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PubMed2002

Acute myeloid leukemia (FAB-M2) with a masked type of t(8;21) translocation revealed by spectral karyotyping.

We report a case of acute myeloid leukemia (AML), M2 subtype according to the French-American-British (FAB) classification, with extramedullary myeloblastoma of the uterus and a masked type of variant translocation of t(8;21)(q22;q22). A 45-year-old Japanese woman presented with metrorrhagia, and AML (M2) with uterine invasion was diagnosed. The patient received an allogeneic peripheral blood stem cell transplantation after remission, and her pelvis was irradiated locally. Cytogenetic study at first showed t(8;17)(q22;p13) by G-banding. Spectral karyotyping (SKY) analysis modified this interpretation to a 3-way translocation involving chromosomes 8,17, and 21 and identified a masked type of variant t(8;21)(q22;q22) translocation. Results of fluorescence in situ hybridization using the AML1/ETO probe, and of detection of the AML1/ETO fusion transcript by reverse transcriptase-polymerase chain reaction were consistent with the karyotyping result. SKY analysis is useful to compensate for the limitations of cytogenetic studies.

Chromosomes, Human, Pair 21↗
PubMed1998

Comparative and library epidemiological typing systems: outbreak investigations versus surveillance systems.

A number of high-resolution molecular typing systems have been developed in recent years. Their availability raises the new issues of selecting the method (s) best suited for a particular purpose and interpreting and communicating typing results. Most of the currently available methods are comparative only: they allow testing of a sample of isolates for delineation of those closely related from those markedly different in genomic backgrounds. This approach is adequate for outbreak investigation, allowing determination of clonal spread in a microenvironment and identification of the source of infection. Comparative methods with sufficient resolution for most pathogens include restriction fragment-length polymorphism (RFLP), pulsed-field gel electrophoresis (PFGE), and arbitrarily primed and randomly amplified polymorphic DNA-polymerase chain reaction (PCR) analysis. For surveillance systems, monitoring clonal spread and prevalence in populations over extended periods of time requires library typing systems. These must be standardized, must have a high throughput, and must use a uniform nomenclature. Promising or validated methods include serotyping, insertion sequence fingerprinting, ribotyping, PFGE, amplified fragment-length polymorphism (AFLP), infrequent-restriction-site amplification PCR, interrepetitive element PCR typing (rep-PCR) and PCR-RFLP of polymorphic loci. PCR methods generating arrays of size-specific amplicons (AFLP, rep-PCR) can be more reproducibly analyzed by using denaturing polyacrylamide gel or capillary electrophoresis with automated laser detection. Binary probe typing systems appear optimal and should be enhanced further through use of DNA chip technology. In these systems, amplification of polymorphic regions is followed by solid-phase hybridization with a reference panel of sequence-variant specific probes. The resulting binary type results allow determination of reproducible, numeric profiles. However, interpretation and nomenclature of typing results for large-scale surveillance purposes still require a better understanding of population structure and microevolution of most microbial pathogens.

Bacterial Infections↗
PubMed1997

Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations.

Nuclear-localized mtDNA pseudogenes might explain a recent report describing a heteroplasmic mtDNA molecule containing five linked missense mutations dispersed over the contiguous mtDNA CO1 and CO2 genes in Alzheimer's disease (AD) patients. To test this hypothesis, we have used the PCR primers utilized in the original report to amplify CO1 and CO2 sequences from two independent rho degrees (mtDNA-less) cell lines. CO1 and CO2 sequences amplified from both of the rho degrees cells, demonstrating that these sequences are also present in the human nuclear DNA. The nuclear pseudogene CO1 and CO2 sequences were then tested for each of the five "AD" missense mutations by restriction endonuclease site variant assays. All five mutations were found in the nuclear CO1 and CO2 PCR products from rho degrees cells, but none were found in the PCR products obtained from cells with normal mtDNA. Moreover, when the overlapping nuclear CO1 and CO2 PCR products were cloned and sequenced, all five missense mutations were found, as well as a linked synonymous mutation. Unlike the findings in the original report, an additional 32 base substitutions were found, including two in adjacent tRNAs and a two base pair deletion in the CO2 gene. Phylogenetic analysis of the nuclear CO1 and CO2 sequences revealed that they diverged from modern human mtDNAs early in hominid evolution about 770,000 years before present. These data would be consistent with the interpretation that the missense mutations proposed to cause AD may be the product of ancient mtDNA variants preserved as nuclear pseudogenes.

Alzheimer Disease↗
PubMed2000

[Demonstration of the calcified osseous component in decalcified bone marrow biopsies. Study of hematological cases].

In order to investigate the possibility of the evidentiation of the mineralized component of decalcified bone a series of Jamshidi-type consecutive bone marrow biopsies for various hematological disorders were pre-stained with von Kossa modified procedure for calcium. Methodologically the controls showed reliable silver staining as far as localization (osteo-medullary interface and mineralization front) and preservation (after decalcification) were concerned. The results were: 1) a good morphology of bone marrow tissue also concerning immunohistochemical stainings; 2) a better overview of the osseous components and related artifacts as induced by biopsy, processing and sampling; 3) precise identification of the osteoid seams and remarkably of the relative angle of sectioning for an appropriate measurement; 4) better evidentiation of the remodelling osteoblastic-osteoclastic units; 5) visualization of the osteocytic lacunae and canaliculi and the mineralized matrix to some extent depending on their effective permeability. Summarizing the osteologic features were: normality or minimal abnormality of difficult interpretation; classical osteometabolic alterations; lesions specifically due to hematological disorders; various combination of these findings. Theoretical and practical aspects are discussed. In conclusion this methodological variant in comparison with the usual paraffin procedure clearly gives more information concerning osteometabolic evaluation in routine hematological biopsies; offers a vicarious or complementary approach to osteometabolic diseases; represents a conceptual stimulus to interpret diagnostically and prognostically the osseous pathology as determined by routinely encountered hematological disorders.

Artifacts↗
PubMed2005

Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma.

BACKGROUND: The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS: A consecutive series of 205 women with primary ovarian carcinoma were screened for mutations in BRCA1 and BRCA2 genes using a conformational sensitive gel electrophoresis and direct sequencing. Data regarding medical and familial history were collected using questionnaires. Clinical and pathologic data were extracted from medical records. RESULTS: Unclassified variant mutations in BRCA1 or BRCA2 genes were found in 16 (8%) patients, and BRCA1 pathogenic mutations were found in 18 (9%) patients. No pathogenic mutation was found in BRCA2 gene. Multivariate analysis showed that BRCA1 pathogenic mutation was an independent predictor of reduced risk of relapse and death (Hazard ratios [HR] 0.52 [confidence interval {CI} 0.28-0.98] and 0.38 [CI 0.10-0.96], respectively). Unclassified variant mutation did not affect recurrence and survival (HR 0.84 [CI 0.43-1.66] and 0.94 [CI 0.48-1.82], respectively). Other factors associated with reduced risk of relapse and death were complete pathologic remission at second-look laparotomy and family history of breast and ovarian carcinoma, respectively. Recurrence and death outcomes among unclassified variant mutation carriers did not differ significantly from those in sporadic cases. CONCLUSIONS: Patients with BRCA1 pathogenic mutation seem to have reduced risk of recurrence and death. These results should be interpreted with caution as they may be influenced by more intensive treatment, better response to cisplatin, and younger age of mutation carriers. Clinical relevance of BRCA1/2 unclassified variant mutations warrants further studies.

Adult↗
PubMed2001

Comparison of PowerPlex 16, PowerPlex1.1/2.1, and ABI AmpfISTR Profiler Plus/COfiler for forensic use.

AIM: Several amplification and detection formats for the analysis of short tandem repeat loci are readily available to the forensic laboratory. Careful consideration must be given to the throughput, sensitivity, concordance, data interpretation, facility requirements, and costs of operation. The Pennsylvania State Police DNA Laboratory sought to establish that of any of the amplification or detection formats generally used in the United States generates concordant results and that the use of several formats within one laboratory provides a solution to the interpretation of difficult evidentiary samples. METHODS: Validation work consisting of sensitivity, precision, mixture, and substrate studies was performed by use of each of three detection formats (ABI Prism(r)310 Genetic Analyzer, ABI Prism(r)377 DNA Sequencer, and the Hitachi FMBIO(r)II Fluorescent Scanner) and three amplification systems (GenePrint(r) PowerPlex 16, GenePrint(r) PowerPlex 1.1/2.1, and AmpflSTR ProfilerPlus/COfiler). The results generated in each of the formats were compared, along with the problems incurred. RESULTS: All allele calls were concordant, with the exception of primer region variants, and all detection systems were sensitive and reliable. Even with the use of multiple formats, a general protocol can be written with only one set of interpretation guidelines. CONCLUSION: National databases can be used with input data from any of these formats. The use of several detection formats allowed the forensic scientist to select a system, based on sample quality, quantity, and throughput requirements. Interpretation issues resulting from complex mixtures, degraded samples, rare microvariants, internal primer variants, unusual heterozygote ratios, above or below ladder alleles, and potential tri-alleles can be verified.

Criminology↗
PubMed1990

Poorly differentiated carcinoma of the thyroid retrospective clinical and morphologic evaluation.

Five thyroid carcinomas showing clinically aggressive biologic behavior were retrospectively reviewed to evaluate the possible presence of morphologic differences from conventional thyroid carcinomas. They were originally diagnosed as follicular carcinomas, medullary carcinoma, papillary carcinoma, and mixed papillary and medullary carcinoma. There were three males and two females. The age at the time of initial diagnosis ranged from 36 years to 67 years (mean 56 years). The size of the tumor varied from 4.5cm to 10cm (mean diameter 7cm). One patient died of brain metastasis four years after the initial therapy and the other four patients are still alive with local recurrences and/or metastases to bone, spinal cord, lung, and buttock. Histologically these lesions are categorized into two different groups: insular variant and columnar cell variant. Insular variant was characterized by well-defined nests (insulae) that are composed of small, uniform cells, frequent tumor necrosis, and hyalinization of the stroma. Columnar cell variant was characterized by tall columnar cells with marked nuclear statification. All five cases stained positively for thyroglobulin and negatively for calcitonin. With the above clinical and histopathological findings, we interpreted these lesions as a poorly differentiated carcinoma, biologically in an intermediate position between well differentiated and anaplastic carcinomas. The rapid and often fatal outcome associated with these variants of poorly differentiated carcinoma warrants aggressive treatment at the time of diagnosis.

Adenocarcinoma↗
PubMed2006

Ion formation mechanisms in UV-MALDI.

Matrix Assisted Laser Desorption/Ionization (MALDI) is a very widely used analytical method, but has been developed in a highly empirical manner. Deeper understanding of ionization mechanisms could help to design better methods and improve interpretation of mass spectra. This review summarizes current mechanistic thinking, with emphasis on the most common MALDI variant using ultraviolet laser excitation. A two-step framework is gaining acceptance as a useful model for many MALDI experiments. The steps are primary ionization during or shortly after the laser pulse, followed by secondary reactions in the expanding plume of desorbed material. Primary ionization in UV-MALDI remains somewhat controversial, the two main approaches are the cluster and pooling/photoionization models. Secondary events are less contentious, ion-molecule reaction thermodynamics and kinetics are often invoked, but details differ. To the extent that local thermal equilibrium is approached in the plume, the mass spectra may be straightforwardly interpreted in terms of charge transfer thermodynamics.

Ions↗
PubMed1998

Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene.

Allelic variation at the melanocyte stimulating hormone receptor (MC1R) gene has been linked with sun-sensitive skin types, suggesting it is a susceptibility candidate for melanoma. We determined the frequency of the val92met, asp294his, and asp84glu MC1R alleles in 190 Caucasian controls and 306 melanoma cases and studied their association with skin type and hair color. The percentage of controls with at least one val92met, asp294his, or asp84glu allele was 17.3%, 6.8%, and 3.5%, respectively. Individually, frequencies of the val92met, asp294his, or asp84glu alleles in the controls with skin types 3 and 4 were similar to those with skin types 1 and 2. Trend analysis, however, did identify an association (exact p = 0.048, two-sided test) between skin type and MC1R variants in the group comprising all controls with any one or more of these alleles. There was no association between MC1R alleles and hair color. Allele frequencies were not different in melanoma cases and controls. There were no associations between skin types and the proportion of cases with the asp294his or asp84glu alleles, though the association between skin type and the val92met allele approached significance (exact p = 0.09, two-sided test). Unexpectedly, in the group comprising all cases with one or more variant alleles, the proportion of subjects with variant alleles increased with skin types associated with tanning rather than burning, although trend analysis showed that this association did not quite reach statistical significance (exact p = 0.08, two-sided test). Asp84glu (but not val92met or asp294his) variant alleles were more common in subjects with blonde hair, although the relationship between the asp84glu allele and hair color did not achieve statistical significance (chi(2)3 = 6.16, exact p = 0.10). We interpret the data presented as indicating that polymorphism at MC1R does not appear a major determinant of skin type, at least in terms of these allelic variants. Furthermore, considered alone, these alleles are not susceptibility candidates for malignant melanoma.

Adult↗
PubMed1981

Characterisation of an epidemic strain of Klebsiella and its variants by computer analysis.

An outbreak of hospital-acquired klebsiella infection was investigated by means of six different typing schemes. Interpretation of the information generated by these schemes proved difficult and allowed only tentative conclusions to be reached concerning the origin of some strains. Consequently, the results were subjected to computer analysis by means of a numerical taxonomic programme adapted for the purpose. A dendrogram was constructed giving the percentage similarity between strains. It established the source of four atypical strains and showed that three of them were derived from the original clone. This form of numerical epidemiological analysis could have useful applications in the investigation of hospital-acquired infection.

Anti-Bacterial Agents↗
PubMed1993

Q-T interval as predictor of serum calcium level.

To assess whether measurement of the electrocardiograhic (ECG) Q-T interval is a useful predictor of total serum calcium concentration, 15 uraemic patients were studied (10 female, five male; age range, 25-60 years). Resting ECGs were interpreted by three independent observers without knowledge of the patients' identity or serum calcium. Three variants of measurement of the Q-T interval were analysed, of which Q-aTc, the interval from the beginning of the Q-wave to the apex of the T-wave, was the most consistent (coefficient of variation, 2.7%). This also provided the best correlation with measured serum calcium concentration (P < 0.001). When compared to biochemical measurements, the predicted serum calcium concentration was within 95% confidence limits in 14 of the 15 patients studied. However, the wide confidence limits of this technique mean that it cannot be recommended in routine clinical practice.

Adult↗
PubMed2003

The structure of DNA within cationic lipid/DNA complexes.

The structure of DNA within CLDCs used for gene delivery is controversial. Previous studies using CD have been interpreted to indicate that the DNA is converted from normal B to C form in complexes. This investigation reexamines this interpretation using CD of model complexes, FTIR as well as Raman spectroscopy and molecular dynamics simulations to address this issue. CD spectra of supercoiled plasmid DNA undergo a significant loss of rotational strength in the signal near 275 nm upon interaction with either the cationic lipid dimethyldioctadecylammonium bromide or 1,2-dioleoyltrimethylammonium propane. This loss of rotational strength is shown, however, by both FTIR and Raman spectroscopy to occur within the parameters of the B-type conformation. Contributions of absorption flattening and differential scattering to the CD spectra of complexes are unable to account for the observed spectra. Model studies of the CD of complexes prepared from synthetic oligonucleotides of varying length suggest that significant reductions in rotational strength can occur within short stretches of DNA. Furthermore, some alteration in the hydrogen bonding of bases within CLDCs is indicated in the FTIR and Raman spectroscopy results. In addition, alterations in base stacking interactions as well as hydrogen bonding are suggested by molecular dynamics simulations. A global interpretation of all of the data suggests the DNA component of CLDCs remains in a variant B form in which base/base interactions are perturbed.

Cations↗
PubMed1996

Idiopathic dysautonomia treated with intravenous gammaglobulin.

BACKGROUND: A previously healthy 23-year-old man presented with a short history of abdominal pain and diarrhoea followed by blurred vision, severe postural hypotension, reduced sweating and unremitting fever. METHODS: Examination revealed fixed dilated pupils, impaired sweating and postural hypotension. Clinical and neurophysiological examination showed no motor or sensory deficit. A diagnosis of idiopathic autonomic neuropathy was made. He became gravely ill with profound life-threatening hypotension and a prolonged ileus. FINDINGS: Within 36 h of receiving intravenous gammaglobulin (IVGG) his pupillary areflexia and severe hypotension resolved. 2 weeks later the autonomic failure recurred but again responded to treatment with IVGG. IVGG is a recognised treatment for Guillain-Barré syndrome. INTERPRETATION: This case report demonstrates that IVGG is also effective in the rare pure dysautonomic variant.

Adult↗
PubMed1994

The structure and antigenicity of a type C foot-and-mouth disease virus.

BACKGROUND: Picornaviruses are responsible for a wide range of mammalian diseases and, in common with other RNA viruses, show considerable antigenic variation. Foot-and-mouth disease viruses (FMDVs) constitute one genus of the picornavirus family and are classified into seven serotypes, each of which shows considerable intratypic variation. This antigenic variation leads to continuing difficulties in controlling the disease. To date the structure of only one serotype, O, has been reported. RESULTS: The three-dimensional structure of a serotype C (isolate C-S8c1) FMDV, has been determined crystallographically at 3.5 A resolution. The main chain conformation of the virion is very similar to that of type O1 virus. The immunodominant G-H loop of VP1, the presumed site of cell attachment, is disordered in both types of virus indicating a functional role for flexibility of this region. There are significant changes in the structure of other antigenic loops and in some internal regions involved in protomer-protomer contacts, including the entire amino-terminal portion of VP2, described here for the first time for a picornavirus. Antigenic sites have been identified by genetic and peptide mapping methods, and located on the capsid. The data reveal a major new discontinuous antigenic site (site D) which is located near to the three-fold axis and involves residues of VP1, VP2 and VP3 which lie adjacent to each other on the capsid. CONCLUSION: In FMDV type C, amino acid substitutions seen in mutants that are resistant to neutralization by monoclonal antibodies (MAbs) map to predominantly surface-oriented residues with solvent-accessible side-chains not involved in interactions with other amino acids, whereas residues which are accessible but not substituted are found to be more frequently involved in protein-protein interactions. This provides a molecular interpretation for the repeated isolation of the same amino acid substitutions in MAb-resistant variants, an observation frequently made with RNA viruses. This first comparison of two FMDV serotypes shows how subtle changes at antigenic sites are sufficient to cause large changes in antigenic specificity between serotypes.

Amino Acid Sequence↗
PubMed2006

Conserved extended haplotypes of the major histocompatibility complex: further characterization.

Since the complete sequencing of a human major histocompatibility complex (MHC) haplotype, interest in non-human leucocyte antigen (HLA) genes encoded in the MHC has been growing. Non-HLA genes, which outnumber the HLA genes, may contribute to or account for HLA and disease associations. Most information on non-HLA genes has been obtained in separate studies of individual loci. To comprehensively address polymorphisms of relevant non-HLA genes in 'conserved extended haplotypes' (CEH), we investigated 101 International Histocompatibility Workshop reference cell lines and nine additional anonymous samples representing all 37 unambiguously characterized CEHs at MICA, NFKBIL1, LTA, NCR3, AIF1, HSPA1A, HSPA1B, BF, NOTCH4 and a single nucleotide polymorphism (SNP) at HLA-DQA1 as well as MICA, NOTCH4, HSPA1B and all five tumour necrosis factor short tandem repeat (STR) polymorphisms. This work (1) provides an extensive catalogue of MHC polymorphisms in all CEHs, (2) unravels interrelationships between HLA and non-HLA haplotypical lineages, (3) resolves reported typing ambiguities and (4) describes haplospecific markers for a number of CEHs. Analysis also identified a DQA1 SNP and segments containing MHC class III polymorphisms that corresponded with class II (DRB3 and DRB4) lineages. These results portray the MHC where lineages containing non-HLA and HLA variants in linkage disequilibrium may operate in concert and can guide more thorough design and interpretation of HLA-disease relationships.

3' Untranslated Regions↗
PubMed2000

Magnetic resonance imaging of the knee menisci.

MRI remains the most useful noninvasive test for diagnosis of meniscal tears. Knowledge of normal anatomy and familiarity with patterns of meniscal tears are prerequisites when interpreting MRI studies of the knee. Radiologists should pay close attention to technical factors, normal variants, and associated abnormalities to maintain high diagnostic accuracy. Details of meniscal tears should be described as to best aid in orthopedic decision-making.

Humans↗
PubMed2001

Residues at the active site of the esterase 2 from Alicyclobacillus acidocaldarius involved in substrate specificity and catalytic activity at high temperature.

The recently solved three-dimensional structure of the thermophilic esterase 2 from Alicyclobacillus acidocaldarius allowed us to have a snapshot of an enzyme-sulfonate complex, which mimics the second stage of the catalytic reaction, namely the covalent acyl-enzyme intermediate. The aim of this work was to design, by structure-aided analysis and to generate by site-directed and saturation mutagenesis, EST2 variants with changed substrate specificity in the direction of preference for monoacylesters whose acyl-chain length is greater than eight carbon atoms. Positions 211 and 215 of the polypeptide chain were chosen to introduce mutations. Among five variants with single and double amino acid substitutions, three were obtained, M211S, R215L, and M211S/R215L, that changed the catalytic efficiency profile in the desired direction. Kinetic characterization of mutants and wild type showed that this change was achieved by an increase in k(cat) and a decrease in K(m) values with respect to the parental enzyme. The M211S/R215L specificity constant for p-nitrophenyl decanoate substrate was 6-fold higher than the wild type. However, variants M211T, M211S, and M211V showed strikingly increased activity as well as maximal activity with monoacylesters with four carbon atoms in the acyl chain, compared with the wild type. In the case of mutant M211T, the k(cat) for p-nitrophenyl butanoate was 2.4-fold higher. Overall, depending on the variant and on the substrate, we observed improved catalytic activity at 70 degrees C with respect to the wild type, which was a somewhat unexpected result for an enzyme with already high k(cat) values at high temperature. In addition, variants with altered specificity toward the acyl-chain length were obtained. The results were interpreted in the context of the EST2 three-dimensional structure and a proposed catalytic mechanism in which k(cat), e.g. the limiting step of the reaction, was dependent on the acyl chain length of the ester substrate.

Bacillus↗