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[Antibodies to the rhamnose determinants of the polysaccharide of streptococci group A in the sera of rheumatism patients and donors].

In the sera of patients with recurrent rheumocarditis, and especially in cases of primary rheumatism, the level of antibodies to group A streptococcal polysaccharide (A-PS) has been found, according to the results of the enzyme immunoassay, to be considerably higher than in the sera of healthy donors. The level of antibodies to rhamnose determinants (RD) of A-PS has been determined by the inhibition of the immunoenzyme reaction with A-PS under the influence of a variant of group A streptococcus and rhamnose disaccharides with the bonds alpha 1-2 and alpha 1-3. In patients with recurrent rheumocarditis the level of antibodies to A-PS has been shown to be considerably higher than in healthy donors having these antibodies. In acute primary rheumatism a high level of antibodies to A-PS has been detected only in a few cases, and at the same time the prevalence of antibodies to the specific RD of A-PS, bound with beta-N-acetylglucosamine, is observed. In the sera of patients with recurrent rheumocarditis and donors having a high content of antibodies to the rhamnose site of A-PS antibodies, seemingly active against at least two RD, have been detected. In acute primary rheumatism an insignificant amount of antibodies to the rhamnose site of A-PS may probably cause the autoimmune process accompanying rheumatism. This suggestion is substantiated by the previously established capacity of these antibodies for inducing the suppression of cytotoxic cell reactions to microbial antigens.

Acute Disease↗

[Immunologic prognostication of development of recurrences in patients with acute myeloid leukemia].

Morphological study of the bone marrow and blood, cytochemical examination with evaluation of lysosomal enzymes activity, concentrations of glycogen and acid sulfated mucopolysaccharides, and immunophenotyping were conducted to develop immunomorphological criteria early detecting leukemic clone in patients with acute nonlymphoblastic leukemia (ANLL) in remission based on dynamic immunological monitoring of peripheral blood lymphocytes for recurrence prognostication. Immunological monitoring of lymphoid population of ANLL patients' peripheral blood allowed to predict recurrence in remission, several months before its morphological identification in all the patients. This was accomplished by a significant increase in the levels of (M + 3 sigma) lymphocytes with antigens of early differentiation stages atypical for mature lymphocytes. Practical value of the method is not only in providing immunophenotypical appearance of the blast cells in various ANLL variants, but also in the control by the detected antigens over the residual leukemic population during treatment, and in prediction of the disease recurrence by reversion in the spectrum of differential antigens on the lymphocytes in remission. The latter indicates the increase of the leukemic clone and may be recognized several months before evident clinicomorphological signs of the aggravation.

Acute Disease↗

Interobserver variability in the semi-quantitative assessment of 201Tl SPECT in cerebral gliomas.

OBJECTIVES: 201Tl SPECT is used successfully in the diagnosis of recurrent supratentorial glioma and in the evaluation of its response to chemotherapy. However, different methods are used to measure relative tracer uptake in tumour and background. The objective of this study was to assess the interobserver variability of such methods, and, if possible, to provide nomograms for data conversion. METHODS: Using baseline and follow-up SPECT scans from 20 patients with recurrent glioma treated with chemotherapy, three observers applied manual and semi-automatic ROI techniques to define activity in tumour (manual, semi-automatic) as well as in reference tissue (scalp, mirror, hemisphere). RESULTS: All tumour ROI techniques had intra-class correlation coefficients (ICC) > or = 0.80 indicating almost perfect agreement. The main source of variation with the manual techniques was the tumour intensity; with the semi-automatic method, observer agreement was independent of the level of tumour activity. Agreement for background ROIs was also adequate, but the mirror technique tended to perform poorer at follow-up SPECT scans (ICC 0.68). Measurement of fractional change during treatment revealed no significant differences between observers for any of the investigated ROI methodology variants. Conversion of quantitative methods to measure fractional change was possible using linear regression analysis. CONCLUSION: 201Tl SPECT in recurrent glioma appears to be a robust method with acceptable interobserver variability. The clinical field in neuro-oncology should consider including 201Tl SPECT parameters in monitoring response to chemotherapy.

Adult↗

[Recurrent Miller-Fisher syndrome].

INTRODUCTION: Miller-Fisher syndrome (MFS) is a rare auto-immune post-infectious syndrome, characterized by an ataxia, an ophthalmoplegia and a generalized areflexia. It is considered as a clinical variant of Guillain-Barré syndrome (GBS). MFS is correlated with the presence of anti-GQ1b antibodies, elevated cerebrospinal fluid (CSF) protein levels, presence of mostly sensitive electrophysiological abnormalities and for some authors central involvement with increased signal intensity of brainstem and cerebellum on MRI. Recurrent MFS is extremely rare with only 21 cases since the first description in 1970. CASE REPORT: A 54-year-old women presented MFS with two episodes in 19 years. Clinically, the first episode was a "classical" MFS, and the second an extensive MFS with tetraparesis and respiratory failure. CSF protein levels and cerebral MRI were normal. Anti-GQ1b antibodies were strongly positive and anti-GM1, anti-GM2 antibodies were slightly positive, campylobacter jejuni serology was negative. Electromyography showed isolated sensory abnormalities in median nerves territory. CONCLUSION: We report a new case of recurrent MFS with unusual clinical, biological and electrophysiological features.

Antibodies↗

A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins.

Leukocyte adhesion deficiency type I (LAD-1) is a disorder associated with severe and recurrent bacterial infections, impaired extravascular targeting and accumulation of myeloid leukocytes, altered wound healing, and significant morbidity that is caused by absent or greatly diminished surface expression of integrins of the beta2 class. We report clinical features and analysis of functions of cells from a patient with a myelodysplastic syndrome and infectious complications similar to those in the severe form of LAD-1, but whose circulating neutrophils displayed normal levels of beta2 integrins. Analysis of adhesion of these cells to immobilized ligands and to endothelial cells and assays of cell-cell aggregation and chemotaxis demonstrated a profound defect in adhesion mediated by beta2 integrins indicative of a variant form of LAD-1. A novel cell line established from Epstein-Barr virus-transformed lymphoblasts from the subject demonstrated deficient beta2 integrin-dependent adhesive function similar to that of the primary leukocytes. In addition, these cells had markedly impaired beta1 integrin-dependent adhesion. Sequence analysis and electrophoretic mobility of beta1 and beta2 proteins from the cell line demonstrated that the defects were not a result of structural abnormalities in the integrin subunit chains themselves and suggest that the adhesive phenotype of these cells is due to one or more abnormalities of inside-out signaling mechanisms that regulate the activity of integrins of these classes. These features define a unique LAD-1 variant syndrome that may reveal important insights that are generally relevant to inside-out signaling of integrins, a molecular process that is as yet incompletely understood.

CD18 Antigens↗

The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connection in bipolar II and related conditions.

The bipolar II spectrum represents the most common phenotype of bipolarity. Numerous studies indicate that in clinical settings this soft spectrum might be as common--if not more common than--major depressive disorders. The proportion of depressive patients who can be classified as bipolar II further increases if the 4-day threshold for hypomania proposed by the DSM-IV is reconsidered. The modal duration of hypomanic episodes is 2 days; highly recurrent brief hypomania is as short as 1 day, and when complicated by major depression, it should be classified as a variant of bipolar II. Another variant of the bipolar II pattern is represented by major depressive episodes superimposed on cyclothymic or hyperthymic temperamental characteristics. The literature is unanimous in supporting the idea that depressed patients who experience hypomania during antidepressant treatment belong to the bipolar II spectrum. So-called alcohol- or substance-induced mood disorders may have much in common with bipolar II spectrum disorders, in particular when mood swings outlast detoxification. Finally, many patients within the bipolar II spectrum, especially when recurrence is high and the interepisodic period is not free of affective manifestations, may meet criteria for personality disorders. This is particularly true for cyclothymic bipolar II patients, who are often misclassified as borderline personality disorder because of their extreme mood instability. Subthreshold mood lability of a cyclothymic nature seems to be the common thread that links the soft bipolar spectrum. The authors submit this to represent the endophenotype likely to be informative in genetic investigations. Mood lability can be considered the core characteristics of the bipolar II spectrum, and it has been validated prospectively as a sensitive and specific predictor of bipolar II outcome in major depressives. In a more hypothetical vein, cyclothymic-anxious-sensitive temperamental disposition might represent the mediating underlying characteristic in the complex pattern of anxiety, mood, and impulsive disorders that bipolar II spectrum patients display throughout much of their lifetimes. The foregoing conclusions, based on clinical experience and the research literature, challenge several conventions in the formal classificatory system (i.e., ICD-10 and DSM-IV). The authors submit that the enlargement of classical bipolar II disorders to include a spectrum of conditions subsumed by a cyclothymic-anxious-sensitive disposition, with mood reactivity and interpersonal sensitivity, and ranging from mood, anxiety, impulse control, and eating disorders, will greatly enhance clinical practice and research endeavors. Prospective studies with the requisite methodologic sophistication are needed to clarify further the relationship of the putative temperamental and developmental variables to the complex syndromic patterns described herein. The authors believe that viewing these constructs as related entities with a common temperamental diathesis will make patients in this realm more accessible to pharmacologic and psychological approaches geared to their common temperamental attributes. The authors submit that the use of the term "spectrum" is distinct from a simple continuum of subthreshold and threshold cases. The underlying temperamental dimensions postulated by the authors define the disposition for soft bipolarity and its variation and dysregulation in anxious disorders and dyscontrol in appetitive, mental, and behavioral disorders, much beyond affective disorders in the narrow sense.

Affect↗

Recurrent cutaneous Langerhans cell histiocytosis in infancy.

We report two infants, aged 4 and 9 months, respectively, who had recurrent cutaneous lesions of Langerhans cell histiocytosis confirmed by immunohistochemical and ultrastructural studies. The lesions were confined to the skin and appeared as transient papules on the trunk in both patients. Since neither showed evidence of internal organ involvement or further recurrences of the skin lesions during follow-up periods of 22 and 24 months, respectively, no therapy was given. These cases may be considered as an uncommon benign variant of the Langerhans cell proliferative disorder.

Female↗

A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family.

OBJECTIVE: To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor alpha (TNFalpha) receptor (TNFR1) in the pathogenesis of the disease. METHODS: The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFalpha promoter by DNA sequencing. RESULTS: Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFalpha promoter. CONCLUSION: TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.

Adolescent↗

Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA).

OBJECTIVE: The somatic point mutation in the BRAF gene, which results in a valine-to-glutamate substitution at residue 600 (BRAF(V600E)), is an ideal hallmark of papillary thyroid carcinoma (PTC). However, its prevalence is varyingly reported in different studies, and its expression in the follicular variant PTC is controversial, reducing its potential usefulness as diagnostic marker. DESIGN AND METHODS: We developed an assay based on mutant allele-specific PCR amplification (MASA) to detect BRAF mutation. We compared the sensitivity of MASA, single-strand conformation polymorphism (SSCP) and direct DNA sequencing of PCR products. Then, we used MASA 78 to analyze 78 archival thyroid tissues, including normal samples, follicular adenomas, follicular carcinomas and PTC. RESULTS: The MASA assay proved to be a more sensitive method than SSCP and DNA sequencing of PCR products. BRAF mutation was found by MASA in 19/43 (44.2%) of PTC, including 14/31 (45.2%) classic forms and 5/12 (41.7%) follicular variants. No mutations of BRAF were detected in the normal thyroid tissues, nor in follicular adenomas or follicular carcinomas. No correlation was found between BRAF mutation and clinicopathologic features nor with recurrence during a postoperative follow-up period of 4-11 years. BRAF(V600E) significantly correlated with absence of node metastasis. CONCLUSIONS: BRAF(V600E) is present in PTC, both in the classic form and in follicular variant with similar prevalence. No correlation was found between BRAF mutation and aggressive clinical behavior. MASA-PCR proved to be a specific, sensitive and reliable method to detect BRAF T1799A in DNA extracted from different sources, including cytologic samples obtained either fresh or from archival glass slides. We propose this method as a useful tool to improve accuracy of preoperative diagnosis identifying PTC from biopsies with indeterminate cytologic findings.

Adult↗

Primary intracerebral mesenchymal chondrosarcoma with rhabdomyosarcomatous differentiation: case report and literature review.

Intracranial chondrosarcoma (Ch-S) is a slow-growing, locally recurrent, malignant cartilaginous tumour of the skull base. Intracranial mesenchymal chondrosarcoma (MsCh-S) is a rarer, more malignant variant associated with the supratentorial meninges. Only seven cases of Ch-S, and six of MsCh-S, that were primarily intraparenchymal in origin have been reported. Moreover, no case of intracranial Ch-S or MsCh-S has been reported in which rhabdomyosarcomatous differentiation was prominent. A 17-year-old Asian girl presented with a 4-week history of occipital headache, vomiting and paraesthesia in the left hand. She was drowsy with a left hemiparesis and had a dilated right pupil with bilateral papilloedema. CT demonstrated a large, partly calcified, contrast-enhancing mass in the right temporo-parietal region with oedema and midline shift. Through a large craniotomy, a tense brain was encountered with no apparent cortical abnormality. Despite a radical tumour excision, with excellent initial clinical recovery, a local recurrence rapidly occurred within weeks prior to the administration of any radiotherapy. Initial histopathological examination revealed a primary MsCh-S with osseous and rhabdomyosarcomatous differentiation, with an indistinct margin. After a second radical excision, a second recurrence rapidly occurred; however, this proved excessively vascular and inoperable. Radiotherapy was declined and death followed within 3 weeks. This is the seventh case of primary intracerebral MsCh-S to be reported and the first to demonstrate rhabdomyosarcomatous differentiation. It was characterized clinically by rapid, local recurrence with increased vascularity.

Adolescent↗

Clear-cell variant of calcifying epithelial odontogenic tumor: clinical and radiographic characteristics.

OBJECTIVES: Clear cells have been reported in approximately 8% of cases of calcifying epithelial odontogenic tumor (CEOT). The purpose of this study was to describe the clinical and radiographic features of clear-cell CEOT (CCEOT). STUDY DESIGN: Eighteen cases of CCEOT were identified by review of the literature from 1958 to 2001, and a new one was added (total 19; 12 central, 7 peripheral). RESULTS: Fourteen tumors (74%) were located in the mandible, with the central lesions favoring the posterior area and the peripheral lesions the anterior-bicuspid area. Radiographic features were as follows: 50% radiolucent, 50% mixed radiolucent-radiopaque; 92% unilocular; 64% well-defined noncorticated borders, 27% well-defined corticated borders, 9% irregular borders. Cortical perforation was common (67%) compared with CEOT without a clear-cell component (6.7%). Recurrence was reported in 17% of the central lesions and none of the peripheral ones. CONCLUSIONS: CCEOT is a distinct variant of CEOT; its high tendency for cortical perforation may indicate a more aggressive behavior.

Adult↗

Ulcerative systematized porokeratosis (Mibelli).

An unusual clinical variant of porokeratosis (Mibelli's disease) appeared in a patient soon after birth; the lesions were widely distributed mostly on the right half of the body. Spontaneous recurrent ulcerations occurred over certain sites. The right foot was grossly deformed as a result of atrophic scarring after ulcerations. Biopsy specimens of the classical lesion showed cornoid lamella. It is suggested that the term "ulcerative systematized porokeratosis" be used to describe this clinical variant of porokeratosis.

Cicatrix↗

The case of the unreliable SNP: recurrent back-mutation of Y-chromosomal marker P25 through gene conversion.

The Y-chromosomal binary marker P25 is a paralogous sequence variant, rather than a SNP: three copies of the P25 sequence lie within the giant palindromic repeats on Yq, and one copy has undergone a C to A transversion to define haplogroup R1b (designated C/C/A). Since gene conversion is known to be active in the palindromic repeats, we reasoned that P25 might be liable to back-mutation by gene conversion, yielding the ancestral state C/C/C. Through analysis of a set of binary markers in Y-chromosomes in two large samples from Great Britain and the Iberian Peninsula we show that such conversion events have occurred at least twice, and provide preliminary evidence that the reverse conversion event (yielding C/A/A) has also occurred. Because of its inherent instability, we suggest that P25 be used with caution in forensic studies, and perhaps replaced with the more reliable binary marker M269.

Chromosomes, Human, Y↗

Glucosephosphate-isomerase type Kaiserslautern. A new variant causing congenital nonspherocytic hemolytic anemia.

In a 13-year-old German girl a GPI deficiency was found to be the cause of a chronic nonspherocytic hemolytic anemia with recurrent hemolytic crises. The hemolytic crises usually occurred after a feverish infection. Only once did the patient require blood transfusion during a crisis. Examination of the family indicated that the patient is doubly heterozygous for the deficiency. The investigation of the biochemical properties of the deficient enzyme revealed an altered electrophoretic migration, a pronounced thermolability, an increased affinity for G-6-P and slightly changed pH optima for both substrates. The described properties of the deficient GPI indicate that we are dealing with a new variant designated GPI-Kaiserlautern.

Adolescent↗

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Adult↗

Reduced CD44 standard expression is associated with tumour recurrence and unfavourable outcome in differentiated thyroid carcinoma.

CD44 was detected with an antibody recognizing all forms of CD44 (CD44 standard) and others specific for its v3 and v6 variant isoforms; their prognostic value was evaluated in 213 patients with differentiated thyroid carcinoma (DTC). The staining patterns of CD44 standard (s) and CD44v6 in tumour tissue were quite similar, 176 cases (83%) being highly positive for CD44s and 153 cases (72%) for CD44v6. Only 18 (9%) tumours showed high expression of CD44v3. Papillary carcinomas were significantly more often high expressors of CD44s and CD44v6 than follicular carcinomas (p<0.001 for both). Age older than 60 years, distant metastases, and advanced pTNM stage were related to loss of expression of CD44s (p<0.001, p=0.021, and p=0.003, respectively). Tumour recurrence and cancer-related mortality were related to the reduced level of CD44s (p=0.049 and p=0.042). CD44v3 did not associate with any of the clinicopathological factors. In univariate analysis, CD44s was the only significant prognostic factor for disease-free survival (p=0.0488). In multivariate analysis, CD44s and thyroglobulin level were significant prognostic factors for disease-free survival (p=0.040 and p<0.001, respectively). The reduced level of CD44s in DTC patients seems to be an independent prognostic factor for unfavourable disease outcome.

Adolescent↗

High urinary excretion of N-(pyrrole-2-carboxyl) glycine in type II hyperprolinemia.

A case report of type II hyperprolinemia in a 5-year-old boy and its biochemical investigation is presented. The child has mild developmental delay, recurrent seizures of the grand mal type and EEG alterations. Although this disorder has been recently considered a benign condition, variants accompanied by characteristic symptomatology cannot be fully ruled out. The urinary excretion of high concentrations of N-(pyrrole-2-carboxylic acid)-glycine conjugate is stressed, since it appears that only one previous report in the literature described this compound in the urine of two patients affected by this disturbance.

Amino Acid Metabolism, Inborn Errors↗