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PubMed2000

[Prions, infections and confusions in the "transmissible" spongiform encephalopathies. The other evidence-based science. III. Review].

There are some neurological disorders with a pathological hallmark called spongiosis which include Creutzfeld-Jakob disease and its new variant, the Gertsmann-Straussler-Scheinker Syndrome and the Fatal Familial Insomnia in humans; and Scrapie and Bovine Spongiform Encephalopathy, among others, in animals. The etiological agent has been considered either transmissible or hereditary or both. Curiously, this agent has no nucleic acids, is impossible to filter, is resistant to inactivation by chemical means, has not been cultured and is unobservable at electron microscopy. All of these facts have led to some researches to claim that these agents are similar to viruses appearing in computers. However, after almost fifty years of research, is still not possible to explain why and how such elements produce the diseases commented about. On the contrary, during these years have been possible to know that these entities called slow viral infections, transmissible amyloidosis, transmissible dementia, transmissible spongiform encephalopathies or prion diseases appear in individuals with genetical predispositions exposed to several worldwide immunological stressors. The possibility that prions are the consequence and not the cause of these diseases in animals and man is day by day more reliable, and supports the suggestion that a systematic intoxication due to pesticides as well as mycotoxin ingestion, produced mainly by different molds such as Aspergillus, Penicillium or Fusarium, seem to be the true etiology of these neurodegenerative disorders.

Adolescent↗
PubMed1997

Role of fimbriae F18 for actively acquired immunity against porcine enterotoxigenic Escherichia coli.

Enterotoxigenic (ETEC) and enterotoxaemic (ETEEC) Escherichia (E.) coli that express F18 (F107) fimbriate colonize the small intestine and cause diarrhoea and/or oedema disease in weaned pigs. So far, two antigenic variants of F18 can be distinguished with a common antigenic factor designated 'a' and two specific factors called 'b' and 'c'. In this study the existence of crosswise anti-colonization immunity between E. coli strains that express F18ab or F18ac fimbrial variants, respectively, was demonstrated. Weaned pigs of susceptible genotype with respect to susceptibility to adhesion of E. coli with fimbriae F18 were inoculated with E. coli strains 3064STM (0157:K-:H-:F18ab; resistant to streptomycin) and 8199RIF (0141ab:K-:H4:F18ac; resistant to rifampicin). The faecal shedding was compared subsequent to immunization and homologous or heterologous challenge. An enzyme-linked immunosorbent assay (ELISA) was applied to measure IgA, IgM and IgG antibodies against the F18ab and F18ac antigens in saliva, faeces, serum and intestinal wash samples. About 8 log CFU/g of the inoculated strains were found in faeces of all pigs following immunization as well as in non-immunized controls after challenge. Bacterial counts of the inoculated strains after challenge were between 2 and 5 log lower, without any difference between homologous and heterologous challenge. Intestinal colonization with fimbriated E. coli resulted in production of significantly increased levels of anti-fimbrial antibodies, especially IgA, in serum and intestinal wash samples. There were higher levels of homologous than of heterologous anti-fimbrial antibodies. Production of antibodies against F18a or against another common fimbrial antigen is probably responsible for crosswise anti-colonization immunity between E. coli strains with F18ab and F18ac fimbrial variants. Serum F18-specific IgA may be a useful indicator of a mucosal immune response directed against F18 fimbriae.

Animals↗
PubMed2025

SPC: a SPectral Component approach leveraging Identity-by-Descent graphs to address recent population structure in genomic analysis.

Population structure is a well-known confounder in statistical genetics, particularly in genome-wide association studies (GWAS), where it can lead to inflated test statistics and spurious associations. Traditional methods, such as principal components (PCs), commonly used to adjust for population structure, are limited in capturing fine-scale, non-linear patterns that arise from recent demographic events - patterns that are crucial for understanding rare variant effects. To address this challenge, we propose a novel method called SPectral Components (SPCs), which leverages identity-by-descent (IBD) graphs to capture and transform local, non-linear fine-scale population structure into continuous representations that can be seamlessly integrated into genetic analysis pipelines. Using both simulated datasets and empirical data from the UK Biobank (N ≈ 420,000), we demonstrate that SPCs outperform PCs in adjusting for fine-scale population structure. In simulations, SPCs explained over 90% of the fine-scale population structure with fewer components, while PCs captured less than 5%. In the UK Biobank, SPCs reduced the inflation of p-values in the GWAS of an environmental-driven phenotype by 12% compared to PCs, while maintaining a similar performance to PCs in height, a highly heritable phenotype. Additionally, SPCs improved rare variant association analyses, reducing genomic inflation (e.g., from 7.6 to 1.2 in one analysis), and provided more accurate heritability estimates. Spatial autocorrelation analysis further confirmed the ability of SPCs to account for environmental effects, reducing Moran's I for both environmental and heritable phenotypes more effectively than PCs. Overall, our findings demonstrate that SPCs provide a robust, scalable adjustment for recent population structure, offering a powerful alternative or complement to PCs in large-scale biobank studies.

GWAS↗
PubMed2001

Empirical comparison of DRG variants using cardiovascular surgery data: initial results of a project at 18 German hospitals.

In 2000, the responsibility for selecting a DRG variant for use in Germany was assigned to a body comprising representatives of hospitals and insurers called the Self-Administration Board (or Board in this paper). To help the Board, we applied cardiac surgery data from 18 German hospitals to eight different DRG variants. The error caused by bad coding quality could be minimized this way, since all diagnoses and procedures in cardiac surgery must be recorded for quality assurance purposes. To match the German code to the appropriate code required by the DRG variant, we created mapping tables whenever needed. As far as cardiac surgery is concerned, the Australian AR-DRG and the French GHM variants provided the best medical relevance, while the AR-DRG variant considered the level of severity better. Other variants would have to be updated to better reflect the level of medical complexity. Three main causes for wrong grouping could be identified for all systems: incomplete mapping, not enough reference to multidisciplinary treatments, and system construction problems.

Cardiovascular Diseases↗
PubMed2005

Granulosa cell tumor-like variant of endometrioid carcinoma of the ovary exhibiting nuclear clearing with biotin activity: a subtype showing close macroscopic, cytologic, and histologic similarity to adult granulosa cell tumor.

CONTEXT: The sex cord-like variant of endometrioid carcinoma of the ovary shows many similarities to Sertoli-Leydig cell tumor and granulosa cell tumor. However, few cases of the granulosa cell tumor-like variant have been reported, suggesting this tumor might often be hidden under the diagnosis of granulosa cell tumor. OBJECTIVE: To investigate the similarities and differences between the granulosa cell tumor-like variant of endometrioid carcinoma and granulosa cell tumor of the ovary and to evaluate a newly observed feature, namely, nuclear clearing (or optically clear nuclei), in this variant tumor. DESIGN: A comparative macroscopic, cytologic, histopathologic, and immunohistochemical study in specimens obtained from the following patients: 1 patient with granulosa cell tumor-like variant of endometrioid carcinoma diagnosed by frozen section examination, 3 patients with granulosa cell tumor, and 6 patients with classic endometrioid carcinoma. RESULTS: The granulosa cell tumor-like variant showed close macroscopic, cytologic, and microscopic similarities to granulosa cell tumor. However, the 2 tumors could be differentiated immunohistochemically. The former also showed intense staining for progesterone receptors and contained nonmorular nests that exhibited the so-called nuclear clearing with biotin activity. CONCLUSION: Because the granulosa cell tumor-like variant is pathologically similar to granulosa cell tumor, showing only some dissimilarities to the latter, it can easily be misdiagnosed if the possibility of this variant is not kept in mind. Identification of the typical endometrioid histologic features or related lesions or immunohistochemistry may lead to a proper diagnosis. The observation of nuclear clearing with biotin activity in nonmorular nests suggests that this tumor has endometrioid epithelial characteristics.

Adult↗
PubMed1987

Biological activity, binding, and metabolic fate of Ac-[Nle4, D-Phe7]alpha-MSH4-11NH2 with the F1 variant of B16 melanoma cells.

The alpha-MSH (alpha-melanocyte-stimulating hormone) agonist, Ac-[Nle4, D-Phe7]alpha-MSH4-11NH2 (hereafter called ND4-11 alpha-MSH), is at least 10-fold more potent than alpha-MSH as a stimulus of tyrosinase activity in F1 variant cells of B16 melanoma. The binding to these cells during an incubation with 5 nM (3H)ND4-11 alpha-MSH at 37 degrees C is maximal at 0-30 min, 22 fmol/10(6) cells, but declines to 40% of this value at 4 hr. in the presence of 5 nM (3H)ND4-11 alpha-MSH at 37 degrees C, the acid soluble (cell surface) radioactivity decreased rapidly from 11.4 fmol/10(6) cells at 5 min to 4.6 fmol/10(6) cells at 4 hr. Chromatographic analysis of media and cellular samples revealed that there was no evidence of degradation of (3H)ND4-11 alpha-MSH in the medium but there was evidence of intracellular degradation of (3H)ND4-11 alpha-MSH. Ammonium chloride (10mM) resulted in an increase in acid resistant radioactivity (internalized hormone) at 4 hr. The binding to F1 variant cells during an incubation with 0.155 nM or 5 nM (3H)ND4-11 alpha-MSH at 4 degrees C was constant from 4 hr to 24 hr. Under these conditions, there was no time-dependent change in the acid soluble radioactivity from 4 to 24 hr. Scatchard analysis of (3H)ND4-11 alpha-MSH binding to F1 variant cells at 4 degrees C demonstrated that there were approximately 4500 receptors per cell and an association constant of 17.1 nM-1. These results are consistent with a process of (3H)ND4-11 alpha-MSH binding to its receptor followed by internalization of the receptor-hormone complex and then intracellular degradation of the hormone.

Ammonium Chloride↗
PubMed2002

Genetic characterization of the paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia: A case report and review of the literature.

Paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is characterized by a diffuse proliferation of cells, called paraimmunoblasts, normally located on the pseudoproliferation centers. Patients usually present with multiple lymphadenopathies and a rapid and aggressive progression of the disease. We report a case with paraimmunoblastic variant of SLL/CLL genetically well-characterized by conventional cytogenetics, comparative genomic hybridization (CGH), IgH/BCL-1, IgH/BCL-2, and p53 fluorescent in situ hybridization (FISH) probes and polymerase chain reaction (PCR) for detection of IgH/BCL-2 translocation. A complex karyotype was found, with p53 deletion confirmed by CGH and FISH; however, no translocations involving either BCL-2 or BCL-1 and the immunoglobulin heavy chain gene were identified. A literature review shows only 20 previously reported cases, 6 of which involve genetic studies.

Aged↗
PubMed1999

Expression in vitro of alternatively spliced variants of the messenger RNA for human apolipoprotein E receptor-2 identified in human tissues by ribonuclease protection assays.

The apolipoprotein E receptor-2 (apoER2), also called LR7/8B, is a member of the low-density lipoprotein (LDL)-receptor family that is expressed in brain. We have identified mRNA splicing variants in human tissues by ribonuclease protection assays and found that some variants are preferentially amplified by reverse transcription-polymerase chain reaction (RT-PCR). Transcripts were found that lacked sequences encoding three repeats in the putative ligand-binding domain, the O-linked sugar domain or a novel region in the cytoplasmic domain. When mammalian expression vectors for eight potential protein isoforms were transfected into LDL-receptor-deficient Chinese hamster ovary cells, the proteins were all expressed on the cell surface, as detected by immunoblotting of cell extracts with a specific antipeptide antiserum to apoER2 before and after treatment of intact cells with pronase. Although cells expressing all the variants bound very low-density lipoprotein of beta mobility (beta-VLDL), it was with lower affinity and capacity than binding by the LDL-receptor and none was able to degrade beta-VLDL. Ligand blotting of cell extracts showed that all variants bound recombinant histidine6-tagged receptor-associated protein (His6-RAP) with high affinity, although variants lacking exon 5 bound less strongly. The presence of vestiges of the novel insert in the cytoplasmic domain of apoER2 in the LDL- or VLDL-receptor genes was investigated, but nucleotide sequencing showed that no sequences homologous to it could be detected in the final intron of these genes.

Alternative Splicing↗
PubMed2024

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome. METHODS: Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. RESULTS: In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family. CONCLUSIONS: The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Humans↗
PubMed2003

Targeting the variable surface of African trypanosomes with variant surface glycoprotein-specific, serum-stable RNA aptamers.

African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.

Animals↗
PubMed1980

[The cellular and tissue patterns of so-called embryonal rhabdomyosarcomas. Histological and histochemical investigations (author's transl)].

Embryonal rhabdomyosarcomas consist of two histological variants; it can be distinguished between solid embryonal rhabdomyosarcomas and botryoid sarcomas. We investigated 13 solid and 7 botryoid rhabdomyosarcomas and used 46 biopsies of 20 patients between 6 weeks and 14 years old. There were 12 male and 8 female patients. The histologic examination yielded variations of cytologic pattern and tissue structure. Besides undifferentiated sarcoma cells which constituted the majority of tumor cells and a changing amount of rhabdomyoblastic cells (but only 40% of all tumors showed cells with cytoplasmic cross striation) in 6 solid and 6 botryoid tumors some other cellular features could be observed. There were tumor cells with characteristics of lipoblasts and histiocytes, and occasionally the potency to form vascular spaces was detected, too. The histochemical examination proved the presence of glycosaminoglycans and mucoproteins. The glycosaminoglycans seemed to contain only a few sulphated groups. In agreement with a preceding electron microscopic study of botryoid sarcomas in the nasopharynx (Katenkamp et al. 1979) we stated that many so-called embryonal rhabdomyosarcomas show the basic pattern of an undifferentiated embryonal sarcoma and have some diverging cellular differentiations. Therefore, it is an open question whether the term "embryonal rhabdomyosarcoma" should be defined more precisely than usually done in the routine histological work today.

Adolescent↗
PubMed2003

[Inflammatory leiomyosarcoma: a case report].

We report an additional case of inflammatory leiomyosarcoma, arising in the shoulder of a 31-year-old male. The rare inflammatory variant of leiomyosarcoma tends to affect young adults. Histologically it is characterized by a prominent lymphohistiocytic infiltrate often masking fascicles of spindle cells, as well as the presence of clusters of xanthoma cells and psammoma bodies. Smooth muscle differentiation is supported by desmin and smooth muscle actin expression. The differential diagnosis includes so-called inflammatory 'malignant fibrous histiocytoma'and inflammatory myofibroblastic tumor. The outcome of this variant seems to be favorable.

Adult↗
PubMed1977

Histologic variants of lipid-secreting carcinoma of the breast.

Ten new cases of so-called lipid-secreting carcinomas of the breast are presented. Histopathologic analysis suggests three different microscopical patterns which are all characterized by abundant intracytoplasmic neutral fat deposits. Review of the literature yielded only 15 well-documented cases. Diagnostic problems are emphasized, with special regard to the secretory differentiation of normal and neoplastic mammary cells.

Adult↗
PubMed2006

Biliary cystic tumors with bile duct communication: a cystic variant of intraductal papillary neoplasm of the bile duct.

Biliary cystic tumors, which are also called biliary cystadenoma and cystadenocarcinoma, are thought to be a heterogeneous disease entity, and some of them are known to show a luminal communication to the bile duct. In this study, we examined the clinicopathological features of nine cases of biliary cystic tumors with bile duct communication. They were composed of five males and four females with an average age of 67 years (52-84 years). They were multilocular (eight cases) or unilocular (one case), and all cases contained mucinous fluid. A direct luminal communication with the bile ducts was identified in five cases on preoperative or intraoperative cholangiographies. Biliary cystic tumors examined in this study were histologically adenoma (one case), adenocarcinoma in situ (six cases), and adenocarcinoma associated with microinvasive mucinous carcinoma (two cases). One case of adenocarcinoma in situ also had the adenoma component (adenocarcinoma in adenoma). Dysplastic mucinous epithelium proliferated in flat, micropapillary and papillary fashions within the intracystic spaces. Intraepithelial neoplasm was observed within non-dilated adjacent bile ducts, suggesting a direct luminal communication between the cystic tumors and the bile duct. Ovarian-like stroma was not observed in their walls in any cases. Immunohistochemically, seven cases expressed MUC1 or MUC2 in the neoplastic biliary epithelium. All cases except one were alive without any evidences of tumor recurrence after total excision (3-156 months after surgery). These clinicopathological features resembled those of intraductal papillary neoplasm of the bile duct, which had been reported as a biliary counterpart of pancreatic intraductal papillary mucinous neoplasm. In conclusion, biliary cystic tumors with bile duct communication could be regarded as intraductal papillary neoplasm with a prominent cystic dilatation of the bile duct and mucin retention, rather than true biliary cystic neoplasms.

Adenocarcinoma, Papillary↗
PubMed1989

The osteoblast-like differentiated phenotype of a variant of MG-63 osteosarcoma cell line correlated with altered adhesive properties.

A cell line, called MG-63.3A, was selected for its resistance to detachment from cell culture by a synthetic peptide containing the fibronectin cell-attachment sequence, Arg-Gly-Asp-Ser. The mechanism of this resistance is probably the 6-fold overproduction of the cell surface fibronectin receptor in MG-63.3A cells (Dedhar et al, J. Cell. Biol. 105, 1175-1182, (1987]. Compared to the parental, tumorigenic MG-63 cells, the non-tumorigenic MG-63.3A cells display strikingly different properties. These include an altered morphology, a slower proliferation rate, ability to form a calcified matrix in vitro, increased synthesis of type I collagen and expression of bone type alkaline phosphatase activity. Studies with purified growth factors indicate that the MG-63 and MG-63.3A cell lines respond to differentially to growth factors; the growth of MG-63 cells if stimulated by PDGF and GM-CSF and inhibited IL-1 beta, whereas the growth of MG-63.3A is unaffected by GM-CSF and IL-1 beta but is stimulated by PDGF and estradiol. We conclude from these data that the MG-63.3A cells may represent a more differentiated cell type with osteoblast-like properties. Studies are currently underway to further characterize, by electron microscopy, the calcified matrix formation by MG-63.3A cells.

Alkaline Phosphatase↗
PubMed2002

Identification of a new variant in the YMDD motif of the hepatitis B virus polymerase gene selected during lamivudine therapy.

A new hepatitis B virus variant selected during lamivudine treatment was detected, in which the methionine (rtM204) in the so-called YMDD motif in the C domain of the catalytic site of the polymerase gene was replaced by a serine (rtM204S). This change simultaneously resulted in a tyrosine-195 into valine variant (sY195V) in the surface protein HBsAg. The detection of this YSDD variant was initially observed, after an increase of HBV DNA levels, by sequencing of amplification products from day 586. A specific RFLP assay was developed that could identify 10% of YSDD-containing variants in the virus pool, which enabled detection of this new variant virus at day 506. However, by cloning several PCR products and sequencing individual recombinant clones, the mutation was first identified at day 477, before a significant increase of HBV DNA was observed in serum. The mutation was followed by a leucine to methionine change at position 180 (rtL180M). The consequences of this mutation for disease management and diagnostic strategies are discussed.

Alanine Transaminase↗
PubMed2006

Turboprop: improved PROPELLER imaging.

A variant of periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) MRI, called turboprop, is introduced. This method employs an oscillating readout gradient during each spin echo of the echo train to collect more lines of data per echo train, which reduces the minimum scan time, motion-related artifact, and specific absorption rate (SAR) while increasing sampling efficiency. It can be applied to conventional fast spin-echo (FSE) imaging; however, this article emphasizes its application in diffusion-weighted imaging (DWI). The method is described and compared with conventional PROPELLER imaging, and clinical images collected with this PROPELLER variant are shown.

Algorithms↗