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Biomedical subjects

A Ranki

Publications and source records attributed to A Ranki.

At least 37 records · Page 2Linked to original sources
PubMed1999

Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla.

The AIRE gene (autoimmune regulator), coding for a putative transcriptional regulatory factor, is mutated in autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). We have investigated the expression of the AIRE gene by mRNA in situ hybridization and immunohistochemistry in various human tissues. Here we show that AIRE is expressed in distinct cells in thymus medulla, and also in rare cells in lymph node paracortex and medulla, and in spleen and fetal liver, but not in the target organs of autoimmune destruction. Double immunofluorescence studies revealed that in thymus medulla both epithelial (cytokeratin positive) and non-epithelial cells expressed AIRE. Subcellularly, AIRE was localised in nuclear dots in thymus and lymph node and also in transfected cells. The cellular localisation of AIRE and its nuclear localisation, compatible with its predicted protein domains, suggest that AIRE may regulate the mechanisms involved in the induction and maintenance of immune tolerance.

Biomarkers↗
PubMed1999

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Amino Acid Sequence↗
PubMed1999

High rates of disseminated infection due to non-tuberculous mycobacteria among AIDS patients in Finland.

OBJECTIVE: to determine the rate of disseminated infection due to non-tuberculous mycobacteria (NTM) among Finnish AIDS patients, and to analyse the epidemiology of these infections. METHODS: in a prospective cohort study HIV-infected patients with CD4 counts < 200 x 10(6)/l were interviewed, and had mycobacterial blood cultures performed at baseline and at 6 months, then subsequently for clinical indications; autopsies were performed on patients who died. The cohort was followed at least for 24 months or to death. Water samples were collected from the homes of patients and from the environment and cultured for organisms of the Myobacterium avium complex (MAC). Environmental and clinical isolates were compared using pulsed field gel electrophoresis (PFGE). RESULTS: NTM infection occurred in 22 (43%) of 51, 19 isolates were Mycobacterium avium, two M. genavense and one M. intracellulare. Multivariate analysis identified urban residence (P=0.04) and eating raw fish (P=0.04) as independent risk factors. Molecular analysis revealed two clusters of related isolates (three M. avium, two M. genavense) among urban residents. CONCLUSION: AIDS patients in Finland have high rates of disseminated infection due to NTM. Clusters of identical organisms and association with urban residence suggests that these are newly acquired infections in advanced AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1999

Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage.

Photodamage is characterized by degradation of collagen and accumulation of abnormal elastin in the superficial dermis and several matrix metalloproteinases have previously been implicated in this process. Using immunohistochemistry and in situ hybridization, we have studied the localization of two elastolytic matrix metalloproteinases, matrilysin (matrix metalloproteinase-7) and human macrophage metalloelastase (matrix metalloproteinase-12) in solar damage. Human macrophage metalloelastase protein was detected in the superficial dermis in areas of elastotic material. Matrix metalloproteinase-7 was seen in the mid-dermis in regions with less damaged elastic fibers and morphologically better preserved collagen as well as in a band-like pattern below basal keratinocytes in eight of 18 solar elastosis. In samples taken from healthy volunteers 3 d after repeated ultraviolet A or ultraviolet B photoprovocation, occasional immunopositive cells for human macrophage metalloelastase (stromal) or matrix metalloproteinase-7 (sweat gland epithelium) were detected. In samples taken 1 d after ultraviolet B exposure, however, basal keratinocytes were matrix metalloproteinase-7 immunopositive, explaining the linear immunostaining below basal keratinocytes noted particularly in ultraviolet B treated 3 d specimens. Upregulation of metalloelastase was also demonstrated in the skin of hairless mice after repeated ultraviolet exposure. In normal skin, no staining for human macrophage metalloelastase or matrix metalloproteinase-7 was observed in association with elastin. The amount of immunoreactivity for the substrates of matrix metalloproteinase-7, versican, and tenascin, was clearly increased in solar elastosis and photoprovocated skin; versican but not tenascin was detected in the same areas as matrix metalloproteinase-7. Our results suggest that both matrix metalloproteinase-7 and -12 may contribute to remodeling of elastotic areas in sun-damaged skin.

Adult↗
PubMed1999

Distribution of naive and memory T-cells in photoprovoked and spontaneous skin lesions of discoid lupus erythematosus and polymorphous light eruption.

Immune response to ultraviolet radiation-modified skin antigens has been suggested as a pathomechanism of skin lesions in discoid lupus erythematosus and polymorphous light eruption. In order to elucidate the role of T-lymphocyte subsets in this response, we studied the distribution of CD45RO+, CD45RA+ and CD31+ cells and the endothelial expression of adhesion molecules E-selectin/P-selectin, intercellular adhesion molecule-1 and CD31 antigen in photoprovoked and spontaneous skin lesions. Typically, CD45RA+ cells were the prevailing inflammatory cell population of discoid lupus erythematosus, whereas CD45RO+ cells prevailed in both diseases and in healthy controls. Epidermotrophism of any T-cell subsets was more typical of discoid lupus erythematosus, whereas no major differences in endothelial adhesion molecule expression was found between the 2 diseases. Strong keratinocyte ICAM-1 expression was associated with adjacent CD45RO+ cell infiltrates, not with CD45RA+ or CD31+ cell infiltrates. We conclude that the cellular immune response to UV radiation is dissimilar in discoid lupus erythematosus and polymorphous light eruption.

Adolescent↗
PubMed1999

Mutational analysis of the HGO gene in Finnish alkaptonuria patients.

Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1,2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.

Alkaptonuria↗
PubMed1998

Absence of p53 mutations in benign and pre-malignant male genital lesions with over-expressed p53 protein.

Mutations of the tumor-suppressor gene p53 are common in epithelial tumors. Clonal mutations of p53 have been found in cervical and vulvar carcinomas negative for human papillomavirus (HPV), though at least in cervical cancer HPV infection and p53 mutations are not mutually exclusive. We have previously shown that about 40% of male genital warts and bowenoid papulosis lesions exhibit immunohistochemically detectable aberrant p53 protein, irrespective of the presence of HPV DNA. We studied p53 mutations in exons 4-8 with SSCP and sequencing in 13 male patients with 1 to 3 therapy-resistant genital warts or intra-epithelial neoplasias each and in 4 patients with penile squamous cell carcinoma. Thus, 13 genital warts, 6 bowenoid papulosis, 1 Queyrat's erythroplasia and 1 carcinoma in situ were studied. p53 protein was detected immunohistochemically, and HPV status was analyzed with DNA in situ hybridization and amplification of HPV-specific DNA. There was no correlation between p53 protein expression and HPV status. No mutations in exons 5-8 of the p53 gene were found in any of the lesions, and furthermore, no exon 4 mutations were found in lesions positive in p53 immunohistochemistry. In conclusion, overexpression of p53 does not indicate a p53 mutation in male genital warts, pre-malignant lesions or malignant squamous cell carcinomas. Our study thus suggests that p53 mutations are not important, or at least not early, events in male genital carcinogenesis.

Biopsy↗
PubMed1998

Disease associations in polymorphous light eruption. A long-term follow-up study of 94 patients.

OBJECTIVES: To examine the long-term outcome of polymorphous light eruption (PLE) in a large patient population and to evaluate associated conditions, especially lupus erythematosus, during the course of the disease. DESIGN: A questionnaire-based follow-up study an average of 32 years after onset of PLE. The study was complemented by clinical examination of the patients with PLE similarly studied 16 years earlier or now reporting equal or worse PLE symptoms compared with the 1978-1979 follow-up or any symptoms suggesting an autoimmune disease. SETTING: A dermatologic clinic in a university hospital. PATIENTS: Ninety-four of the original cohort of 138 patients with PLE (87% of living patients) returned the questionnaire, and 46 (84%) of the 55 patients invited volunteered for clinical examination. INTERVENTION: None. MAIN OUTCOME MEASURES: Clinical characteristics of PLE and clinical laboratory findings referring to associated diseases, especially lupus erythematosus. RESULTS: Twenty-three (24%; 95% confidence interval [CI], 16%-34%) of the 94 patients were cured, 48 (51%; 95% CI, 41%-62%) experienced milder symptoms, and 23 (24%; 95% CI, 16%-34%) experienced equal or worse symptoms than in the 1978-1979 follow-up. At least 1 autoimmune disease was diagnosed at some point in 14 patients (15%; 95% CI, 12%-29%) (in 13 [18%] of the female patients) and lupus erythematosus specifically in 2 (2%; 95% CI, 0%-7%) (in 2 [3] of the female patients). The prevalence of a thyroid disease was 14% (13 patients) (95% CI, 8%-23%). CONCLUSION: Polymorphous light eruption is a long-standing slowly ameliorating disease with some tendency to development of autoimmune disease or thyroid disorder, especially in female patients, but the risk for lupus erythematosus is not increased.

Adult↗
PubMed1998

Infrequent p53 mutations in arsenic-related skin lesions.

Oral arsenic exposure increases the risk for a variety of benign and malignant skin lesions, but the molecular mechanism of the carcinogenic effect is poorly understood. Arsenic-related squamous cell carcinomas of the skin can develop either de novo or progress from Bowen's disease lesions. Arsenic-related basal cell carcinomas develop usually in non-sun-exposed areas and are multiple. Because p53 tumor suppressor protein is a protective cellular molecule against environmental carcinogens and mutations in the p53 gene are frequent in nonmelanoma skin cancers, we studied p53 in 23 premalignant or malignant skin lesions from seven patients with a history of arsenic medication. The eighth patient studied (with six lesions) had a long standing exposure to UV radiation. Accumulation of the p53 protein was detected (with a monoclonal DO-7 antibody) in 78% of the lesions from cases with arsenic exposure. Two of the six (30%) arsenic-related premalignant lesions and in addition one UV related carcinoma in situ lesion were clearly and repeatedly positive when p53 exons 5 to 8 were screened by a nonradioactive single-strand conformation polymorphism (SSCP) analysis. Only one of the arsenic-related lesions was confirmed by sequencing to have a mutation (a CC to TT double transition). No indications of mutations were found among the 18 basal cell carcinoma or two squamous cell carcinoma lesions studied. Our results suggest that the frequent accumulation of p53 protein in arsenic-related skin lesions is not due to p53 mutations. which may not be a prerequisite in the development of arsenic-induced skin cancers.

Aged↗
PubMed1997

B-cell epitopes in HIV-1 Tat and Rev proteins colocalize with T-cell epitopes and with functional domains.

We describe the characterization of the B-cell epitopes of HIV-1 regulatory proteins Tat and Rev. The prevalence of antibodies to these proteins among human immunodeficiency virus (HIV)-1-infected individuals was examined by enzyme-linked immunosorbent assay (ELISA) and by Western blotting. The Tat and Rev antibody-positive sera were selected for epitope mapping performed with partially overlapping synthetic peptides bound to polyethylene pins. Eighteen and twelve percent of HIV-infected individuals had antibodies against Tat or Rev, respectively. In Tat, four epitopic regions were identified, situated within amino acids 6-10 (PRLEP), 21-37 (ACTNCYCKKCCFHCQVC), 39-58 (ITKALGISYGRKKRRQRRRA) and 74-82 (TSQSRGDPT). The most frequently recognized epitopic regions were located in the middle of the protein. In Rev, the two most frequently recognized epitopic regions were near the amino terminus of the protein within amino acids 12-20 (LIRTVRLIK) and 38-49 (RRNRRRRWRERQ). A third epitope was mapped around amino acids 55-62 (ISERILGT) and a fourth around amino acids 78-83 (LERLTU). To analyze the specificity of Tat and Rev epitopes, soluble synthetic peptides representing the identified epitopes were used in an ELISA assay, and the recognition of most epitopes was shown to be specific for HIV-1-infected individuals. In addition, many of the Tat and Rev epitopes were shown to overlap with regions having functional activity or with regions previously identified as T-cell epitopes.

Amino Acid Sequence↗
PubMed1997

Chromosomal abnormalities in cutaneous T-cell lymphoma and in its premalignant conditions as detected by G-banding and interphase cytogenetic methods.

The etiology of cutaneous T-cell lymphomas (CTCL) is unknown. We studied the pattern of chromosomal abnormalities with G-banding and interphase in situ hybridization methods in blood mononuclear cells in 17 patients representing the different phases of CTCL or the premalignant condition, parapsoriasis en plaque, and in 10 control persons. We used biotinylated centromere-specific probes with fluorescent detection (FISH) for chromosomes 1, 11, 8, and 17 and similar, enzymatically detectable, digoxigenin-labeled probes for chromosomes 1, 6, 12, 17, and 18. In G-banding, all patients showed numerical and structural chromosome aberrations. Numerical aberrations of chromosomes 6, 13, 15, and 17, marker chromosomes, and structural aberrations of chromosomes 3, 9, and 13 were increased in mycosis fungoides (MF) compared with healthy controls. In four of five patients the detection of a chromosomal clone preceded relapse or progression of the disease. In FISH of interphase cells, the cells abnormal for chromosomes 8 or 11, and for all four chromosomes collectively, were increased in MF and in Sezary Syndrome (SS). FISH and G-banding methods agreed statistically significantly for the detection of monosomy. Also, digoxigenin-labeled probes hybridized to interphases or mitoses detected aberrations corresponding to those observed with G-banding. Thus, chromosomally abnormal cells can be found in the peripheral blood of both parapsoriasis en plaque and CTCL patients. They can be detected with interphase cytogenetical methods, which obviates the need for dividing cells, often difficult to accomplish in CTCL.

Adult↗
PubMed1997

Occurrence of polymorphous light eruption in lupus erythematosus.

Photosensitivity is a well-known manifestation of lupus erythematosus (LE). Since there are no strict criteria for photosensitivity, varying prevalence figures have been reported. Also, distinction from polymorphous light eruption (PLE) can be difficult. The purpose of this study was to characterize photosensitivity in more detail and to determine the occurrence of PLE in a series of well-documented LE patients. A questionnaire was answered by 337 LE patients seen at dermatology departments in Finland and Sweden, and 63 of the patients were invited for interview. According to the questionnaire, LE lesions were made worse by sunlight in 242 (72%) patients. Symptoms consistent with PLE were reported by 165 (49%) patients. Detailed personal interviews supported the results from the questionnaire, and revealed that PLE had started 2-45 years before the onset of LE in 23 of 37 patients with both diagnoses, and more than 7 years before in 18 of 37 (49%). PLE proved to be common in patients with both systemic and cutaneous LE. The two conditions may often coexist and, in about half of the cases, PLE preceded LE. These two diseases may share pathogenic factors. PLE might predispose to LE in a subgroup of PLE patients.

Adolescent↗