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PubMed1980

5'-Nucleotidase activities in cultured rat liver epithelial and fibroblast cells.

Cell cultures of adult rat liver produced two distinct morphologic cell types: epithelial cells polygonal in shape and growing in nests of closely apposed cells, and fibroblast cells stellate in shape with little cell-cell contact at low density growth, but aligning in parallel arrays at high density. These two morphologic variants displayed dramatic differences in histochemically demonstrable 5'-nucleotidase activities. Fibroblast cells exhibited great activity throughout the cytoplasm with no concentration of activity in the cell membrane. The lesser activity in epithelial cells was concentrated on the cell membrane. The importance of this finding to the interpretation of data derived from experiments with whole liver homogenates is discussed.

Animals↗

PubMed1994

Extraspinal abnormalities detected on MR images of the spine.

Surface-coil MR imaging of the spine is one of the most commonly performed MR imaging procedures. As the spine is the region of interest in these studies, extraspinal abnormalities may be overlooked. Such lesions can be difficult to perceive because they are out of the area of interest or distant from the surface coil. MR studies may be interpreted without other radiographic studies for comparison, as the other studies often have been performed elsewhere. Consequently, it is important for radiologists to be aware of the extraspinal anatomy and the appearances of extraspinal abnormalities. We describe the appearances of some common extraspinal diseases and normal variants detected with surface-coil MR imaging of the spine.

Adult↗

PubMed1986

Genetic basis for altered idiotype expression in the hyperimmune response to (4-hydroxy-3-nitrophenyl)acetyl hapten.

To assess the significance of somatic point mutation in the hyperimmune response to the hapten NP, an in vivo enrichment procedure was followed. Mice that expressed high titers of B1-8 idiotopic determinants were selected as donors for serial transfer of small numbers of immune spleen cells into syngeneic irradiated recipient mice. Cells expressing B1-8 idiotopic determinants were chosen for enrichment because B1-8 cross-reactive determinants constitute a significant portion of the primary response. Furthermore, B1-8 is a monoclonal antibody derived from a primary response to NP, and its heavy and light chains are unmutated products of the germ-line genes VH186.2 and VL lambda 1, respectively. The germ-line sequence is thus available for comparison with the somatic mutants that arise during enrichment and hyperimmunization. The data show that serial transfer of spleen cells from mice with a high titer of idiotypic determinants results in a dramatic decrease in the titers of antibodies that bind antigen. Three lines of evidence indicate that progeny cells from the initial lambda-positive, idiotype-bearing, antigen-binding cells are successfully transferred and expanded during successive adoptive transfers. First, the proportion of lambda-bearing antibodies relative to NP-specific lambda-bearing antibodies increases with transfer, which is consistent with mutation away from antigen binding. Second, analysis of serum antibodies and hybridoma proteins derived from transfer-recipient mice confirm the presence of idiotype-positive antibodies that do not bind antigen. Third, RNA dot blot analysis of hybridomas constructed from a recipient mouse in the fourth transfer indicates a high frequency of expression of the VH gene predominantly used in the NP response. Many of the antibodies expressed by these hybridomas not only do not bind antigen, but have also lost the determinants recognized by the anti-idiotypic reagents. Most of these VH-positive hybridomas express lambda L chain. The most likely interpretation of the data is that somatic mutation is occurring during the hyperimmune response. Because we selected donor mice that expressed a high titer of idiotype-positive, antigen-specific antibody and immunized the recipient mice, we expected to observe a selective expansion of somatic variants that bound antigen. This was not the case. The observed loss of antigen binding suggests that the majority of mutations arising result in antibodies with lower affinity for the immunizing antigen.

Animals↗

PubMed1996

Correlation of membrane lipid peroxidation with oxidation of hemoglobin variants: possibly related to the rates of hemin release.

Experiments were performed to delineate the biochemical mechanism of hemoglobin (Hb)-catalyzed lipid peroxidation in human red blood cells (RBCs). Using a modified Langmuir trough lipid monolayer technique, we found that oxidized Hb induced an increase in lipid monolayer surface pressure, suggesting that oxidized Hb readily releases its heme moiety into the lipid monolayer. To confirm our interpretation that oxidized Hb readily releases its heme moiety, we monitored the fluorescence of Hb tryptophan upon oxidation of Hb. We found an increase in Hb fluorescence in the aqueous phase of our monolayer system after the addition of H2O2. The increase in fluorescence should reflect the departure of heme from globin due to a decrease in fluorescent quenching effect by the heme moiety. The rate of increase in lipid monolayer surface pressure upon Hb oxidation differed from Hb to Hb with an order of Hb E > F > S > A. The ability of various Hbs to affect lipid peroxidation in the RBC membrane, as monitored by the parinaric acid oxidation technique, followed this same order. In addition, hemin was shown to be a more potent catalyst of lipid peroxidation in RBC membrane than nonheme irons.

Adult↗

PubMed1981

Variant Turner features in a female with X-isochromosome [46,X, i(Xq)]: is it a distinct clinical entity?

A thirty seven year-old Caucasian female presented with short stature and primary amenorrhea. Employing multiple banding techniques, an isochromosome of the long arm of the X chromosome [i(Xq)] was identified in her peripheral blood and skin fibroblast cultures. This chromosomal abnormality can be interpreted as 46,X,i(X)(qter leads to cen leads to qter). The i(Xq) is late replicating and selectively inactive. The present case was found to have minimal abnormal features when compared with previously published cases. Since patients with i(Xq) have quite variable clinical features, the existence of a distinct clinical entity of "X-isochromosome syndrome" is questioned.

Adult↗

PubMed2005

Comparison between MAP and postprocessed ML for image reconstruction in emission tomography when anatomical knowledge is available.

Previously, the noise characteristics obtained with penalized-likelihood reconstruction [or maximum a posteriori (MAP)] have been compared to those obtained with postsmoothed maximum-likelihood (ML) reconstruction, for emission tomography applications requiring uniform resolution. It was found that penalized-likelihood reconstruction was not superior to postsmoothed ML. In this paper, a similar comparison is made, but now for applications where the noise suppression is tuned with anatomical information. It is assumed that limited but exact anatomical information is available. Two methods were compared. In the first method, the anatomical information is incorporated in the prior of a MAP-algorithm and is, therefore, imposed during MAP-reconstruction. The second method starts from an unconstrained ML-reconstruction, and imposes the anatomical information in a postprocessing step. The theoretical analysis was verified with simulations: small lesions were inserted in two different objects, and noisy PET data were produced and reconstructed with both methods. The resulting images were analyzed with bias-noise curves, and by computing the detection performance of the nonprewhitening observer and a channelized Hotelling observer. Our analysis and simulations indicate that the postprocessing method is inferior, unless the noise correlations between neighboring pixels are taken into account. This can be done by applying a so-called prewhitening filter. However, because the prewhitening filter is shift variant and object dependent, it seems that MAP reconstruction is the more efficient method.

Algorithms↗

PubMed2004

Depth estimation and image restoration using defocused stereo pairs.

We propose a method for estimating depth from images captured with a real aperture camera by fusing defocus and stereo cues. The idea is to use stereo-based constraints in conjunction with defocusing to obtain improved estimates of depth over those of stereo or defocus alone. The depth map as well as the original image of the scene are modeled as Markov random fields with a smoothness prior, and their estimates are obtained by minimizing a suitable energy function using simulated annealing. The main advantage of the proposed method, despite being computationally less efficient than the standard stereo or DFD method, is simultaneous recovery of depth as well as space-variant restoration of the original focused image of the scene.

Algorithms↗

PubMed2026

Molecular residual disease assessment in colorectal and bladder cancer by somatic structural variant analysis of cell-free DNA whole-genome sequencing data.

BACKGROUND: Whole-genome sequencing (WGS)-based methods for circulating tumor DNA (ctDNA) detection typically rely on tumor-informed identification of somatic single nucleotide variants (SNVs). Somatic structural variants (SVs) are another type of cancer-specific genomic alteration, which owing to their larger genomic footprint and unique breakpoint junctions, are easier to distinguish from sequencing noise than SNVs. They are, however, rarely used for ctDNA detection because of (1) artifacts from WGS procedures that SV callers may falsely interpret as genuine SVs. This makes it difficult to establish high-confidence SV catalogos from short-read tumor WGS and can cause false-positive ctDNA detections. (2) Lack of robust strategies to quantify SV-supporting reads in plasma WGS. To address these barriers and enable integration of SV biomarkers into WGS-based ctDNA detection, we present a bioinformatic framework for algorithmic curation of somatic SV calls from fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tumors, coupled with a novel approach for sensitive, accurate mapping and quantification of SV breakpoint-supporting reads in plasma WGS. METHODS: Tumor, normal and plasma WGS data from 144 patients with stage III colorectal cancer was used to establish the bioinformatic framework. This included ~30x WGS data from 1564 serially collected plasma samples. The framework was validated using tumor/normal/plasma WGS data from 32 patients with muscle-invasive bladder cancer. SV-based ctDNA detection was benchmarked against previously published SNV-based ctDNA results for the same samples. RESULTS: After curation of SV calls and quantification in plasma WGS, our SV-based approach enabled robust ctDNA detection with overall specificity exceeding 99% in plasma samples. Furthermore, we observed strong concordance (Pearson’s r > 0.93, p < 2.2 × 10− 16) between ctDNA-positive samples identified by our SV-based method and previous SNV-based analyses, validating the reliability of our approach. Finally, we demonstrated application of the method in an independent bladder cancer cohort, highlighting its generalizability and potential clinical use. CONCLUSIONS: We provide a bioinformatic framework that establishes somatic SVs as ultra-specific biomarkers for WGS-based, tumor-informed ctDNA detection. The approach delivers specific detection even when the SV catalogos are established from FFPE samples. The SV framework can stand alone or enhance SNV-based analysis pipelines.

Humans↗

PubMed1988

Cerebral venous sinuses: anatomical variants or thrombosis?

Anatomical variations of the posterosuperior dural venous sinuses and, in particular, the absence or hypoplasia of one of them has been described in several studies. However, no recent detailed analysis on the subject exists. Cerebral venous thrombosis is quite often evoked, although rarely confirmed, when the physician is faced with patients having various neurological problems. In fact, for a number of cases the image interpreted as thrombosis is nothing but the total or partial absence of a dural sinus. It was considered of interest to undertake an anatomical study in order to define these variations. The results of anatomoradiological investigations of 70 fresh cadavers were compared to those obtained by angiographic examination of 100 patients not suffering from any kind of venous pathology (patients explored angiographically for glioma, meningioma or aneurysm). Our conclusions and a review of the embryology literature enabled us to demonstrate that a number of radiological findings, quite often considered pathognomonic of venous thrombosis (i.e. 'delta sign'), are in fact the result of anatomical variations.

Cerebral Veins↗

PubMed1997

Patterns of amino acid variability in NSI-like and SI-like V3 sequences and a linked change in the CD4-binding domain of the HIV-1 Env protein.

The V3 domain plays a central role in the biology of the HIV-1 Env glycoprotein gp 120 as a dominant target for neutralizing antibodies for some HIV-1 isolates, and as a major determinant in the switch from the nonsyncytium-inducing (NSI) to the syncytium-inducing (SI) form of HIV-1 that is associated with accelerated disease progression. Basic amino acid substitutions are known to play an important role in the SI phenotype. We have used the presence of basic amino acid substitutions in V3 sequences to divide sequences in a large data base into SI-like and NSI-like. We found significant differences in features of sequence variability between these two groups of sequences. Of the thirty-six most frequent substitutions in V3, twenty appear disproportionately among either the SI-like sequences or the NSI-like sequences. The fourteen favored substitutions among the SI-like sequences account for 50% of the twofold increased variability seen in this group. In addition, we found a linked change within the CD4-binding domain of gp 120 downstream of V3. These differences are interpreted in the context of structure, function, and selective pressure. An understanding of these patterns of sequence variability offers the possibility of designing a degenerate SI-specific V3 immunogen to use as a therapeutic vaccine with the hope of slowing or preventing the appearance of SI variants.

Amino Acid Sequence↗

PubMed1986

Restriction endonuclease map variation in the Adh region in populations of Drosophila melanogaster.

Variation within a 12-kb region of the second chromosome of Drosophila melanogaster which includes the Adh transcriptional unit was studied in 59 isochromosomal lines drawn from two populations. A number of restriction-fragment length polymorphisms due to both restriction-site presence/absence and insertions/deletions were revealed and the proportion of polymorphic nucleotides was estimated as 0.017 in population "Chateau Tahbilk" and 0.025 in population "Groningen." The presence within population Groningen of two complementary haplotypes at a high frequency was noted and its possible origin is discussed. The distribution of insertion/deletion variants within the populations was consistent with an associated deleterious effect and significant clustering of such variants to a 1-kb region approximately 4 kb from the transcriptional unit was also revealed. Analysis of gametic disequilibrium showed that its intensity was not related to the physical distance separating the markers on the chromosome and that strong disequilibria may flank weaker disequilibria. Two alternative interpretations of these data are advanced based upon natural selection and the hitchhiking effect of a favorable mutation. Comparisons of gametic disequilibrium among the four populations now surveyed at this locus were made using model fitting by weighted least squares and several significant contrasts were revealed.

Alcohol Dehydrogenase↗

PubMed2001

Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases.

BACKGROUND: In 1998, the US Centers for Disease Control and Prevention was notified of three patients who developed severe illnesses days after yellow fever vaccination. A similar case occurred in 1996. All four patients were more than 63 years old. METHODS: Vaccine strains of yellow fever virus, isolated from the plasma of two patients and the cerebrospinal fluid of one, were characterised by genomic sequencing. Clinical samples were subjected to neutralisation assays, and an immunohistochemical analysis was done on one sample of liver obtained at biopsy. FINDINGS: The clinical presentations were characterised by fever, myalgia, headache, and confusion, followed by severe multisystemic illnesses. Three patients died. Vaccine-related variants of yellow fever virus were found in plasma and cerebrospinal fluid of one vaccinee. The convalescent serum samples of two vaccinees showed antibody responses of at least 1:10240. Immunohistochemical assay of liver tissue showed yellow fever antigen in the Kuppfer cells of the liver sample. INTERPRETATION: The clinical features, their temporal association with vaccination, recovery of vaccine-related virus, antibody responses, and immunohistochemical assay collectively suggest a possible causal relation between the illnesses and yellow fever vaccination. Yellow fever remains an important cause of illness and death in South America and Africa; hence, vaccination should be maintained until the frequency of these events is quantified.

Adverse Drug Reaction Reporting Systems↗

PubMed2000

Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasms.

The majority of renal neoplasms can be distinguished on the basis of histologic examination alone; however, there are morphologic similarities between clear cell renal carcinoma and chromophobe cell carcinoma, as well as between the granular/eosinophilic variants of these tumors and renal oncocytoma. Only a limited number of histochemical markers are available to aid in the differential diagnosis of these neoplasms. Hale's colloidal iron usually yields strong, diffuse cytoplasmic staining of chromophobe cell carcinomas whereas clear cell carcinomas are generally negative; however, interpretation of this stain is not always straightforward. By immunohistochemistry, vimentin is detectable in most clear cell carcinomas and is absent from most chromophobe cell tumors and oncocytomas, but reliance on a single antibody can be misleading. In this report we examine the use of commercially available monoclonal antibodies to RCC and CD10 in the differential diagnosis of common renal tumors. Eighty-five percent of clear cell carcinomas (53 of 62) had detectable surface membrane staining for RCC, and 94% (58 of 62) were positive for CD10. Papillary carcinomas were likewise strongly positive for RCC and CD10 in nearly all cases (13 of 14 each). In contrast, all 19 chromophobe cell carcinomas examined were completely negative for surface membrane staining with both of these markers. Oncocytomas were also negative for RCC (0 of 9), but CD10 was detectable in some cases (3 of 9). These results suggest that the presence of surface membrane staining for RCC and CD10 may be used to confirm a diagnosis of suspected clear cell or papillary renal carcinoma. Chromophobe cell carcinomas should be negative for both markers. The absence of RCC staining may also be helpful in the diagnosis of renal oncocytoma.

Adenocarcinoma, Clear Cell↗

PubMed1981

Effect of test system on the ability of monoclonal antibodies to detect antigenic drift in influenza A(H1N1) virus haemagglutinins.

Results of analysing antigenic variation in the haemagglutinin (HA) molecule of naturally occurring influenza A (H1N1) viruses from 1977 to 1979 with monoclonal antibodies were found to be dependent in some instances on the test system used. In several instances A/USSR/90/77 HA-specific monoclonal antibodies had sharply reduced haemagglutination-inhibition (HI) titres with variant virus although they bound to the variant and A/USSR/90/77 HAs with similar efficiencies as judged by titration in a sensitive and accurate solid-phase immunofluorimetric assay. In another instance, the converse situation was observed: monoclonal antibodies having a reduced efficiency of binding to the HA of a variant virus nevertheless had comparable HI titres with the variant and with A/USSR/90/77. The chemical basis and epidemiological significance of these observations remain to be elucidated. Nevertheless, the finding that the reaction of monoclonal antibodies can, in some cases, be markedly dependent on the test system employed is of significance for the efficient design and correct interpretation of immunochemical studies which employ monoclonal antibodies to investigate the basis for variation in influenza strains.

Antibodies, Monoclonal↗

PubMed2025

Inference and visualization of complex genotype-phenotype maps with gpmap-tools.

Understanding how biological sequences give rise to observable traits, that is, how genotype maps to phenotype, is a central goal in biology. Yet our knowledge of genotype-phenotype maps in natural systems is limited due to the high dimensionality of sequence space and the context-dependent effects of mutations. The emergence of Multiplex assays of variant effect (MAVEs), along with large collections of natural sequences, offer new opportunities to empirically characterize these maps at an unprecedented scale. However, tools for statistical and exploratory analysis of these high-dimensional data are still needed. To address this gap, we developed gpmap-tools (https://github.com/cmarti/gpmap-tools), a python library that integrates a series of models for inference, phenotypic imputation, and error estimation from MAVE data or collections of natural sequences in the presence of genetic interactions of every possible order. gpmap-tools also provides methods for summarizing patterns of epistasis and visualization of genotype-phenotype maps containing up to millions of genotypes. To demonstrate its utility, we used gpmap-tools to infer genotype-phenotype maps containing 262,144 variants of the Shine-Dalgarno sequence from both genomic 5'UTR sequences and experimental MAVE data. Visualization of the inferred landscapes consistently revealed high-fitness ridges that link core motifs at different distances from the start codon. In summary, gpmap-tools provides a flexible, interpretable framework for studying complex genotype-phenotype maps, opening new avenues for understanding the architecture of genetic interactions and their evolutionary consequences.

Gaussian process↗

PubMed2001

Effect of polymorphisms on ligand binding by mouse major urinary proteins.

Mouse urine contains an abundance of major urinary proteins, lipocalins, whose roles include slow release of semiochemicals. These proteins are highly polymorphic, with small sequence differences between individual members. In this study, we purified to homogeneity four of these proteins from two strains of inbred mice and characterized them by mass spectrometry. This analysis has led to the discovery of another variant in this group of proteins. Three of the polymorphic variants that map to the surface have no effect on the binding of a fluorescent probe in the binding cavity, but the fourth, characterized by a Phe to Val substitution in the cavity, shows a substantially lower affinity and fluorescence yield for the probe. These results are interpreted in light of the known crystal structure of the protein and molecular modeling calculations, which rationalize the experimental findings. This work raises the possibility that the calyx-binding site can show specificity for different ligands, the implications of which on pheromone binding and chemical communication are discussed.

1-Naphthylamine↗

PubMed1991

Effect of abdominal straining on urinary flow rate in normal males.

The measurement of urinary flow rate by uroflowmetry and its relationship to voided volume and age have been extensively studied. It is well recognised that some men void with abdominal straining, but any effect of this on the urinary flow rate is usually not taken into account in urological practice. The aim of this study was to determine whether abdominal straining had any significant influence on the urinary flow rate. Three male volunteers performed multiple voidings either with or without abdominal straining. Statistical transformation of the data and the use of co-variant analysis allowed a comparison between "normal" or passive voiding and voiding with abdominal straining. The results showed that abdominal straining caused a significant improvement in both the average and maximum urinary flow rate. If the effect of abdominal straining is not taken into account during the interpretation of uroflowmetry results, incorrect conclusions may be made which could influence subsequent management. It is suggested that the method of voiding should be standardised by instructing patients, if possible, to avoid abdominal straining during uroflowmetry assessment.

Abdomen↗

PubMed1981

Radiological appearances of the xiphoid process presenting as an upper abdominal mass.

In three patients prominent, jointed xiphoid processes were confused with abdominal masses on clinical examination. In the first case, ultrasound showed acoustic shadowing at the site of the xiphoid extension. This was interpreted as a calcified abdominal mass prior to obtaining a lateral chest radiograph, which showed it to be a jointed extension from the normal xiphoid process. In the other two cases, the mass was recognized on ultrasound as a jointed xiphoid process. Awareness of this important normal variant can prevent unnecessary surgery.

Abdominal Neoplasms↗