Toxic epidermal necrolysis after allogeneic haematopoietic stem cell transplantation.
Explore the source record for details and available documents.
Adrenal Cortex Hormones↗
Biomedical subjects
L Sviland
Publications and source records attributed to L Sviland.
Patient knowledge, practices and challenges to health care system in early diagnosis of mycobacterial adenitis.
OBJECTIVE: To assess diagnostic delay, knowledge and practices related to tuberculosis among patients with mycobacterial adenitis. DESIGN: A cross sectional study involving comparison analysis of high-risk groups. SETTING: Seven hospitals in rural and semi-rural districts of Arusha. SUBJECTS: Four hundred and twenty six clinically diagnosed adenitis patients. INTERVENTIONS: Biopsy specimens were processed for culture, histology, and sera for HIV testing. A questionnaire was used to assess knowledge, practice, and diagnostic time. MAIN OUTCOME MEASURES: Tribal comparisons were made using proportions and means. RESULTS: About 90% (387/423) of patients first visited medical facilities within a mean time of 10.1(SD, 15.7) weeks after becoming aware of their illness, and a diagnosis was made at a mean of 27 (SD, 25) weeks. Non-Iraqw patients, especially the Datoga, practised drinking raw milk (35.2% 43/122), eating raw animal products (18.8% 24/128) and living in houses with poor ventilation (33.6% 44/131), more than Iraqw patients. Of the investigations done, 14.5% (60/415) were culture positive, 11.3% (16/142) were HIV positive, and 73.6% (128/174) had histological features consistent with tuberculosis. The knowledge of TB spread by air droplets was poorer in Iraqw (74.1%, 203/274) than in non-lraqw (61.1%, 77/126) patients. About 35.0% (45/129) of non-lraqw and 27.3% (79/289) of Iraqw patients were not aware that TB could be transmitted from animals to humans. CONCLUSIONS: The health system diagnostic delay is about twice the patient delay. The knowledge and practices related to both human and bovine TB transmission were poor in all patients, especially in the patients from nomadic tribes.
Adolescent↗
Skin biopsies for early diagnosis and prognosis of graft-versus-host disease in recipients of allogeneic stem cells from blood or bone marrow.
A total of 61 patients with haematological malignancies were randomised either to allogeneic transplantation with blood stem cells (BSC) or bone marrow (BM), of whom 37 patients gave their consent to participate in a skin biopsy trial. Skin biopsies were performed before and after transplantation. The main objective was to assess whether biopsies of normal and affected skin from patients allografted with BSC showed a different histopathological and immunohistochemical pattern as compared to biopsies taken from patients allografted with BM. In addition, we wished to clarify whether sequential skin biopsies could be of prognostic value with regard to graft-versus-host disease (GVHD). Biopsies from normal or affected skin in BSC allografted did not disclose a different pattern as compared to BM transplants. Biopsies taken before the outbreak of acute and chronic GVHD showed no substantial differences between the groups. Irrespective of the type of allograft, the immunohistochemical picture of affected skin consistent with acute GVHD was dominated by a significantly higher number of T-lymphocytes (CD8+). Biopsies from normal skin before the outbreak of GVHD had no predictive value with regard to the development of acute or chronic GVHD. Immunohistochemistry is of supplementary help in distinguishing changes caused by cytotoxic agents from those caused by acute GVHD.
Adolescent↗
Heat shock protein 70: correlation of expression with degree of graft-versus-host response and clinical graft-versus-host disease.
BACKGROUND: The heat shock proteins are increasingly becoming associated with immunopathologic phenomena, being induced in response to inflammation. They are highly immunogenic and are postulated as playing a role in both innate and adaptive immunity. Their proposed role in peptide binding and antigen presentation could suggest a potential role in the alloreactive process that leads to graft-versus-host disease (GVHD) after bone marrow transplantation. METHODS: In this study we examined the expression of the widely studied heat shock protein 70 (hsp70) in an in vitro-generated graft-versus-host reaction in human skin, using streptavidin biotin immunohistochemistry and laser scanning confocal microscopy. RESULTS: Hsp70 expression was correlated with high graft-versus-host responses (P<0.001) and was confirmed using laser scanning confocal microscopy. Increased expression of hsp70 was further defined due to increases in the inducible form of hsp70. Expression of inducible hsp70 was predictive of both clinical acute GVHD (P=0.001) and incidence of chronic GVHD (P<0.001). CONCLUSIONS: This investigation has demonstrated for the first time the expression of hsp70 in a human model of GVHD, suggesting involvement in the pathogenesis of the disease and providing the basis for further investigation. Increased expression of inducible hsp70 in the model could provide a biologic marker for the prediction of clinical acute and chronic GVHD.
Acute Disease↗
In situ expression of CD40, CD40L (CD154), IL-12, TNF-alpha, IFN-gamma and TGF-beta1 in murine lungs during slowly progressive primary tuberculosis.
The distribution and expression of CD40, its ligand CD40L (154) and related cytokines interleukin-12 (IL-12), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were studied in the lungs of B6D2F1 hybrid mice during slowly progressive primary tuberculosis (TB) by immunohistochemistry. CD40 and CD40L are implicated in cell-mediated immunity (CMI) causing activation or apoptosis of infected cells. The phenomenon of apoptosis is associated with Mycobacterium tuberculosis survival. In this study, using frozen lung sections (n = 33), our results showed increased CD40, IL-12 and TGF-beta1 expression in macrophages with progression of disease. High percentages of mycobacterial antigens (M.Ags), CD40L and IFN-gamma expression were maintained throughout infection, and TNF-alpha-expressing cells were decreased. In lymphocytes, the percentage of IFN-gamma-positive cells was increased, but CD40L and IL-12 were maintained with the progression of disease. M.Ags, CD40 and CD40L were expressed in the same areas of the lesions. We conclude that changes in the expression of CD40-CD40L and cytokines associated with M. tuberculosis infection favour the hypothesis that M. tuberculosis causes resistance of host cells to apoptosis causing perpetuation of infection.
Animals↗
Increased Bcl-2 and reduced Bax expression in infected macrophages in slowly progressive primary murine Mycobacterium tuberculosis infection.
Mycobacterium tuberculosis (MTB) persists in host macrophages (Mphis) because it has developed mechanisms to escape Mphi killing. In vitro studies have shown that MTB can induce and inhibit apoptosis by causing the expression of Bax and Bcl-2, respectively, suggesting that the infected cells' fate depends on pro- and antiapoptotic signals. In the present study, we investigated the role of Bcl-2 in MTB infection in situ. The aim was to study the pattern and distribution of Bcl-2 and Bax in cellular infiltrates of MTB-infected B6D2F1 hybrid mice and correlate the expression with the presence of MTB antigens (MAgs). Using formalin-fixed lung tissues (n = 45), our results showed a significant difference in the percentage of Mphis stained for Bcl-2 or MAgs and Bax (P < 0.0001). Bcl-2 expression was increased in a population of Mphis and corresponded in intensity, colocalization and percentage with that of MAgs on the same cells, while Bax expression was reduced. In lymphocyte aggregates, Bcl-2 and Bax did not show any differences. We conclude that overexpression of Bcl-2 in Mphis containing MTB may be associated with intracellular survival of the bacilli, thus demonstrating one way by which MTB can escape the host's cellular response and killing.
Animals↗
The detection of apoptosis in a human in vitro skin explant assay for graft versus host reactions.
AIMS: Keratinocyte apoptosis is a major pathogenic mechanism in dermal complications, such as graft versus host disease (GVHD), after allogeneic bone marrow transplantation. However, the mechanisms by which recipient target cells undergo apoptosis in GVHD are still unclear, but may result from DNA damage caused by chemotherapeutic agents and/or by direct cytokine action. The basis of this investigation was to correlate keratinocyte apoptosis with (1) the severity of graft versus host reactions (GVHR) in vitro and (2) the clinical grade (0--III) of GVHD. METHODS: Skin sections generated from an in vitro skin explant model for detecting experimental or clinically relevant GVHR were investigated for the detection of apoptotic nuclei using the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) technique. This investigation also aimed to establish whether the TUNEL assay could be used as an additional, predictive method for the severity of GVHD before transplantation in potential patient/donor pairs given standard GVHD prophylaxis (cyclosporin A and methotrexate). RESULTS: By comparing mean values of apoptosis for each GVHR grade in a cohort of 83 retrospective skin sections it was shown that as the severity of GVHR increased there was a parallel increase in the percentage of apoptotic cells (p < 0.0001). However, the correlation between clinical GVHD grade II--III and overall keratinocyte apoptosis (> 2.6%) did not reach this degree of significance (chi(2): 4.2; degrees of freedom, 1; p = 0.04; Fisher's exact test: p = 0.06). CONCLUSIONS: The detection of apoptosis correlated with degree of GVHR using an in vitro assay and a higher degree of apoptosis tended to correlate with more severe GVHD. Further studies in a larger cohort of patients, using other methods to detect apoptosis in conjunction with the TUNEL assay, may give additional insight into the complex immunopathophysiology of GVHD.
Apoptosis↗
[A method for modeling skin explants--an in vitro predictive test for graft vs host disease in allogenic hematopoietic cell transplantation].
BACKGROUND: Acute graft versus host disease (GvHD) remains a severe complication of allogeneic haematopoietic stem cell transplantation (HSCT). Our study summaries results of skin explant assay (SEA) as a pretransplant GvHD predictive test in a cohort of paediatric (n = 33) and adult (a = 8) patients receiving grafts from their HLA identical siblings (n = 28), haploidentical relatives (n = 3) and unrelated donors (n = 10). Results GvHD prediction are correlated with the occurrence and severity of acute GvHD posttransplant and effect of GvHD prophylaxis on GvHD clinical outcome is evaluated. METHODS AND RESULTS: SEA utilises responding lymphocytes of the donor, which are sensitized firstly in vitro by mononuclears cells of patient in allogeneic mixed lymphocyte culture (MLC) and subsequently co-cultured with recipient's skin. Histopathological changes found in patients' skin explants are evaluated according to standard Lerner classification for acute GvHD. In general, GvHD predictive results in SEA correlated with GvHd clinical outcome in 28 out of 41 tested patients (68%, p = 0.015). In a cohort of HLA identical sibling transplants GvHD predictive results correlated with clinical manifestation of acute GvHD only in 15 out of 28 patients on individual GvHD prophylaxis. GvHD prophylaxis in the form of cyclosporine A (CsA) combined with short-term methotrexate (MTX) reduced the risk of acute GvHD in 10 out of 14 transplanted patients (71%) meanwhile CsA alone prophylaxis only in 1 out of 5 patients (20%). In a cohort of unrelated pairs on CsA/MTX prophylaxis combined with horse anti-lymphocyte globuline (ALG) correlated the GvHD prediction with GvHD clinical outcome (100%, p = 0.003). In all patients transplanted with the grafts from their haploidentical relatives the occurrence of severe GvHD was predicted. CONCLUSION: Skin explant assay helps identify pretransplant patients at higher risk of severe acute GvHD. GvHD predictive results enable the transplantation team to individualise GvHD prophylaxis and to optimise selection of the donor.
Acute Disease↗
Histological correlation between different centers using the skin explant model to predict graft-versus-host disease following bone marrow transplantation.
Acute graft-versus-host disease (GVHD) remains the major complication of allogeneic stem cell transplantation (SCT) with an incidence of 40-60% and a mortality of up to 50%. Several assays have been developed to try to predict the development of GVHD including the mixed lymphocyte culture reaction, cytotoxic and helper T lymphocyte precursor frequency assays. In the Northern region of England we have used an in vitro skin explant model for predicting GVHD in MHC compatible bone marrow transplant recipients since 1988. The aims of the present study was to test the reproducibility of the model in two other bone marrow transplant centers in Europe. The assay consists of incubating patient skin explants with effector cells from mixed donor versus recipient lymphocyte cultures and the subsequent detection of graft-versus-host reactions by histopathological grading (0-IV) of the skin explants. 503 slides from 134 patients were evaluated. All were graded for negative GVHR grade 0-I or positive grade II-IV. Results from control and test slides significantly correlated between centers to the p value of 0.0001 by Fisher's exact probability test. These results show that the skin explant assay is reproducible between centers and supports the continued use of the assay to predict GVHD in allogeneic stem cell transplant recipients.
Biopsy↗
GvHD risk assessment in hematopoietic stem cell transplantation: role of cytokine gene polymorphisms and an in vitro human skin explant model.
This present review concentrates on the recent results investigating the role of certain cytokine gene polymorphisms, including tumor necrosis factor alpha, interferon gamma, interleukin-6 (IL-6), IL-10, and IL-1 receptor antagonist, in allogeneic stem cell transplantation. The review discusses their potential role in predicting outcome and the development of a genetic risk index for graft-versus-host disease in human leukocyte antigen matched sibling transplants. By the comparative use of an in vitro human skin explant model, initial results suggest that certain polymorphisms may be associated with more severe disease.
Bone Marrow Transplantation↗
An in vitro skin explant assay as a predictive assay for graft-versus-host disease in a cohort of pediatric transplants.
Severe acute graft-versus-host disease (GvHD) remains a serious complication of allogeneic stem cell transplantation. An in vitro skin explant assay was used to predict the occurrence and severity of acute GvHD in a cohort of 30 pediatric patients undergoing human leucocyte antigen (HLA)-matched sibling transplants (20 patients) and matched or one antigen mismatched unrelated donor transplants (10 patients). In the cohort of HLA-matched sibling transplants, the result appeared to reflect the degree of GvHD prophylaxis. The skin explant assay correlated with GvHD outcome in 12 of 20 children, but this did not reach statistical significance (chi-square 0.95, d.f.=1, p=0.32). These results support previous observations. In this present cohort, patients were treated either with cyclosporin A (CsA) monotherapy (n=7) or with CsA plus additional methotrexate (MTX) (n=13). We have previously demonstrated that the skin explant assay was not as predictive in patients receiving CsA plus additional MTX compared to cohorts treated with CsA alone. In the group of patients treated with CsA alone, four of five patients (80%) predicted to develop GvHD developed acute GvHD of grade II or above; of two patients predicted to develop only grade 0-I GvHD, one patient developed no GvHD and the other grade II GvHD. In the CsA plus MTX group, nine patients were predicted to develop GvHD. Five of nine (55%) developed acute GvHD of grade II or above, while three of four with grade 0 or I skin explant assay results developed only grade 0-I GvHD. In a cohort of 10 patients who received unrelated donor transplants, the skin explant assay correlated with GvHD outcome in all 10 patients (Fisher's exact test p=0.008). Hence, the skin explant assay is a pretransplant in vitro GvHD predictive test that predicts the occurrence and severity of acute GvHD in pediatric unrelated donor transplants and to varying degrees, depending on the GvHD prophylaxis protocols, in HLA-matched sibling cohorts.
Acute Disease↗
Mitochondrial enteropathy: the primary pathology may not be within the gastrointestinal tract.
BACKGROUND: Mitochondrial DNA (mtDNA) defects are an important cause of disease. Although gastrointestinal symptoms are common in these patients, their pathogenesis remains uncertain. AIM: To investigate the role of the mtDNA defect in the production of gastrointestinal dysfunction. PATIENT: A 20 year old woman who presented at 15 years of age with recurrent vomiting and pseudo-obstruction, who did not respond to conservative management and ultimately had subtotal gastrectomy and Roux-en-y reconstruction. She subsequently presented with status epilepticus and was found to have a mitochondrial respiratory chain disorder due to a pathogenic mtDNA point mutation (A3243G). METHODS: Resected bowel was studied using light and electron microscopy and mtDNA analysed from both mucosal and muscular layers using polymerase chain reaction generated RFLP analysis. RESULTS: Histological and electron microscopic studies revealed no morphological abnormalities in the resected stomach, and molecular genetic analysis failed to identify the genetic defect in either the mucosal or muscle layers. CONCLUSION: This study suggests that in some individuals with gastrointestinal symptoms associated with established mitochondrial DNA disease, the primary pathology of the mitochondrial enteropathy lies outside the gastrointestinal tract.
Adolescent↗
PUVA-related punctate keratoses of the hands and feet.
BACKGROUND: We have observed, in patients undergoing high-dose PUVA treatment, a type of keratosis not previously described. The lesions usually occur on the sides of the palms or soles and are clinically distinct. They are generally painless and often go unnoticed by patients. OBJECTIVE: We sought to further characterize these lesions both clinically and histologically. METHODS: Patients attending a PUVA clinic were screened for these keratoses. Other PUVA-related complications were recorded. Representative lesions were photographed, and biopsy specimens were taken. RESULTS: Biopsy specimens were taken from lesions in 10 patients. All had plaque psoriasis and had received high UVA doses (>1000 J/cm(2)) through PUVA therapy. All patients had PUVA-induced keratoses elsewhere, but the number varied greatly between patients. The hand and foot keratoses were well defined and circular and had a characteristic histologic appearance, with a sharp demarcation between normal and abnormal markedly pale-staining epidermis. CONCLUSION: These lesions are a further cutaneous manifestation of prolonged PUVA therapy.
Adult↗
Keratin expression in the normal nail unit: markers of regional differentiation.
Differentiation within the nail unit was examined using a range of antikeratin monoclonal antibodies including the recently described antibody LHTric-1, specific to the acidic hair-type keratin Ha1. Keratinocytes of the nail matrix, nail bed and the digit pulp were characterized by different patterns of keratin expression. Nail matrix was the sole site of expression of Ha1, which colocalized in suprabasal matrix epidermis with epidermal keratins K1 and K10. Small amounts of K17 were found at the apex of the matrix in some cases. K6 and K16 were found where the epidermal surface folds forwards to become the ventral aspect of the proximal nail fold. The nail bed was distinguished by the absence of hair-type keratin Ha1 and the absence of markers of cornified epidermis and mucosal differentiation K1/K10 and K4/K13, respectively, while K6, K16 and K17 were detected. The basal keratin conformation marker, LH6, was expressed suprabasally throughout the nail bed. This complement of keratins exists in the nail bed in the absence of notable proliferative activity, and suggests a state of minimally developed differentiation which may be afforded by the physical or biological properties of the overlying nail. Keratins, K6, K16 and K17 were all found in the digit pulp in limited amounts, possibly in association with the epidermal component of the eccrine duct. The simple epithelial keratins, K7, K8 and K18, were found in small amounts in the specimens from younger individuals, mainly in epibasal cells of the apex of the matrix and in putative Merkel cells.
Cell Differentiation↗
Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma.
The CDKN2A (p16INK4alpha) cell cycle-inhibitory gene has been associated with development of familial melanoma. Additionally, recent studies indicate that p16 alterations occur frequently in sporadic melanomas. To investigate whether differences in p16 expression are associated with tumor cell proliferation, tumor progression, and patient survival, we examined the immunohistochemical staining of p16 protein in a consecutive series of 202 vertical growth phase melanomas and 68 corresponding metastases and compared the results with Ki-67 expression, p53 expression, clinicopathological variables, and survival data. Forty-five percent of the primary tumors showed absent or minimal nuclear staining for p16 protein. These cases were significantly associated with high Ki-67 expression (P < 0.0001), ulceration (P = 0.001), and vascular invasion (P = 0.03). Further loss of p16 expression was observed in metastatic lesions (77% were negative; P < 0.0001). Absent/minimal nuclear p16 staining significantly predicted poor patient survival (log-rank test, P = 0.0003), with 37% and 67% estimated 10-year survival rates for cases with absent or present p16 expression, respectively. In multivariate analysis, p16 staining was an independent prognostic factor (hazard ratio, 2.5; 95% confidence interval, 1.5-4.2; P = 0.0008), along with p53 expression, Ki-67 expression, anatomical site, Clark's level of invasion, and vascular invasion. Our findings indicate that loss of nuclear p16 protein expression in vertical growth phase melanomas is associated with increased tumor cell proliferation (Ki-67) and independently predicts decreased patient survival. Cases without p53 expression had improved survival.
Aged↗
Use of a skin explant model for predicting GVHD in HLA-matched bone marrow transplants - effect of GVHD prophylaxis.
Over the last decade we have successfully evaluated the use of a human skin explant assay for predicting acute GVHD in HLA-matched sibling transplants. In the present study, we modified GVHD prophylaxis on an individual patient basis depending on the GVHD outcome predicted by the skin explant model. We have summarised our previous data describing how the skin explant assay results correctly predict GVHD occurrence and severity in 45/56 patients (80%); P< 0.0001, chi2 19.97, df = 1. In a further cohort of 19 patients, all were predicted to develop grade II or above GVHD. These patients were given increased GVHD prophylaxis with the addition of methotrexate and a significant reduction in the expected incidence of GVHD was observed (P = 0.02; chi2 7.7, df = 1; Fisher exact test P = 0.04). The results from these studies suggest that modifying GVHD prophylaxis, based on skin explant assay results, may reduce the expected incidence and severity of GVHD. We suggest that the technique might be used for selective GVHD prophylaxis in T cell non-depleted HLA matched sibling transplants.
Adolescent↗
Non-Langerhans cell histiocytosis associated with lymphocyte-predominant Hodgkin's disease.
We report a 74-year-old man who presented with a rash on the trunk showing clinical and histological features of non-Langerhans cell histiocytosis. Two years after presentation he developed weight loss, lymphadenopathy and hepatosplenomegaly; a diagnosis of lymphocyte-predominant Hodgkin's disease was made on lymph node biopsy. The cutaneous signs and lymphoma responded to chemotherapy. Taken in conjunction with previously published reports of associations between cutaneous histiocytoses and haematological malignancies, we recommend close observation of patients in whom a diagnosis of non-Langerhans cell histiocytosis is made.
Aged↗
A human skin explant model for predicting graft-versus-host disease following bone marrow transplantation.
Graft-versus-host disease (GVHD) is the most serious complication following bone marrow transplantation, with an incidence of 40-60%. The disease can be fatal in 50% of cases, even in patients receiving marrow from an HLA identical sibling. Several assays have been developed to try to predict the development of GVHD, including mixed lymphocyte culture reaction, cytotoxic T lymphocyte precursor, and helper T lymphocyte precursor frequency assays. This review describes an in vitro skin explant model which has been used since 1988 for both predicting acute GVHD in HLA identical sibling bone marrow transplantation and studying the pathophysiology of the disease. The model involves sensitising donor lymphocytes in vitro in a primary mixed lymphocyte reaction and then evaluating the secondary response on patient skin biopsies by grading the graft-versus-host reactivity (grades I-IV) histopathologically. From analysis of collective data the model is a clear predictor of GVHD and superior to the other assays widely used, with a correlation of 82% with clinical outcome. The skin explant model allows the investigator to study the pathogenesis of GVHD. The cytokines TNF alpha and IFN gamma are shown to be important mediators of cellular damage in graft-versus-host reactions. Recent work has also involved using the model to study the alloreactivity of cord blood. The model is currently being assessed in several bone marrow transplantation centres in Europe on different patient groups including those who receive marrow from haploidentical and matched unrelated donors.
Bone Marrow Transplantation↗