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PubMed1995

Serum lipoprotein(a) concentrations and apolipoprotein(a) phenotypes in the families of NIDDM patients.

We studied the quantitative and qualitative characteristics of lipoprotein(a) [Lp(a)] as a function of apolipoprotein(a) [apo(a)] phenotype in 87 members (42 males, 45 females) of 20 diabetic families, 26 of whom were diagnosed with non-insulin-dependent diabetes mellitus (NIDDM) with moderate glycaemic control (HbA1c 7.1 +/- 1.2%). Apo(a) phenotyping was performed by a sensitive, high-resolution technique using SDS-agarose/gradient PAGE (3-6%). To date, 26 different apo(a) phenotypes, including a null type, have been identified. Serum Lp(a) levels of NIDDM patients and non-diabetic members of the same family who had the same apo(a) phenotypes were compared, while case control subjects were chosen from high-Lp(a) non-diabetic and low-Lp(a) nondiabetic groups with the same apo(a) phenotypes in the same family. Serum Lp(a) levels were significantly higher in NIDDM patients than in non-diabetic subjects (39.8 +/- 33.3 vs 22.3 +/- 19.5 mg/dl, p < 0.05). The difference in the mean Lp(a) level between the diabetic and non-diabetic groups was significantly (p < 0.05) greater than that between the high-Lp(a) non-diabetic and low-Lp(a) non-diabetic groups. An analysis of covariance and a least square means comparison indicated that the regression line between serum Lp(a) levels [log Lp(a)] and apo(a) phenotypes in the diabetic patient group was significantly (p < 0.01) elevated for each apo(a) phenotype, compared to the regression line of the control group. These data together with our previous findings that serum Lp(a) levels are genetically controlled by apo(a) phenotypes, suggest that Lp(a) levels in diabetic patients are not regulated by smaller apo(a) isoforms, and that serum Lp(a) levels are greater in diabetic patients than in non-diabetic family members, even when they share the same apo(a) phenotypes.

Apolipoproteins↗

PubMed2007

Power matters in closing the phenotyping gap.

Much of our understanding of physiology and metabolism is derived from investigating mouse mutants and transgenic mice, and open-access platforms for standardized mouse phenotyping such as the German Mouse Clinic (GMC) are currently viewed as one powerful tool for identifying novel gene-function relationships. Phenotyping or phenotypic screening involves the comparison of wild-type control mice with their mutant or transgenic littermates. In our study, we explored the extent to which standardized phenotyping will succeed in detecting biologically relevant phenotypic differences in mice generated and provided by different collaborators. We analyzed quantitative metabolic data (body mass, energy intake, and energy metabolized) collected at the GMC under the current workflow, and used them for statistical power considerations. Our results demonstrate that there is substantial variability in these parameters among lines of wild-type C57BL/6 (B6) mice from different sources. Given this variable background noise in mice that serve as controls, subtle phenotypes in mutant or transgenic littermates may be overlooked. Furthermore, a phenotype observed in one cohort of a mutant line may not be reproducible (to the same extent) in mice coming from a different environment or supplier. In the light of these constraints, we encourage researchers to incorporate information on intrastrain variability into future study planning, or to perform advanced hierarchical analyses. Both will ultimately improve the detectability of novel phenotypes by phenotypic screening.

Animals↗

PubMed2002

Phenotyping of human glutathione S-transferase hGSTT1-1: a comparison of two ex vivo routine procedures.

The human glutathione S-transferase hGSTT1-1 is characterized by a polymorphism displaying three phenotypes: the "non-conjugator" (NC) phenotype expresses no or only a residual activity due to a homozygous deletion of the hGSTT1 gene, a medium hGSTT1-1 activity can be demonstrated for the "low conjugator" (LC) phenotype as the heterozygous bearer of one hGSTT1 allele, and a high hGSTT1-1 activity is detected for the "high conjugator" (HC) phenotype as the homozygous bearer of two hGSTT1 alleles. We have developed a routine ex vivo photometric phenotyping procedure based on the determination of bromide release rates from the hGSTT1-1-catalyzed glutathione conjugation of the substrate methyl bromide in EDTA blood samples under standard conditions (1,000 ppm methyl bromide, 10 min incubation). The bromide release rates were standardized to the hemoglobin (Hb) value. Twenty-six individuals were phenotyped following the new procedure. Four individuals were classified as NCs (24-33 pmol Br(-)/mg Hb per min), 21 individuals were regarded as LCs (107-206 pmol Br(-)/mg Hb per min) and one person of the study group was designated HC (236 pmol Br(-)/mg Hb per min). The results were validated by qualitative hGSTT1 genotyping and demonstrated a 100% match for conjugators and non-conjugators. A second HPLC phenotyping routine procedure based on the formation of S-methylglutathione from methyl chloride in erythrocyte lysate incubations (Müller et al. 2001, Arch Toxicol 74:760-767) was established and validated by genotyping. The phenotyping results obtained with both methods were correlated, resulting in a good correlation with R(2)=0.64 (y=0.8997x +51.535). Three distinct phenotype clusters for NCs, LCs and HCs, consistent with the proposed genetics, were demonstrated. Assay-dependent storage experiments revealed an excellent stability of the hGSTT1-1 activity. In conclusion, the evaluated methods provide powerful tools for determination of hGSTT1-1 activity as a clinical parameter.

Adult↗

PubMed2003

Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells.

PURPOSE: It is well known that gastric cancers (GCs) at early stages, independent of the histological type, mainly consist of gastric phenotype malignant cells, while those at advanced stage tend to have a more intestinal phenotype with progression. However, the connection between this shift and expression of homeobox genes, which are important factors to maintain tissue character, has remained unclear. We therefore evaluated the expression of Cdx1/2 in relation to the phenotype of GCs. METHODS: We analyzed the expression of Cdx1/2 mRNAs by Northern blotting and Cdx2 protein by immunohistochemistry in seventy advanced GCs, and evaluated phenotypically using mucin- and immunohistochemistry. RESULTS: Seventy GCs were divided phenotypically into 16 gastric (G type), 18 gastric and intestinal mixed (GI type), 18 intestinal (I type), and 18 null (N type) phenotypes, independent of the histological classification. Cdx1 and Cdx2 mRNAs statistically demonstrated an increase with shift from G to I ( P=0.042 and P=0.0082, respectively). Cdx2 nuclear staining was observed immunohistochemically in the intestinal phenotypic cancer cells, but could not be detected in those with only the gastric phenotype. CONCLUSIONS: These results show that Cdx1 and Cdx2 might be indispensable for intestinal phenotypic expression even in gastric cancer cells.

Biomarkers, Tumor↗

PubMed1981

Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: relationship to dysbetalipoproteinemia and hyperlipidemia.

The largest reported kindred of a proband with type III hyperlipoproteinemia was investigated by assessment of lipid and lipoprotein levels and very low density lipoprotein (VLDL) isoapolipoprotein E distributions in all accessible family members (56% of the 124 living blood relatives and 59% of the 37 spouses). The results confirm in this kindred a trimodal distribution of apoE3/E2 ratios, and segregation analysis of 16 informative matings classified according to E3/E2 ratio demonstrated classical Mendelian inheritance of the autosomal codominant type: the E3/E2 ratio is determined by two alleles, apoE3d and apoE3n, which produce three phenotypes apoE3-D, apoE3-ND, and apoE3-N, corresponding to the low, intermediate, and high modes, respectively. Vertical transmission of the apoE3-D phenotype occurred in two branches of the second generation. In both instances this represented pseudodominance; i.e., products of heterozygous (apoE3-ND) x homozygous (apoE3-D) matings. Hyperlipidemia (defined as a low density lipoprotein cholesterol and/or plasma triglyceride level exceeding the respective age-, sex-, and sex-steroid-specific 95th percentiles derived from Lipid Research Clinics population studies) was present in 15 blood relatives in multiple lipoprotein patterns, consistent with the presence of familial combined hyperlipidemia in this kindred. Eight of nine members with the apoE3-D phenotype had either type III hyperlipoproteinemia or, in the absence of hyperlipidemia, beta-VLDL and at least marginally cholesterol-rich VLDL (VLDL-cholesterol/plasma triglyceride greater than 0.25) (defined as dysbetalipoproteinemia). The ninth such member, the only child with this phenotype, was normal. beta-VLDL and marginally cholesterol-rich VLDL was seen in but one of six hyperlipidemic family members of phenotype apoE3-ND, in none of seven hyperlipidemic blood relatives of phenotype apoE3-N, in no normolipidemic family members of phenotype apoE3-ND or apoE3-N, and in no spouses (three of whom were hyperlipidemic and nine of phenotype apoE3-ND). Thus, among adult members of the O'D kindred the apo3-D phenotype was nearly specifically associated with dysbetalipoproteinemia or, when hyperlipidemia was present, type III hyperlipoproteinemia.

Adolescent↗

PubMed1984

Further studies of the RNA synthesis phenotype selected during persistent infection with vesicular stomatitis virus.

Vesicular stomatitis virus (VSV) isolated from two independently established lines of persistently infected mouse L cells expressed an altered phenotype of RNA synthesis at 37 degrees, the temperature at which the persistently infected cultures were maintained (T.K. Frey and J.S. Youngner, 1982, J. Virol. 44, 167-174). In comparison to the viruses used to initiate the two lines, wild-type (wt) VSV and ts-0-23 (ts-, RNA+ complementation group III), the VSV expressing this RNA phenotype synthesized much less mRNA but equal or greater amounts of 40 S genomic RNA (rt- phenotype). In the line initiated with wt-VSV, at 17 days after initiation, when 85% of the clones were ts-, 36% of the ts- clones were rt-. By 63 days the VSV-PI population was uniformly ts- and rt- and this phenotype prevailed for at least 2 years of persistence. In the line initiated with ts-0-23, the rt- phenotype was stable for at least 3 years of persistence. To study the relationship of the ts- and rt- phenotypes which were coselected during persistence, ts+ revertants of a ts- rt- VSV-PI clone were isolated. All of the ts+ revertants expressed a wt-VSV phenotype of RNA synthesis at 37 degrees (rt+), indicating that the two phenotypic markers may be pleiotropic manifestations of the same mutation. rt-VSV inhibited host cell RNA and protein synthesis more slowly than did wt-VSV. However, rt-VSV synthesized equivalent or greater amounts of all the virus proteins, compared to wt-VSV, despite the reduced amount of mRNA transcription. The attenuated shutoff of host cell macromolecular synthesis by rt- VSV and the concomitant efficient 40 S genome replication and virus protein synthesis may in part explain the selective advantage of the rt- mutation during persistence. The rt- phenotype was not unique to persistent infection; ts- rt- mutants also evolved during serial undiluted passages of wt-VSV in L cells and one ts- rt- mutant was identified in a group of spontaneous mutants isolated from a wt-VSV stock.

Animals↗

PubMed2004

Haptoglobin phenotypes and malaria infection in pregnant women at delivery in western Cameroon.

Plasmodium falciparum-infected erythrocytes have been reported to sequester in the placenta by adhering to chondroitin 4-sulfate during pregnancy. Earlier studies have highlighted higher susceptibility of primigravidae to P. falciparum compared to multigravidae living within the same endemic areas. The haptoglobin phenotype (Hp1-1) has been associated with susceptibility to severe P. falciparum malaria and the presence of Hp in human endometrium has been reported. The possible role of different Hp phenotypes in susceptibility to or protection from placental infection by P. falciparum in both primigravid and multigravid women at delivery in western Cameroon was investigated in this study. Only the three major haptoglobin phenotypes; Hp1-1, Hp2-1 and Hp2-2, were found in the study population with the Hp1-1 phenotype being the predominant (53%). There was no significant difference in the distribution of the three Hp phenotypes between the two gravidity groups. Women carrying the Hp1-1 phenotype had higher parasite prevalences in both peripheral blood (21.6% against 9.1%) and placentas (42% against 16.7%) when compared to those with the Hp2-2 phenotype. The difference in the parasite density between women carrying the Hp1-1 and Hp2-2 phenotypes was statistically significant for placental infection (P=0.001) but not for maternal peripheral blood infection. Placental parasitaemias without peripheral blood parasitaemias were detected in 42.6% of all the P. falciparum positive women while 27.7% of the women had peripheral blood parasitaemias in the absence of placental infection and 29.8% of the women had both placental and peripheral blood parasitaemias. A statistically significant difference was observed between the primigravidae and multigravidae in the parasite density in placental biopsies (P=0.02) but not for maternal peripheral blood parasitaemia. Our data suggest that the Hp1-1 phenotype may play a role in susceptibility to placental infection by P. falciparum during pregnancy.

Adult↗

PubMed2004

Role of Rho-kinase in maintaining airway smooth muscle contractile phenotype.

This study aims to investigate the role of Rho-kinase in phenotype switching and proliferation of bovine tracheal smooth muscle. To induce different phenotypic states, bovine tracheal smooth muscle strips were cultured (8 days) in 10% foetal bovine serum (foetal bovine serum, less contractile phenotype) or insulin (1 microM, hypercontractile phenotype) and compared to strips cultured in serum-free medium. In contraction experiments, the Rho-kinase inhibitor (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide (Y-27632, 1 microM) decreased sensitivity to methacholine and KCl and lowered maximal responsiveness to KCl in all strips irrespective of the phenotype present. To investigate the effects of Rho-kinase bovine tracheal smooth muscle phenotypic regulation, strips were pretreated with Y-27632 (1 microM) for 8 days. This resulted in a decreased maximal contractility to both methacholine and KCl, quantitatively comparable to the decrease in contractility induced by platelet-derived growth factor (PDGF, 10 ng/ml). The combination of Y-27632 and PDGF responded additively. Y-27632 did not affect basal or PDGF-induced bovine tracheal smooth muscle cell proliferation, determined both as increases in [3H]thymidine incorporation and cell number. Inhibitors of the p42/p44 mitogen-activated protein kinase (MAPK) pathway, the p38 MAPK pathway and the phosphatidyl inositol (PI) 3-kinase pathway all inhibited PDGF-induced proliferation and phenotype changes. These results show that the functional contribution of Rho-kinase to bovine tracheal smooth muscle contraction is not dependent on phenotypic state. In addition, Rho-kinase is not involved in phenotypic modulation or proliferation induced by PDGF, whereas p42/p44 MAPK, p38 MAPK and PI 3-kinase are. Rho-kinase is, however, a major regulator involved in the basal maintenance of contractility in bovine tracheal smooth muscle.

Animals↗

PubMed1990

Neophenogenesis: a developmental theory of phenotypic evolution.

An important task for evolutionary biology is to explain how phenotypes change over evolutionary time. Neo-Darwinian theory explains phenotypic change as the outcome of genetic change brought about by natural selection. In the neo-Darwinian account, genetic change is primary; phenotypic change is a secondary outcome that is often given no explicit consideration at all. In this article, we introduce the concept of neophenogenesis: a persistent, transgenerational change in phenotypes over evolutionary time. A theory of neophenogenesis must encompass all sources of such phenotypic change, not just genetic ones. Both genetic and extra-genetic contributions to neophenogenesis have their effect through the mechanisms of development, and developmental considerations, particularly a rejection of the commonly held distinction between inherited and acquired traits, occupy a central place in neophenogenetic theory. New phenotypes arise because of a change in the patterns of organism-environment interaction that produce development in members of a population. So long as these new patterns of developmental interaction persist, the new phenotype(s) will also persist. Although the developmental mechanisms that produce the novel phenotype may change, as in the process known as "genetic assimilation", such changes are not necessary in order for neophenogenesis to occur, because neophenogenetic theory is a theory of phenotypic, not genetic, change.

Animals↗

PubMed2001

The influence of apo E phenotypes on the plasma triglycerides response to hormonal replacement therapy during the menopause.

OBJECTIVE: To study the influence of apo E phenotype in plasma lipids, especially in triglycerides levels, in menopausal women receiving hormonal replacement therapy (HRT). METHODS: One hundred and ten postmenopausal women were studied. Plasma total cholesterol (TC), HDL-C and triglycerides (TG) were measured before and after 3 months of HRT and the apo E phenotype was determined. According to the apo E phenotype the sample was divided into three groups: E2/E3 (n=28), E3/E3 (n=96) and E4/E3 (n=25). RESULTS: In the pre-treatment state, higher plasma levels of TC and TC/HDL-C ratio were observed in women with phenotype E3/E4 (P<0.0001 and P<0.02, respectively), while higher plasma TG levels were found in the apo E2/E3 group (P<0.0001). After HRT, women with phenotype E3/E4 showed higher levels of TC and TC/HDL-C ratio (P<0.0001 and P<0.006, respectively). The apo E2/E3 phenotype group showed increased levels of TG (P<0.0001). In the multivariant analysis the changes of TG after HRT were related to the type of treatment used (P<0.001), age (P=0.05) and the apo E phenotype (E2/E3). CONCLUSION: Women with phenotype E2/E3 have higher plasma TG levels and show a significant post HRT increase compared with the other phenotypes. Other factors with a lower impact on TG levels are age and progestagen association.

Administration, Cutaneous↗

PubMed2004

Identification of quantitative trait Loci for anxiety and locomotion phenotypes in rat recombinant inbred strains.

Anxiety disorders are phenotypically complex and may involve multiple genetic influences on many neurotransmitter systems. Rodent tests used to investigate genetic influences on anxiety-like phenotypes have face and predictive validity as models for anxiety in humans. If multiple genes contribute additively to a trait, the trait will be continuously distributed and be amenable to detection of associations between allelic variation at specific chromosomal loci and the phenotypes being studied via quantitative trait loci (QTL) mapping. The elevated plus-maze test provides quantitative measures of both anxiety-like and locomotion phenotypes. Using this test, we assessed four phenotypes in a set of 22 rat recombinant inbred (RI) strains derived from Brown Norway (BN.Lx /Cub) and Spontaneously Hypertensive rat (SHR/Ola) progenitors. QTL analyses were used to determine whether allelic variation at specific chromosomal loci contribute significantly to RI strain-dependent variance in each phenotype. Significant QTL for an anxiety phenotype were found on chromosomes 2, 5, 6, and 7. For a phenotype reflecting both anxiety and locomotion, QTL were found on chromosomes 2, 7, and 8, while for a locomotion phenotype, significant QTL were found on chromosomes 3 and 18.

Alleles↗

PubMed1979

Surface phenotyping, histology and the nature of non-Hodgkin lymphoma in 157 patients.

In a study of 157 patients with lymphoid malignancy, the phenotype of the tumour cells was correlated with the histological classification of the tumour using the Rappaport and the Kiel classifications. The markers used included E, Fc gamma, Fc micron (IgM) and C3d rosetting, estimation of SIg and CyIg, and tests for the expression of HTLA, Ia and ALL. Repeat biopsy specimens were studied in 23 of these patients. The phenotypic features of lymphoblastic malignancy indicated B-cell, T-cell and ALL-positive null-cell tumours in this group. Immunoblastic lymphomas were predominantly of non-capping B-cell type, but T-cell immunoblastic lymphoma occurred in 2 patients. Immunoblastic lymphomas of receptor-silent cells occur, and are ALL- and HTLA-negative. In the category of diffuse, poorly differentiated lymphocytic lymphomas, most cases are of centroblastic and centrocytic tumour of diffuse type, but pure centrocytic tumours and centroblastic tumours occur. The dominant phenotype in this group is of B cells expressing C3d receptors. Nodular poorly differentiated lymphocytic lymphomas (Rappaport) are classified as centroblastic and centrocytic follicular (Kiel) and most express SIg+ C3d+ phenotype. The frequency of this phenotype appeared the same in both diffuse and nodular poorly differentiated lymphocytic neoplasms. The Rappaport group of diffuse well-differentiated lymphocytic lymphoma includes 2 Kiel categories, malignant lymphoma lymphocytic, and malignant lymphoma lymphoplasmacytoid. Cells of the former tumour were considered to be immature B cells resembling those seen in CLL, and characteristically expressing SIg weakly, with a high frequency of single kappa light chain. Cells of the latter tumour are by contrast mature, and are related to the centroblastic and centrocytic follicular tumour by their histogenesis and phenotypic features. Repeat biopsy examinations indicate that T-cell predominance occurs in the prodromal phase of B-cell-predominant tumours of SIg+ C3d+ phenotype. It is concluded that non-Hodgkin lymphoma can be divided into 2 categories: (1) tumours of immature immunologically incompetent cells of lymphoblastic histology and with phenotypic features akin to T, B and Null-cell ALL, and (2) tumours of differentiated lymphocytes expressing the phenotypic features of B lymphocytes, with maturation arrested at one of several stages of an antigen-dependent immune response.

Adult↗

PubMed2024

Longitudinal characterization of impulsivity phenotypes boosts signal for genomic correlates and heritability.

Genomic correlates of impulsivity have been identified in several genome-wide association studies (GWAS) using cross-sectional designs, but no studies have investigated the molecular genetic correlates of impulsivity phenotypes using longitudinally constructed traits. In 3860 unrelated European participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), we constructed longitudinal phenotypes for delay discounting and impulsive personality traits (as measured by the UPPS-P impulsive behavior scales) via assessment at ages 24, 26, and 28. We conducted GWASs of impulsivity using both cross-sectional and longitudinal phenotypes, estimated heritability and their phenotypic and genetic correlations, and evaluated their association with recently-developed polygenic risk scores (PRSs) for the impulsivity indicators themselves and also related psychiatric conditions. Latent growth curve modeling revealed a stable intercept over time for all impulsivity phenotypes. High genetic correlation of cross-sectional measures over time suggested a stable genetic component for delay discounting (rg = 0.53-0.99) and sensation seeking (rg = 0.99). Heritability estimates of the stable longitudinal phenotypes substantively improved as compared to their cross-sectional counterparts, revealing a significant SNP-heritability for delay discounting (0.22; p = 0.03) and sensation seeking (0.35; p = 0.0007). Consistent with previous reports, GWAS and gene-based analyses revealed associations between specific longitudinal impulsivity indicators and CADM2 and NCAM1 genes. The PRSs for the impulsivity indicators and disorders related to self-regulation were also significantly associated with longitudinal impulsivity traits. Finally, we validated the associations between longitudinal impulsivity phenotypes and their PRSs in an independent 13-wave longitudinal study (n = 1019) and the benefit of longitudinal phenotypes in simulation studies. In this first longitudinal genetic study of impulsivity traits, the results revealed stable genomic correlates of delay discounting and sensation seeking over time and further validated the utility of recently-developed PRSs, both in relation to the observed traits and in connecting them to psychiatric disorders. More generally, these findings support using latent intercepts as novel longitudinal phenotypes to boost signal for heritability and genomic correlates of mechanisms contributing to psychiatric disease liability.

Humans↗

PubMed2000

Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a significant cause of renal artery stenosis, especially in young females. A rare association between FMD and alpha 1-antitrypsin (alpha 1-AT) deficiency has been reported. We compared the alpha 1-AT phenotype distribution in 83 patients with renal arterial FMD with those published for Australian populations. alpha 1-AT phenotyping was performed by isoelectric focusing between pH 4.2 and pH 4.9 on polyacrylamide gels with PiM1M2, PiFM (non-deficiency alleles), PiMS and PiMZ (deficiency alleles) markers. Following phenotyping, alpha 1-AT genotyping was performed in 10 patients to confirm the presence of S and/or Z alleles. The phenotype distribution and allele frequencies were similar to those reported for normal subjects from two Australian populations (72 (86.7%) PiMM phenotype, one (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) PiMZ and one (1.2%) PiSZ), suggesting that alpha 1-AT deficiency is not a common aetiological factor in renal arterial FMD. However, despite FMD being three times less common in males than females, and carotid artery dissection being a rare occurrence, a male with PiMS deficiency phenotype presented with internal carotid artery dissection and had bilateral renal artery FMD. Further, a patient with PiSZ deficiency phenotype was one of two sisters with FMD and was more severely affected than her PiMM normal phenotype sibling. These two patients from the present series together with nine culled from the literature with alpha 1-AT deficiency phenotype and FMD suggest that the chance combination of alpha 1-AT deficiency and FMD may predispose to severe manifestations of FMD.

Female↗

PubMed2003

Molecular genetic analysis of the Bel phenotype.

BACKGROUND AND OBJECTIVES: In addition to the common ABO phenotypes, numerous phenotypes with a weak expression of the A or B antigens on the red blood cells have been found. This study describes the molecular genetic analysis of the Bel phenotype in Taiwanese individuals. MATERIALS AND METHODS: The exon 6-7 region of the ABO gene of an individual with the Bel phenotype was amplified by the polymerase chain reaction (PCR), cloned, and the sequences of the exons and their adjacent splice sites were analysed. A PCR-based restriction fragment length polymorphism (RFLP) analysis was designed to detect the 502C>T nucleotide change identified in the Bel allele. Six unrelated individuals with the Bel phenotype were analysed, and samples from 40 randomly selected individuals with the common B phenotype were also assessed. RESULTS: All six unrelated Taiwanese individuals with the Bel phenotype were shown to possess a B gene with the 502C>T mutation. The mutation was not detected in the general group B population. The 502C>T nucleotide change predicts an amino acid alteration of Arg168-->Trp in the encoded B transferase. CONCLUSIONS: The results suggest a new molecular basis, a 502C>T missense mutation in the B allele, for the Bel phenotype and an association of the Bel502C>T allele with the Bel phenotype in the Taiwanese population.

ABO Blood-Group System↗

PubMed2001

Contacts with fibrils containing collagen I, but not collagens II, IX, and XI, can destabilize the cartilage phenotype of chondrocytes.

OBJECTIVE: Cell-matrix interactions are important regulators of cellular functions, including matrix synthesis, proliferation and differentiation. This is well exemplified by the characteristically labile phenotype of chondrocytes that is lost in monolayer culture but is stabilized in suspension under appropriate conditions. We were interested in the role of collagen suprastructures in maintaining or destabilizing the cartilage phenotype of chondrocytes. DESIGN: Primary sternal chondrocytes from 17-day-old chick embryos were cultured in gels of fibrils reconstituted from soluble collagen I from various sources. The culture media either contained or lacked FBS. Cells were cultured for up to 28 days and the evolution of the phenotype of the cells was assessed by their collagen expression (collagens II and X for differentiated chondrocytes and hypertrophic chodrocytes, repectively; collagen I for phenotypically modulated cells), or by their secretion of alkaline phosphatase (hypertrophic cartilage phenotype). RESULTS: The cells often retained their differentiated phenotype only if cultured with serum. Under serum-free conditions, cartilage characteristics were lost. The cells acquired a fibroblast-like shape and, later, synthesized collagen I instead of cartilage collagens. Shape changes were influenced by beta1-integrin-activity, whereas other matrix receptors were important for alterations of collagen patterns. Heterotypic fibrils reconstituted from collagens II, IX, and XI did not provoke this phenotypic instability. CONCLUSIONS: Chondrocytes sensitively recognize the suprastructures of collagen fibrils in their environment. Cellular interactions with fibrils with appropriate molecular organizations, such as that in cartilage fibrils, result in the maintenance of the differentiated cartilage phenotype. However, other suprastructures, e.g. in reconstituted fibrils mainly containing collagen I, lead to cell-matrix interactions incompatible with the cartilage phenotype. The maintenance of the differentiated traits of chondrocytes is pivotal for the normal function of, e.g., articular cartilage. If pathologically altered matrix suprastructures lead to a dysregulation of collagen production also in vivo compromised cartilage functions inevitably will be propagated further.

Alkaline Phosphatase↗

PubMed2006

Prevalence of and risk factors for Barrett's esophagus with intestinal predominant mucin phenotype.

OBJECTIVE: Barrett's esophagus with the intestinal predominant mucin phenotype is considered to have a higher malignant potential than that with the gastric predominant mucin phenotype. The purpose of this prospective study was to investigate the prevalence of and risk factors for Barrett's esophagus with the intestinal predominant mucin phenotype in patients undergoing endoscopy. MATERIAL AND METHODS: A total of 1699 consecutive patients undergoing esophagogastroduodenoscopy were enrolled in the study. A targeted biopsy was performed when endoscopically observed columnar-appearing esophagus was stained with crystal violet. The sample, histologically evidenced as Barrett's esophagus, was immunohistochemically evaluated and categorized as of either gastric or intestinal predominant mucin phenotype. All the patients were requested to complete the structured questionnaire indicating their symptoms and food consumption patterns. Prevalence of and risk factors for Barrett's esophagus with and without the intestinal predominant mucin phenotype were investigated. RESULTS: Out of 1668 patients, 629 (37.7%) were found to have endoscopic Barrett's esophagus. In 333 out of 1668 patients (19.9%), histological studies were diagnostic of Barrett's esophagus. One hundred and six of these 333 patients (31.8%) had the intestinal predominant mucin phenotype. Age, male gender and the presence of hiatal hernia were confirmed by multivariate analysis as the independent predictors for the presence of Barrett's esophagus with the intestinal predominant mucin phenotype. CONCLUSIONS: Barrett's esophagus with the intestinal predominant mucin phenotype was immunohistochemically found in 6.4% of all study patients. Older age, male gender and the presence of hiatal hernia were the risk factors for the presence of Barrett's esophagus with the intestinal predominant mucin phenotype.

Adolescent↗

PubMed2001

Length variation of glycoprotein 120 V2 region in relation to biological phenotypes and coreceptor usage of primary HIV type 1 isolates.

Conflicting data have been published concerning the correlation between the length of the second variable region (V2) in the HIV-1 envelope and the biological phenotype of the virus. Here the V2 region length of primary HIV-1 isolates was compared with biological phenotype and coreceptor usage. The V2 region variation was determined by DNA fragment length analysis, virus biological phenotype by the MT-2 cell assay, and coreceptor usage by infection of U87.CD4 cells expressing CCR3, CCR5, or CXCR4. Ninety-three primary virus isolates from 40 patients were analyzed. This panel of viruses included sequential isolates obtained from patients who progressed to AIDS with or without a virus phenotypic switch. We found that NSI MT-2-negative isolates had significantly shorter V2 regions than SI MT-2-positive isolates. However, when V2 region lengths of viruses were analyzed in more detail, we observed that NSI isolates obtained from patients shortly before the phenotypic switch had V2 region lengths similar to those of SI isolates. V2 regions of NSI isolates obtained from patients who progressed to AIDS without a virus phenotypic switch had, in contrast, shorter V2 region than isolates obtained just before virus phenotypic switch. Coreceptor analysis revealed that CCR5-using (R5) isolates generally had shorter V2 regions than virus isolates with the ability to enter CXCR4-expressing cells. Moreover, no significant difference in V2 region length was observed between monotropic SI isolates, that is, X4 isolates, and multitropic SI isolates, that is, R3R5X4 or R5X4 isolates. Thus, we conclude that R5 NSI isolates obtained from patients with stable virus phenotype through the whole disease course display shorter V2 regions than isolates obtained from patients at switch of virus phenotype, suggesting that V2 region length may influence virus coreceptor usage.

Adult↗