long-term effects. RESULTS: Data on treatment of 17 patients indicated that 12 patients (70%) experienced a beneficial clinical response to IVIg. In 5 patients (30%) no clinical benefit was observed. A minimum dose of 2 g/kg per cycle at monthly intervals for 3 months has been the most common approach. However, this should not be perceived as a "standard dose" at the present time. In some patients the use of IVIg appears to permit a systemic corticosteroid-sparing effect. Longer use has achieved sustained clinical remission in some patients. Lack of response was observed in patients who received low-dose IVIg or who received a single infusion only. Minimal side effects in the form of headaches and nausea and vomiting were observed in some patients. CONCLUSION: The present experience consists only of open uncontrolled trials in a few patients and does not allow for definitive conclusions. However, at this time IVIg appears to be a promising agent for the treatment of BP, especially for patients who do not respond to conventional therapy. Adequate doses for longer periods may be required to induce and maintain sustained clinical remissions. Large-scale controlled studies with defined entry criteria, objectives, end points, and long-term follow-up are necessary to determine the specific role of IVIg in the overall management of BP.