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PubMed2005

Expression of a novel cytokine, IL-4delta2, in HIV and HIV-tuberculosis co-infection.

BACKGROUND: Correcting the Th2 shift in HIV/AIDS represents a potential intervention strategy. However data on interleukin (IL)-4 expression in HIV or AIDS are un-interpretable because of failure to distinguish between IL-4 and its splice variant and natural antagonist, IL-4delta2. OBJECTIVE: To determine Th1 [interferon (IFN)-gamma], IL-4delta2 and Th2 (IL-4) expression in whole blood and lung lavage from healthy volunteers and in HIV or HIV-tuberculosis (TB) co-infection. DESIGN: Cross-sectional with prospective cohort. METHODS: Expression of IL-4delta2, IL-4 and IFN-gamma were determined by quantitative real-time PCR, using unstimulated cells from whole blood and lung lavage, in 20 HIV-TB (pulmonary) co-infected patients, 20 matched HIV-positive controls and 20 HIV-negative healthy volunteers. Results were correlated with plasma viral load, CD4 cell counts, radiological scores and response to anti-TB treatment. RESULTS: Compared to HIV negative donors, stable HIV-positive donors did not have increased levels of mRNA encoding IL-4, IL-4delta2 or IFN-gamma in blood or lavage. By contrast, the HIV-TB co-infected donors had increased IL-4 and IFN-gamma in both compartments. However the antagonist, IL-4delta2 was increased only in lavage. Consequently the dominant form was IL-4delta2 in lavage, but IL-4 itself in blood. The lung IL-4/IFN-gamma ratio correlated with radiological disease extent. With anti-TB treatment, IL-4 levels did not change whilst IL-4delta2 levels increased significantly. CONCLUSIONS: IL-4 and its natural antagonist, IL-4delta2 and are not upregulated in the absence of opportunistic infection. However in HIV-TB co-infection both cytokines increase in lung, but only IL-4 in the periphery. Further studies are required to determine if IL-4 facilitates systemic HIV progression.

AIDS-Related Opportunistic Infections↗

PubMed2006

Phylogeography of the deer mouse (Peromyscus maniculatus) provides a predictive framework for research on hantaviruses.

Phylogeographical partitioning of Sin Nombre and Monongahela viruses (hantaviruses) may reflect that of their primary rodent host, the deer mouse (Peromyscus maniculatus). Lack of a comprehensive assessment of phylogeographical variation of the host has precluded the possibility of predicting spatial limits of existing strains of these viruses or geographical regions where novel viral strains might emerge. The complete cytochrome b gene was sequenced for 206 deer mice collected from sites throughout North America to provide a foundation for future studies of spatial structure and evolution of this ubiquitous host. Bayesian analyses of these sequences partitioned deer mice into six largely allopatric lineages, some of which may represent unrecognized species. The geographical distributions of these lineages were probably shaped by Quaternary climatic events. Populations of mice were apparently restricted to refugia during glacial advances, where they experienced genetic divergence. Expansion of these populations, following climatic amelioration, brought genetically distinctive forms into contact. Occurrence of parallel changes in virus strains can now be explored in appropriate regions. In New Mexico, for example, near the location where Sin Nombre virus was first discovered, there are three genetically distinctive lineages of deer mice whose geographical ranges need to be delineated precisely. The phylogeography of P. maniculatus provides a framework for interpreting geographical variability, not only in hosts, but also in associated viral variants and disease transmission, and an opportunity to predict the potential geographical distribution of newly emerging viral strains.

Animals↗

PubMed1994

Homolog-scanning mutagenesis reveals poliovirus receptor residues important for virus binding and replication.

Poliovirus initiates infection of primate cells by binding to the poliovirus receptor, Pvr. Mouse cells do not bind poliovirus but express a Pvr homolog, Mph, that does not function as a poliovirus receptor. Previous work has shown that the first immunoglobulin-like domain of the Pvr protein contains the virus binding site. To further identify sequences of Pvr important for its interaction with poliovirus, stable cell lines expressing mutated Pvr molecules were examined for their abilities to bind virus and support virus replication. Substitution of the amino-terminal domain of Mph with that of Pvr yields a molecule that can function as a poliovirus receptor. Cells expressing this chimeric receptor have normal binding affinity for poliovirus, yet the kinetics of virus replication are delayed. Results of virus alteration assays indicate that this chimeric receptor is defective in converting native virus to 135S altered particles. This defect is not observed with cells expressing receptor recombinants that include Pvr domains 1 and 2. Because altered particles are believed to be an intermediate in poliovirus entry, these findings suggest that Pvr domains 2 and 3 participate in early stages of infection. Additional mutants were made by substituting variant Mph residues for the corresponding residues in Pvr. The results were interpreted by using a model of Pvr predicted from the known structures of other immunoglobulin-like V-type domains. Analysis of stable cell lines expressing the mutant proteins revealed that virus binding is influenced by mutations in the predicted C'-C" loop, the C" beta-strand, the C"-D loop, and the D-E loop. Mutations in homologous regions of the immunoglobulin-like CD4 molecule alter its interaction with gp120 of human immunodeficiency virus type 1. Cells expressing Pvr mutations on the predicted C" edge do not develop cytopathic effect during poliovirus infection, suggesting that poliovirus-induced cytopathic effect may be induced by the virus-receptor interaction.

Amino Acid Sequence↗

PubMedDate not supplied

Contrast-enhanced MR angiography of the hand.

Contrast material-enhanced magnetic resonance (MR) angiography of the hand noninvasively provides information comparable to that provided by conventional angiography. It is a quick and easy examination that takes less than 5 minutes to perform and produces high-quality images with use of a dedicated surface coil that provides a high signal-to-noise ratio, allowing small pixel size and high spatial resolution. Contrast-enhanced MR angiography requires intravenous injection of gadopentetate dimeglumine and acquisition of a volumetric slab of image data from the hand. This information is then projected with a maximum-intensity-projection algorithm. The technique is generally robust with reproducible findings. Image interpretation requires an understanding of (a) the normal vascular anatomy and anatomic variants of the hand and (b) common vascular diseases. MR angiography of the hand is commonly used to create an arterial "road map" prior to surgery, manage traumatic transection, and identify emboli. Vascular malformations are readily identified and connective tissue disorders including vasculitis are well demonstrated with this technique, which can also be used to assess bone viability following trauma to the carpus or to evaluate the viability of vascularized bone. Common artifacts may be secondary to contracture deformities or "wraparound" effect. However, most potential pitfalls can be avoided by being vigilant.

Adult↗

PubMed1996

Significance of dual left anterior descending coronary artery in interventional cardiology. A case report.

The variants of the left anterior descending (LAD) coronary artery are important in interpretation of coronary angiograms and in interventional procedures. The authors present a patient who had percutaneous transluminal coronary angioplasty and stent implantation to a presumed proximal LAD without the realization that dual LAd was present because of the total occlusion of the long LAD.

Angioplasty, Balloon, Coronary↗

PubMed2002

Association between serotonin transporter gene polymorphism and family history of attempted and completed suicide.

The purpose of this study was to examine the association of the serotonin transporter gene to family history of suicidality. Forty-seven volunteers responded to questionnaires about family history of suicide, and provided buccal swabs for analysis of the polymorphism. Allelic homozygocity (the short variant) was associated with family history of suicidality. These data, to be interpreted with the study's limitations in mind, suggest a link between the serotonin transporter gene polymorphism and suicide-related variables, which should be the focus of future research.

Adult↗

PubMed2001

[Disseminated intravascular coagulation(DIC)].

Disseminated intravascular coagulation (DIC) remains a multifaced syndrome, which may develop with different background and aetiology into venous thromboembolism (mainly chronic, paraneoplastic DIC) or into severe bleeding, factor consumption, thrombocytopenia (i.e. gynaecological acute DIC) or may appear as microthrombotic organ hypoperfusion, organ-failure and necrosis (septic DIC variant). The understanding and consideration of pathogenetic events promotes better identification and interpretation of DIC syndrome and its categories, render more adequate diagnostics and therapy available. The vast majority of new data accumulated in the septic type of DIC, and this general review also tries to put the major emphasis on sepsis-DIC link, laboratory diagnosis and apparent new therapeutic approaches.

Acute Disease↗

PubMed2004

The electrocardiogram in healthy northwest Ethiopians.

The normal values for ECG have not been fully investigated on Ethiopians. This cross sectional study was conducted in 1999/2000 to obtain baseline ECG information on normal healthy northwest Ethiopians and to find out whether normal ranges of ECG parameters in our population differ from those of Caucasians or other black Africans. A standard 12-lead electrocardiogram was done in 690 selected healthy northwest Ethiopians. They were 392 (56.8%) male and 298 (43.2%) female with a median age of 23 years. The systolic and diastolic blood pressures were within the normal range in all subjects. The total incidence of deviation from the accepted normal ECG was recorded in 393 (57.0%) subjects. This was found in 294 (75.0%) male and 99 (33.2%) female subjects. The most common type of "abnormalities" were high peaked T wave, 104 (26.5%), elevated S-T segment, 70 (17.8%), and elevated ST segment with high peaked T wave, 32 (10.9%) in male and negative or flat T wave, 35 (11.7%) in female. All types of variations were more pronounced in young subjects of both sexes and less common in those aged 40 years and above. The normal ECG variants found in Ethiopians were similar to those found in other subjects of black African origin. In conclusion, the normal variants identified in this study must be taken into consideration in the interpretation of ECG from cardiac patients which prevents this useful test from being understood wrongly.

Adult↗

PubMed1991

Nuclear magnetic resonance studies of antibody-antigen interactions.

NMR is a useful method for studying antibody-antigen interactions in solution but the large size of the molecules makes interpretation of the data difficult. Multinuclear NMR and a family of switch variant antibodies and their proteolytic fragments are used to circumvent this problem and investigate the process of molecular recognition in antibody function. An Fv fragment has been prepared in high yield from a mouse IgG2a anti-dansyl-L-lysine monoclonal antibody in which the entire CH1 domain is deleted. 13C NMR resonances are observed for switch variant antibodies selectively labelled by 13C at the carbonyl carbon. Using a double-labelling method, site-specific assignments have been completed for all the methionine resonances in these antibodies. Comparison of the NMR spectra for intact antibodies and those of their proteolytic fragments suggests that carbonyl carbon chemical shift data can provide information on the way in which information is transmitted through different domains on antigen binding. Selective labelling of the antibody with 1H, 13C or 15N followed by nuclear Overhauser effect spectroscopy has identified some of the residues involved in antigen binding and indicated that the structure of the Fv fragment is significantly affected by antigen binding.

Animals↗

PubMed1996

Trans-acting factors regulate the expression of CD44 splice variants.

Variant isoforms of the cell surface glycoprotein CD44 (CD44v) are expressed during development, in selected adult tissues and in certain metastatic tumor cells. CD44v differ from the standard isoform (CD44s) by up to ten additional exon sequences included by alternative splicing. By cell fusion experiments, we have obtained evidence for the existence of cell-type specific trans-acting factors recruiting CD44 variant exon sequences. Stable cell hybrids of CD44s and CD44v expressing cells indicated a dominant mechanism for variant-exon inclusion. In transient interspecies heterokaryons of human keratinocytes and rat fibroblasts, the ability of the keratinocytes to include all variant exon sequences in CD44 was conferred completely on the rat fibroblast nucleus. Fusions of cells with complex CD44 splice patterns do not permit interpretation of splice control by the relative abundance of a single trans-acting factor, but rather by (a) positively acting factor(s) recruiting variant exon sequences in the 3' to 5' direction and additional factors selecting individual exons. Since the pancreatic carcinoma cell line BSp73ASML (in contrast to the cervix carcinoma cell lines SiHa and ME180) could not transfer its specific splice pattern in cell fusions, we conclude that in some tumors, splicing is also controlled by mutation of cis-acting recognition sites.

Alternative Splicing↗

PubMed2006

Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity.

Mutations in the parkin gene, encoding an E3 ubiquitin-protein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitin-protein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.

Amino Acid Motifs↗

PubMed1991

Papillary carcinoma of thyroid with exuberant nodular fasciitis-like stroma. Report of three cases.

Three examples of an unusual morphologic variant of papillary thyroid carcinoma (PTC) are reported. The presence of a prominent stromal component resulted in low-power microscopic appearances resembling fibroadenoma, phyllodes tumor, or fibrocystic disease of the breast in two cases. The carcinomatous component grew in the form of anastomosing narrow tubules, clustered glands, solid sheets with or without squamous differentiation, and/or papillae, and exhibited the typical nuclear features of PTC. The abundant stroma had a nodular fasciitis-like quality and was composed of short fascicles of spindle cells separated by varying amounts of mucoid matrix, collagen, and extravasated red blood cells; this was interpreted as an exuberant mesenchymal reaction to the carcinoma. The importance of recognizing this variant of PTC is that, when one encounters a fibroproliferative lesion of the thyroid, a diligent search should be made for papillary carcinoma. This variant also must be distinguished from the vastly more aggressive papillary carcinomas with anaplastic transformation and the so-called carcinosarcomas.

Adult↗

PubMed2007

Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients.

OBJECTIVE: Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects. METHODS: A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects. RESULTS: Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects. INTERPRETATION: parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined.

Adult↗

PubMed1998

Identification of point mutations in mixtures by capillary electrophoresis hybridization.

We have developed a rapid method for unambiguous identification and mutant fraction determination of individual mutants in mixtures of DNA sequence variants each differing by one or a few nucleotides. This method has applications to such diverse areas as interpretation of mutational spectra, screening of populations for polymorphisms and identification of species in environmental mixtures. In our approach, a mixture of unknown sequences labeled with a fluorescent dye is combined with a set of predetermined sequences (standards) representing the variants to be assayed. Labeling the standards with another dye allows the two sets of variants to be measured independently. Using constant denaturing capillary electrophoresis, the sequence variants are separated as individual peaks on the basis of differential melting equilibria. The unknown sequence variants are initially identified based on co-migration with particular standards. This preliminary identification is verified by hybridization of the unknown variants with the co-migrating standards within the capillary. We demonstrate the use of capillary electrophoresis hybridization to dissect complex mutational spectra of human cells in culture.

Animals↗

PubMed1978

A new variant of methylmalonic acidemia-defective coenzyme-apoenzyme binding in cultured fibroblasts.

Cultured fibroblasts from a patient with methylmalonic acidemia, clinically responsive to vitamin B-12, were studied in vitro. Kinetic analysis revealed abnormal binding of the coenzyme, 5'-deoxyadenosylcobalamin, for its methylmalonyl-CoA carbonylmutase apoenzyme, i.e., KM of 3.8 X 10(-5) M versus control KM of 1.5 X 10(-8) M. These data are interpreted as indicating a structural defect of the apoenzyme at the coenzyme binding site, and represent another variant of this genetic disorder.

Amino Acid Metabolism, Inborn Errors↗

PubMed2002

Acinic-cell carcinoma, papillary-cystic variant: a diagnostic dilemma in salivary gland aspiration.

Fine-needle aspiration (FNA) plays a pivotal role as the initial diagnostic modality of choice when dealing with salivary gland (SG) lesions. Due to the heterogeneous nature of most SG neoplasms, cytologic interpretation on FNA can be quite challenging. This is particularly valid when dealing with rare tumor types, such as the papillary-cystic variant of acinic-cell carcinoma (ACC-PCV), resulting in a high rate of false-negative cytologic diagnoses. Seven cases of ACC-PCV diagnosed on tissue resection with a prior FNA performed in cytology were studied. Material consisted of Diff-Quik and Papanicolaou stained cytologic smears, as well as hematoxylin-eosin stained cell block and histopathologic sections. In no case did the FNA performed prior to the surgical resection eventuate in a cytopathologic diagnosis of cancer. A retrospective morphologic review of the smears disclosed several characteristics common to all 7 cases, i.e., mostly tightly cohesive fragments of neoplastic epithelium seen as monolayered sheets or with a prominent papillary architecture, high nuclear:cytoplasmic ratio ductal-type epithelium, cystic material and degenerated cellular debris, histiocytes, cells with squamoid and metaplastic oncocytic changes, vacuolated and pigmented histiocyte-like tumor cells, and lack of a predominant single-cell component or naked neoplastic cell nuclei. ACC-PCV represents a rare yet significant cause of false-negative results for cancer on SG aspirations. An erroneous interpretation may occur due to lack of experience in dealing with this tumor type, the rarity of published literature on ACC-PCV, and a predominantly cystic, somewhat variegated appearance of the tumor mimicking other benign and malignant SG lesions.

Adenocarcinoma, Sebaceous↗

PubMed2002

Complex variant Philadelphia translocations involving the short arm of chromosome 6 in chronic myeloid leukemia.

BACKGROUND AND OBJECTIVES: Around 5% of chronic myeloid leukemias (CML) are characterized by complex variant Philadelphia (Ph) translocations involving one or more chromosomal regions in addition to 9 and 22. The BCR/ABL1 fusion gene is usually found on der(22). The additional gene(s) involved in complex variant Ph rearrangements have not been characterized. DESIGN AND METHODS: We performed fluorescent in situ hybridization (FISH) in three complex variant Ph translocations involving the short arm of chromosome 6 in addition to 9 and 22. The BCR/ABL1 D-FISH probe was applied to localize the BCR/ABL1 fusion gene as well as the 5'ABL1 and the 3'BCR. Locus-specific probes were used to narrow the 6p breakpoint. RESULTS: In all cases the BCR/ABL1 fusion gene was located on the Ph chromosome whereas the reciprocal ABL1/BCR gene was detected only in patient #2. On 6p, breakpoints were narrowed to three different regions: centromeric to the human major histocompatibility complex (MHC), between PAC 524E15 and PAC162J16, in the first patient, and telomeric to the MHC, between PAC 329A5 and PAC 145H9, and between PAC 136B1 and PAC 206F19, in the second and third patients, respectively. In patients #2 and 3 a chromosomal rearrangement different from a true complex variant was discovered. In both cases, a classical t(9;22) was associated with an additional translocation involving the der(9)t(9;22). INTERPRETATION AND CONCLUSIONS: Rearrangements at 6p in complex Ph aberrations involve more than one gene/locus. Classical t(9;22), masked by additional chromosomal rearrangements, can resemble complex variant Ph translocations, and can be detected only using appropriate FISH probes.

Aged↗

PubMed1982

Variant cell lines from the human promyelocyte line HL60.

The continuous human promyeloid cell line HL60 may be induced to differentiate into neutrophils by the presence of 1.25% dimethylsulphoxide (DMSO) and related compounds [4]. When treated with 12-O-tetradecanoylphorbol-13-acetate (TPA), the cells exhibit may features characteristic of monocytes/macrophages [13]. In both cases, the induced HL60 cells lose their proliferative ability. The availability of this inducible cell line has led to an increasing number of studies aimed at dissecting the process of myeloid differentiation. However, the correct interpretation of such studies may only be reached through the use of appropriate cellular controls; specifically, variant HL60 cell lines which do not differentiate in response to the inducing agents. Here we report the isolation and characterization of two variant cell lines of HL60 which do not differentiate in the presence of 1.25% dimethylsulphoxide but still respond to TPA. Comparison of these HL60 variants with the parental line should facilitate the elucidation of molecular events which regulate myeloid differentiation.

Cell Division↗