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PubMed1998

Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia.

Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARalpha fusion protein. Both PML- and PLZF-RARalpha possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARalpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARalpha, it had a very little effect on its association with the PLZF-RARalpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARalpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARalpha on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA.

Chromosomes, Human, Pair 15↗

PubMed1995

CD44v6 expression in non-Hodgkin's lymphoma: an association with low histological grade and poor prognosis.

The family of CD44 glycoproteins has diverse functions in cell-cell and cell-matrix interactions. The standard form of CD44 is of importance in the dissemination of lymphoma, whereas the clinical significance of the variant exon v6-containing forms of CD44 (CD44v6) is not known. The expression of different forms of CD44 was investigated by using antibodies against the constant part of CD44 (CD44c) and CD44v6 in 56 primary and 17 recurrent non-Hodgkin's lymphomas and correlated with several clinicopathological parameters and with prognosis. Fifty-seven per cent of the primary non-Hodgkin's lymphomas expressed CD44v6 and 73 per cent expressed the constant epitope. Expression of both CD44c and CD44v6 was associated with low histological grade of malignancy. CD44c expression was associated with a low cellular proliferation rate as assessed by DNA flow cytometry. Of several factors tested, high expression of the variant from v6 was the only factor that was associated with unfavourable recurrence-free survival (P = 0.04). We conclude that CD44v6 is associated with a low histological grade, but, on the other hand, with an unfavourable outcome, which suggests that the combination of CD44v6 and histological grading may form a particularly strong prognostic parameter in non-Hodgkin's lymphoma.

Adolescent↗

PubMed2000

Extensive sequence divergence among bovine respiratory syncytial viruses isolated during recurrent outbreaks in closed herds.

The nucleotides coding for the extracellular part of the G glycoprotein and the full SH protein of bovine respiratory syncytial virus (BRSV) were sequenced from viruses isolated from numerous outbreaks of BRSV infection. The isolates included viruses isolated from the same herd (closed dairy farms and veal calf production units) in different years and from all confirmed outbreaks in Denmark within a short period. The results showed that identical viruses were isolated within a herd during outbreaks and that viruses from recurrent infections varied by up to 11% in sequence even in closed herds. It is possible that a quasispecies variant swarm of BRSV persisted in some of the calves in each herd and that a new and different highly fit virus type (master and consensus sequence) became dominant and spread from a single animal in connection with each new outbreak. Based on the high level of diversity, however, the most likely explanation was that BRSV was (re)introduced into the herd prior to each new outbreak. These findings are highly relevant for the understanding of the transmission patterns of BRSV among calves and human respiratory syncytial virus among humans.

Animals↗

PubMed2003

The development of asthma in children infected with Chlamydia pneumoniae is dependent on the modifying effect of mannose-binding lectin.

BACKGROUND: Although several studies found associations between infection with Chlamydia pneumoniae and asthma, these were mainly restricted to the exacerbation of the symptoms in adults with known asthma. Data about the role of C pneumoniae in the initiation and development of asthma in children are controversial. OBJECTIVE: We investigated the role of C pneumoniae infection in 139 children with asthma, comparing them with 174 healthy control subjects. Furthermore, we studied the modifying effect of mannose-binding lectin (MBL) variant alleles on the susceptibility to asthma in children infected with C pneumoniae. METHODS: C pneumoniae-specific antibodies were measured by means of ELISA, and MBL genotypes were determined by means of PCR-RFLP. RESULTS: There were no significant differences in the percentage of children with positive results for C pneumoniae-specific antibodies between patients and control subjects. Among asthmatic children carrying variant MBL alleles, there were significantly more patients with positive results for C pneumoniae-specific IgG than among control children with variant MBL genotypes (63.7% vs 40.7% of asthmatic vs control children, respectively; odds ratio adjusted for age and sex, 2.21; 95% CI, 1.10-4.41; P =.02). Infected children with variant MBL alleles were found to have a higher risk of asthma development than infected children with normal MBL genotype. This risk was especially high in children with chronic or recurrent infection (positive results for both IgA and IgG; adjusted odds ratio, 5.38; 95% CI, 1.75-14.36; P =.01), but no increased risk was seen in children with current C pneumoniae infection (positive results for IgM). CONCLUSION: This study indicates the important role of variant MBL alleles in the susceptibility to asthma in children infected with C pneumoniae.

Adolescent↗

PubMedDate not supplied

[MRI and computerized tomography in the evaluation of lumbar spine after herniated disk surgery].

The authors analyze the results of comprehensive radio-diagnosis in 44 patients previously operated on for lumbar hernias. All the findings of magnetic resonance tomography and computer-aided tomography were divided into 3 groups: (1) natural consequences of a surgical intervention without clinical manifestations; (2) complications after a surgical intervention; (3) recurrent hernias or hernias on an adjacent level. The most intricate problem was the differential diagnosis between a recurrent hernia and a postoperative epidural cicatrix. Criteria to distinguish between these two conditions are suggested. The authors emphasize that the optimal variant for examination of the patients operated on is a combination of magnetic resonance tomography and computer-aided tomography.

Adult↗

PubMed1989

[The prognostic significance of anaplastic variants in patients with testicular seminoma subjected to exclusive radiotherapy].

Three-hundred and sixty-six patients affected with seminoma testis (234 stage I, 85 stage II low, 47 advanced diseases) were treated between January 1968 and December 1985. Overall incidence of anaplastic lesions (43 patients) was 12%, progressively increasing with stage of the disease (9% stage I, 13% stage II low, 21% advanced disease). Only 343 patients submitted to exclusive curative/prophylactic radiotherapy were studied: 35 of them were anaplastic (22 stage I, 11 stage II low, 2 advanced disease). Radiation therapy was always performed regardless of the histologic subtype. Recurrences occurred in 14% of anaplastic tumors (5/35) and in 7.5% of classical seminomas (23/308). There was no statistically-significant difference between global and stage-by-stage failures. After literature review and complete analysis of the patterns of recurrence, the authors stress the lack of evidence suggesting a different radioresponsiveness of anaplastic versus classical seminomas; nonetheless, a more accurate staging is recommended for anaplastic variants, since they tend to appear in the advanced stages of the disease.

Adult↗

PubMed2002

Distinctive pleomorphic xanthoastrocytoma-like tumor with exclusive abortive or aberrant neuronal differentiation and repeated recurrence--case report.

A 9-year-old girl with a 1-month history of generalized seizure presented with a distinctive tumor resembling pleomorphic xanthoastrocytoma. Neuroimagings showed a right frontotemporal lobe tumor. Histological examination of the resected tumor indicated similarity to pleomorphic xanthoastrocytoma without staining for glial fibrillary acidic protein. The neuronal immunoreactivity and ultrastructural features showed two discrepancies: Numerous cytoplasmic processes containing rich structures suspected to be microtubules and neurofilaments were present, but neurofilament protein 70 kd/200 kd staining was negative; and many tumor cells showed synaptophysin staining, but no synaptic structures or vesicles were observed. She suffered recurrence 14 months after the first surgery. The specimen from the second operation revealed no malignant transformation with a MIB-1 labeling index of 1.9%. Only 2 months after the second operation, there was a second recurrence. Irradiation was administered (60.2 Gy). Twenty-eight months later, no tumor progression was seen. This tumor was an unconventional type with "abortive" or "aberrant" neuronal differentiation or an extreme variant of pleomorphic xanthoastrocytoma.

Astrocytoma↗

PubMed1992

Cerebral infarction in a heterozygote with variant antithrombin III.

BACKGROUND: We report a heterozygous case of familial qualitative deficiency of antithrombin III associated with cerebral infarction. CASE DESCRIPTION: A 33-year-old man had a history of recurrent transient ischemic attacks from the age of 28. Cerebral computed tomography at age 29 disclosed a low-density area in the left frontal lobe, and an internal carotid angiogram showed branch occlusion of the right anterior cerebral artery and stenosis of the left middle cerebral artery. Occlusion of the right middle cerebral artery developed thereafter. The plasma antithrombin III antigen concentration and progressive antithrombin activity were normal, but plasma heparin cofactor activity was low in the patient and his father. Nucleotide sequence analysis of the proband's deoxyribonucleic acid showed no mutation in exons II and VI of antithrombin III. CONCLUSIONS: We conclude that abnormal antithrombin III with defective heparin binding, even though heterozygous, may cause ischemic stroke in young adults. We named this antithrombin III variant "Antithrombin III Nagasaki."

Adult↗

PubMed2002

A recurrent case of odontogenic ghost cell tumour of the mandible.

Odontogenic ghost cell tumour (OGCT), also referred to as dentinogenic ghost cell tumour, is an extremely rare tumour classified as a neoplastic variant of calcifying ondontogenic cyst (COC). To date, only 13 cases of OGCT arising in the maxilla or mandible have been reported. We describe an OGCT that recurred after segmental resection of the mandible in a 59-year-old man. Histopathological examination revealed tumour invasion of the surrounding cortical bone, areas containing numerous calcifying flaky cell nests, and dentinoid matrix near epithelial cell nests. No atypical mitosis was found. There has been no evidence of recurrence or metastasis in the 4 years after operation.

Dentin↗

PubMed2000

Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells.

Cerebral amyloid angiopathy is commonly associated with normal aging and Alzheimer's disease and it is also the principal feature of hereditary cerebral hemorrhage with amyloidosis Dutch type, a familial condition associated to a point mutation G to C at codon 693 of the amyloid beta (Abeta) precursor protein gene resulting in a Glu to Gln substitution at position 22 of the Abeta (E22Q). The patients carrying the AbetaE22Q variant usually present with lobar cerebral hemorrhages before 50 years of age. A different mutation described in several members of three Italian kindred who presented with recurrent hemorrhagic strokes late in life, between 60 and 70 years of age, also associated with extensive cerebrovascular amyloid deposition has been found at the same position 22, this time resulting in a Glu to Lys substitution (E22K). We have compared the secondary structure, aggregation, and fibrillization properties of the two Abeta40 variants and the wild type peptide. Using flow cytometry analysis after staining with propidium iodide and annexin V, we also evaluated the cytotoxic effects of the peptides on human cerebral endothelial cells in culture. Under the conditions tested, the E22Q peptide exhibited the highest content of beta-sheet conformation and the fastest aggregation/fibrillization properties. The Dutch variant also induced apoptosis of cerebral endothelial cells at a concentration of 25 micrometer, whereas the wild type Abeta and the E22K mutant had no effect. The data suggest that different amino acids at position 22 confer distinct structural properties to the peptides that appear to influence the onset and aggressiveness of the disease rather than the phenotype.

Aged↗

PubMed1982

Paravertebral widening in a case of recurrent Wilms' tumour.

In infants and children the association of paravertebral widening and abdominal tumour has been regarded as typical of neuroblastoma. However, a paraspinal mass may develop in other malignant tumours too, but seems to be extremely rare in nephroblastoma. The fourth case so far on record is reported. Microscopically the tumour was of the sarcomatous clear cell variant.

Child, Preschool↗

PubMed1996

Intraepithelial Neutrophils in Thyroid Fine-Needle Aspiration: A Portent of Aggressive Thyroid Cancer?

We report three patients with papillary thyroid carcinoma in whom fine-needle aspiration (FNA) showed neutrophils within tumor cells. All three patients presented with large neck masses; at excision, two proved to be tall cell variants of papillary cancer. Nodal metastasis, extrathyroidal extension, and vascular invasion were found in both cases. One patient has experienced recurrent disease; the other has an increasing thyroglobulin titer but no clinically appreciable recurrence. The third patient refused further therapy, but brain metastases were noted clinically; this patient died of disease. In each case, FNA showed tumor clusters with characteristic nuclear features, papillary groups, and psammoma bodies. Neutrophils were present in the cytoplasm of tumor cells in the absence of necrosis. Immunostaining for proliferating cell nuclear antigen (PCNA), MIB-1 (Ki-67), and p53 tumor suppressor gene product was markedly positive. lntraepithelial neutrophils have not been previously reported in differentiated thyroid tumors. We postulate that these neoplasms produce specific leukocyte-attracting cytokines analogous to those produced by anaplastic and poorly differentiated thyroid carcinomas. We believe the finding of intraepithelial leukocytes in the absence of necrosis in thyroid FNA specimens represents a characteristic of clinically aggressive differentiated papillary neoplasms; in our small series, each represented a tall cell variant of papillary carcinoma.

Journal Article↗

PubMed2000

[Etiology and precipitating factors of cyclic vomiting].

The aim of the study was to determine the nature, severity, precipitants and associated features of attacks and the incidence of potential aetiological factors of cyclic vomiting syndrome (CVS). Ten patients (6 boys and 4 girls aged 2-12 years) with CVS, defined as recurrent episodes of vomiting with symptom-free intervals occurring two or more times per year, with episodes having a similar pattern and for which no other cause could be found, ten patients (7 boys and 3 girls aged 7-14 years) with migraine, defined as recurrent headache with symptom-free intervals and at least three of the following symptoms or associated findings: abdominal pain, nausea or vomiting, throbbing headache, unilateral location, associated aura (visual, sensory, motor), relief after sleeping and ten controls (6 boys and 4 girls aged 4-13 years) were studied. The mean age at onset of symptoms in patients with CVS was 3.9 years and the mean number of attacks per year was 4, the average duration of episodes was 20.5 hours and the mean number of school missed days were 6 per year. The mean age at onset of symptoms in patients with migraine was 7.6 years and the mean number of attacks per year was 9.9, the average duration of episodes was 8 hours and the mean number of school missed days were 6.4 per year. A family history of migraine was significantly higher in both groups of patients, compared with controls (p = 0.009). A personal history of headache and/or migraine and associated sign or symptoms like recurrent abdominal pains, limb pain and kinetosis was significantly higher in both patients compared with controls (p < 0.001). CVS is a chronic, disabling condition and is a migraine variant, with attacks usually precipitated by stress and intercurrent infections.

Child↗

PubMed1989

Programmed ventricular stimulation during variant angina: report of a case.

Programmed ventricular stimulation was performed in a 74-year-old patient who had a history of syncope following chest pain. In the baseline state, ventricular tachycardia was not inducible. Immediately following the study protocol, the patient complained of her usual chest pain and ST elevation was documented in lead II with reciprocal ST depression in leads AVF and V1. Programmed ventricular stimulation was repeated (presumably during the occlusive phase of coronary spasm) and a polymorphic ventricular tachycardia with a cycle length of 200 msec was repeatedly induced. Following intravenous nitroglycerin and resolution of chest pain, ventricular tachycardia was not inducible. Coronary angiography with ergonovine testing confirmed coronary spasm of the right coronary artery. We speculate that syncope was caused by ventricular tachycardia following coronary artery spasm. During a 12-month follow-up with calcium blockers and nitrates, there has been no recurrence of chest pain or syncope.

Aged↗

PubMed2006

p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients.

BACKGROUND: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress. METHODS: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen. RESULTS: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12-0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088). CONCLUSION: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

Alleles↗

PubMed2003

[Identification of two novel WASP gene mutations in 3 boys with Wiskott-Aldrich syndrome].

OBJECTIVE: The Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by mutations in the WAS protein (WASP) gene. The disease is characterized by recurrent infections, eczema, and thrombocytopenia with small platelets, and it is known to be associated with extensive clinical variability, and mutation studies indicated that genotypes are also highly variant among WAS patients. The present study was conducted to identify the mutation types of Wiskott-Aldrich syndrome protein (WASP) gene in 3 boys suffering from Wiskott-Aldrich syndrome. METHODS: Based on the typical clinical manifestations of Wiskott-Aldrich syndrome including thrombocytopenia, eczema, and recurrent infections and scanning electron micrographs, 3 patients were suspected of having WAS. The WASP gene of the 3 patients and their mothers were detected by PCR-direct sequencing analysis. RESULTS: By sequence analysis using sense and antisense primer separately, the authors found two novel WASP gene mutations. For the twin brothers, a C deletion at nucleotide 984 was detected in exon 10 of WASP gene (984delC). The consequence of the C deletion involved frameshift mutation after H317 and premature stop at 444 (H317fsX444). Their mother was a carrier of the mutated WASP gene. For another WAS patient, a nonsense mutation with nucleotide substitution of G to T at position 1388 (1388G-->T) in exon 11 of WASP gene, led to premature translational termination at amino acid position 452 (E452X). His mother had not been found to have WASP gene mutation. CONCLUSION: Genetic analysis is useful in definite diagnosis of Wiskott-Aldrich syndrome patients and in carrier detection and prenatal diagnosis, especially of atypical or sporadic WAS patients.

Blood Platelets↗

PubMed1984

[Results of coronary transluminal angioplasty following Prinzmetal's angina or fixed stenosis with associated spasm].

Transluminal coronary angioplasty (TCA) was carried out in 130 patients (109 men and 21 women) with an average age of 51 years (range 20 to 76 years) between April 1980 and December 1982. The most commonly affected artery was the LAD (100). All patients were on heparin, coronary vasodilators and calcium antagonists before the procedure, and on calcium antagonists and platelet antiaggregant drugs after TCA. The material and methods used were those described by Gruntzig. In this population, we identified a group of patients, Group I, with fixed stenosis and associated coronary spasm--either Prinzmetal angina (13 cases, 6 of which had both ST-T elevation and other ECG changes) or spontaneous spasm with a variable degree of stenosis (2 cases). The stenosis remained greater than or equal to 70% in all cases after intracoronary injection of nitrate derivatives. There were no differences between this group and that of fixed stenosis (Group II) with respect to age and type of diseased vessel (although the right coronary artery was more commonly involved in cases of spasm). The overall primary success rate was 72.8% (14/15--93%--in Group I, and 85/121--70.2%--in Group II: no statistically significant difference). The angiographic relapse rate at 6 months was significantly higher in Group I (8/12: 67%) than in Group II (15/63: 23.8%) p less than 0.02. When "redilatation" with stable success is taken into consideration the difference is not significant (33% and 22.2% respectively). The relapses may be dissociated in Group I (2 cases with recurrent spastic angina and normal angiography).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage.

Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is an autosomal dominant form of severe cerebrovascular amyloid angiopathy causing recurrent strokes during the fifth and sixth decades of life. The major constituent of the amyloid deposits in HCHWA-D is the amyloid beta-protein (A beta), also found in Alzheimer's disease. A point mutation in the DNA sequence encoding A beta has been found in 2 unrelated patients with HCHWA-D, and an assay detecting the single base change was developed for diagnostic purposes. We describe the detection of the point mutation in a patient living in the United States, suffering from recurring cerebral hemorrhages, who only recently was diagnosed with HCHWA-D. In addition, we tested a number of family members, and found the mutation in 2 additional individuals, one of them too young to exhibit clinical manifestations. This study combined with the study of two other families in Holland indicates that the codon 618 variant in the amyloid precursor protein gene segregates with HCHWA-D.

Aged↗