Retroviruses. Closing the joint.
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Animals↗
Biomedical subjects
N Rosenberg
Publications and source records attributed to N Rosenberg.
Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males.
Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C --> T, factor V (F V) nt 1691G --> A (F V Leiden), and factor II (F II) nt 20210 G --> A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v 5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9). The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women.
Activated Protein C Resistance↗
Analysis of prothrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy.
OBJECTIVE: To determine whether genetic or acquired thrombophilias and other risk factors are associated with nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: Retrospective case-control study. PARTICIPANTS: Sixty-one patients with NAION diagnosed between 1984 and 1997. Ninety consecutive patients who visited the Eye Institute made up the control group. INTERVENTION: Protein C, protein S, antithrombin III, lupus anticoagulant, and three recently described prothrombotic polymorphisms (i.e., factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase [MTHFR] C677T) were analyzed. In addition, risk factors for arteriosclerotic vascular disease were assessed. MAIN OUTCOME MEASURES: Parameters of thrombophilia. RESULTS: None of the thrombophilic markers (genetic and acquired) constituted a significant risk factor for NAION. Ischemic heart disease, hypercholesterolemia, and diabetes mellitus were discerned as risk factors for NAION with odds ratios of 2.9 (95% confidence interval [CI], 1.3-6.4), 2.6 (95% CI, 1.2-5.5), and 2.3 (95% CI, 1.1-4.8), respectively. Multiple logistic regression analysis indicated that ischemic heart disease and hypercholesterolemia exerted an additive risk for NAION with a combined odds ratio of 4.5 (95% CI, 1.4-14.5). However, none of these risk factors statistically predicted second eye involvement. CONCLUSION: NAION was not found to be associated with thrombophilic risk factors, yet it was related to ischemic heart disease, hypercholesterolemia, and diabetes mellitus.
Adult↗
p53 mediates apoptotic crisis in primary Abelson virus-transformed pre-B cells.
Transformation of pre-B cells by Abelson murine leukemia virus (Ab-MLV) involves a balance between positive, growth-stimulatory signals from the v-Abl oncoprotein and negative regulatory cues from cellular genes. This phenomenon is reflected by the clonal selection that occurs during Ab-MLV-mediated transformation in vivo and in vitro. About 50% of all Ab-MLV-transformed pre-B cells express mutant forms of p53 as they emerge from this process, suggesting that this protein may play an important role in the transformation process. Consistent with this idea, expression of p19(Arf), a protein whose function depends on the presence of a functional p53, is required for the apoptotic crisis that characterizes primary Ab-MLV transformants. To test the role of p53 in pre-B-cell transformation directly, we examined the response of Trp53(-/-) mice to Ab-MLV. The absence of p53 shortens the latency of Abelson disease induction but does not affect the frequency of cells susceptible to Ab-MLV-induced transformation. However, primary transformants derived from the null animals bypass the apoptotic crisis that characterizes the transition from primary transformant to fully malignant cell line. These effects do not require p21(Cip-1), a major downstream target of p53; however, consistent with a role of p19(Arf), transformants expressing mutant p53 and abundant p19 retain wild-type p19 sequences.
Abelson murine leukemia virus↗
Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment.
The inherited thrombophilias--deficiencies of protein C, protein S, and antithrombin III--and the prothrombotic polymorphisms factor V G1691A and factor II G20210A predispose patients toward venous thromboembolism (VTE). The aim of this study was to determine the prevalence of single and combined prothrombotic factors in patients with idiopathic VTE and to estimate the associated risks. The study group consisted of 162 patients referred for work-up of thrombophilia after documented VTE. The controls were 336 consecutively admitted patients. In all subjects factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were analyzed by specific polymerase chain reactions and restriction enzymes. Activities of antithrombin III and protein C, free protein S antigen, and lupus anticoagulant were determined in a subset of 109 patients who were not receiving oral anticoagulants. The prevalences of heterozygotes and homozygotes for factor V G1691A and factor II G20210A among patients and controls were 40.1% versus 3.9% and 18.5% versus 5.4%, respectively (P=0.0001). The prevalence of homozygotes for MTHFR C677T in patients was 22.8% and in controls, 14.3% (P=0.025). Heterozygous and homozygous factor V G1691A, factor II G20210A, and homozygous MTHFR C677T were found to be independent risk factors for VTE, with odds ratios of 16.3, 3.6, and 2.1, respectively. Two or more polymorphisms were detected in 27 of 162 patients (16.7%) and in 3 of 336 controls (0.9%). Logistic regression analysis disclosed odds ratios of 58.6 (confidence interval [CI], 22.1 to 155.2) for joint occurrence of factor V and factor II polymorphisms, of 35.0 (CI, 14.5 to 84.7) for factor V and MTHFR polymorphisms, and of 7.7 (CI, 3.0 to 19.6) for factor II and MTHFR polymorphisms. Among 109 patients in whom a complete thrombophilic work-up was performed, 74% had at least 1 underlying defect. These data indicate that in most patients referred for evaluation of thrombophilia due to idiopathic VTE, 1 or more underlying genetic predispositions were discernible. The presence of >1 of the prothrombotic polymorphisms was associated with a substantial risk of VTE.
Adult↗
p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation.
The Ink4a/Arf locus encodes p16(Ink4a) and p19(Arf) and is among the most frequently mutated tumor suppressor loci in human cancer. In mice, many of these effects appear to be mediated by interactions between p19(Arf) and the p53 tumor-suppressor protein. Because Tp53 mutations are a common feature of the multistep pre-B cell transformation process mediated by Abelson murine leukemia virus (Ab-MLV), we examined the possibility that proteins encoded by the Ink4a/Arf locus also play a role in Abelson virus transformation. Analyses of primary transformants revealed that both p16(Ink4a) and p19(Arf) are expressed in many of the cells as they emerge from the apoptotic crisis that characterizes the transformation process. Analyses of primary transformants from Ink4a/Arf null mice revealed that these cells bypassed crisis. Because expression of p19(Arf) but not p16 (Ink4a) induced apoptosis in Ab-MLV-transformed pre-B cells, p19(Arf) appears to be responsible for these events. Consistent with the link between p19(Arf) and p53, Ink4a/Arf expression correlates with or precedes the emergence of cells expressing mutant p53. These data demonstrate that p19(Arf) is an important part of the cellular defense mounted against transforming signals from the Abl oncoprotein and provide direct evidence that the p19(Arf)-p53 regulatory loop plays an important role in lymphoma induction.
3T3 Cells↗
Capturing the unexpected benefits of medical research.
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Diffusion of Innovation↗
A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.
The polymorphism G20210A in the 3' untranslated region of the prothrombin gene is associated with an increased level of factor II activity and confers a twofold to fivefold increase in the risk for venous thromboembolism. Among Caucasian populations, the prevalence of factor II G20210A heterozygotes is 1% to 6%, whereas in non-Caucasian populations it is very rare or absent. The aim of the present study was to discern whether factor II G20210A originated from a single or recurrent mutational events. Allele frequencies of four dimorphisms spanning 16 of 21 kb of the factor II gene were determined in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II G20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (P = .0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and only in 34% of 20210G normal alleles (P < .0001). These data strongly support a single origin for factor II G20210A that probably occurred after the divergence of Africans from non-Africans and of Caucasoid from Mongoloid subpopulations.
Africa, Northern↗
The importance of combined clinical and sonographic examination of instability of the neonatal hip.
A clinically unstable hip in a new-born may be an early sign of congenital dysplasia. Unless followed and treated at a young age, it can progress to a degenerative hip joint disorder with considerable functional disability in adult life. For this reason, the early diagnosis of neonatal hip instability is crucial. We present our experience with 9199 neonates examined independently by clinical and ultrasonographic techniques. Instability was diagnosed in 0.8% of the hips. Only 47% of the unstable hips were diagnosed by the initial clinical examination, in the remainder the dysplasia was recognised only by sonography. Sonographic changes were also detected on re-examination in 6% of the unstable hips following the recognition of clinical instability. It is evident that combined clinical and ultrasonographic examination significantly improves the detection rate of dysplastic hips in new-borns.
Female↗
Glanzmann thrombasthenia in two Iraqi-Jewish siblings is caused by a novel splice junction mutation in the glycoprotein IIb.
An A-->G transition in the acceptor splice site at the intron 19/exon 20 junction of the glycoprotein IIb gene was defined as a novel mutation causing Glanzmann thrombasthenia in two Iraqi-Jewish siblings. This mutant DNA was transcribed into four distinct species of mRNA, one of which resulted in a premature termination codon and the other three predicting deletions of 50, 61 or 72 amino acids, respectively.
Aged↗
Analysis of genetic polymorphisms related to thrombosis and other risk factors in patients with retinal vein occlusion.
The purpose of this study was to investigate the role of genetic polymorphisms associated with venous and arterial thrombosis in patients with retinal vein occlusion (RVO). One-hundred and two consecutive patients with RVO were examined for factor V G1691A and factor II G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and apolipoprotein E4 by amplification of specific DNA fragments and restriction analysis. The risks exerted by these polymorphisms and by the conventional risk factors of RVO were evaluated by comparing their frequencies among patients and controls and by estimating the respective odds ratios. We found that the prevalences of the factor V G1691A, factor II G20210A, and apolipoprotein E4 polymorphisms were similar in the study and control groups. Logistic regression analysis involving the parameters for which significant differences were detected disclosed an odds ratio of 1.9 for MTHFR C677T homozygosity (95% confidence interval 0.95-3.81), an odds ratio of 2.12 for hypertension (95% confidence interval 1.16-3.73) and an odds ratio of 3.25 for a family history of stroke (95% confidence interval 1.07-9.51). Our data suggests that homozygosity for the MTHFR C677T polymorphism is a risk factor of RVO in addition to arterial hypertension and a family history of stroke.
Adult↗
Use of Emergency Medical Service transport system in medical patients up to 36 months of age.
OBJECTIVES: To determine the frequency of inappropriate transport by Emergency Medical Service (EMS). DESIGN: A retrospective study. SUBJECTS: Patients up to 36 months of age with medical complaints transported by EMS to an urban pediatric emergency department (ED). INTERVENTIONS: None. MEASUREMENTS: Arbitrary criteria for appropriate use of EMS transport system were developed. The age, triage status, number of previous uses of EMS, health insurance status, time of calls, chief complaint, and clinical management of patients in the ED were determined. The frequency of inappropriate use of EMS was determined and also the percentage of patients up to 36 months of age who used EMS transport system on more than one occasion. RESULTS: Charts of 341 patients were reviewed of which 126 patients (37%) could have been transported by nonemergent vehicles according to our arbitrary criteria. In addition 97 (28%) of these patients had used the EMS transport system on at least one other occasion. CONCLUSIONS: EMS is utilized for inappropriate transportation in approximately 37% of our pediatric patients less than 36 months of age with medical complaints. In addition, 28% of these same patients utilized the EMS system on more than one occasion. It would appear that education of care providers in the appropriate use of EMS and use of alternate means of transportation would make the system more efficient and productive.
Ambulances↗
Screening for carbon monoxide in children.
OBJECTIVE: Carbon monoxide (CO), a colorless, odorless gas, accounts for the majority of fatal poisonings in the United States. To date, few screening studies that evaluate pediatric exposure are available. The objectives of this study were to determine the value of a CO breath analyzer for detecting pediatric CO exposure and to identify potential CO sources. DESIGN: Prospective screening study. SETTING: Emergency department of an urban children's hospital. PATIENTS: A convenience random sample of 470 noncritically ill children, aged five to 20 years, who presented to a pediatric emergency department and could blow into a CO breath analyzer. INTERVENTION: After informed consent and demographic and clinical variables were ascertained, eligible patients blew into a CO breath analyzer. Those with breath CO levels > or = 9 ppm underwent confirmatory cooximetric analysis of capillary blood. Sources of CO exposure were determined by history and a home-site evaluation by the local gas company. Patients with carboxyhemoglobin (COHb) levels of more than 5% were given normobaric 100% oxygen until their COHb levels were less than 5%. RESULTS: 1.9% (9/470) of patients had elevated breath CO levels and COHb levels by cooximetry. Putative sources of CO exposure were active cigarette smoking for five patients and a faulty furnace in the home for one patient. On the basis of the history, we believe environmental tobacco smoke or automobile exhaust or both contributed to the elevated COHb levels in the other three patients. There was a good correlation between COHb by cooximetry and breath analysis (concordance correlation = 0.739) CONCLUSION: Breath analysis for CO is a convenient tool to estimate exposure and identify older children at risk.
Adolescent↗
Mutations in the alphaIIb and beta3 genes that cause Glanzmann thrombasthenia can be distinguished by a simple procedure using transformed B-lymphocytes.
Glanzmann thrombasthenia (GT) is caused by a defect in either glycoprotein (GP)IIb (alphaIIb) or GPIIIa (beta3) genes and therefore screening of both genes is required for mutation identification. The beta subunit of the GPIIb/IIIa complex (beta3) forms a complex with another alpha subunit (alpha(v)) yielding the alpha(v)beta3 vitronectin receptor (VnR). GT patients with mutations in the GPIIIa gene that cause diminished synthesis of GPIIIa are deficient in both GPIIb/IIIa and VnR, whereas patients with mutations in the GPIIb gene are deficient in GPIIb/IIIa, yet express normal or increased VnR in their platelets. The presence or absence of VnR in platelet membranes of GT patients has therefore been used for distinguishing between mutations in the GPIIb gene and mutations in the GPIIIa gene. However, the method of assessing VnR in platelets is cumbersome and use of fresh platelets is indispensible. In the present work we devised a procedure for detection of the VnR in B-lymphocytes transformed by Epstein-Bar virus (EBV). The transformed lymphocytes transcribed GPIIIa mRNA but not GPIIb mRNA and expressed VnR on their surface. Using flow cytometry analysis or immuno-precipitation and western blotting VnR was found in B-lymphocytes of GT patients bearing a well characterized mutation in the GPIIb gene. In contrast, in B-lymphocytes of GT patients bearing 2 different mutations in the GPIIIa gene no VnR was detectable. Thus, for determining which gene is mutated in a GT patient, EBV-transformed B-lymphocytes are useful and can as well be used for analyses of GPIIIa mRNA and genomic DNA. Ten ml of blood are sufficient for the procedure.
B-Lymphocytes↗
Kappa and lambda rearrangement occur simultaneously in transformed pre-B cells.
Murine B-lineage cells can express either kappa or lambda Ig light chains. However, most of these cells express kappa protein, a phenomenon that appears to be controlled in part at the level of gene rearrangement. This feature may reflect a preference for the kappa locus by the recombinase machinery, or it may indicate that kappa rearrangement begins before lambda rearrangement. These possibilities can be distinguished by measuring the kinetics with which light chain gene rearrangement at both loci actually occurs. To this end, we have used pre-B cells transformed by temperature-sensitive mutants of Abelson virus that undergo kappa and lambda gene rearrangement when shifted to the nonpermissive temperature. Competitive PCR analyses of rearrangement kinetics demonstrate that the kappa and lambda loci rearrange at about the same time in these cells. Consistent with this, some clones isolated from cells induced for a short period of time have rearranged only the lambda locus. However, the frequency with which lambda genes are rearranged is three- to sixfold lower than that with which kappa genes rearrange. These data indicate that the recombinase machinery targets both light chain loci at the same time, but acts preferentially at the kappa locus. The reduced ability of the recombinase machinery to target the lambda locus and selection pressures occurring during B cell development probably both contribute to the preferential usage of kappa genes in normal murine B lineage cells.
3T3 Cells↗
Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta3) is a second mutation in Iraqi Jews that stemmed from a distinct founder.
Glanzmann thrombasthenia (GT) is a rare bleeding disorder resulting from mutations in either glycoprotein (GP) IIb or GPIIIa genes. The disease is relatively frequent in highly inbred populations such as Iraqi Jews. The molecular basis of GT in 6 unrelated Iraqi-Jewish patients was previously identified as an 11-bp deletion in exon 12 of the GPIIIa gene. We now describe a second mutation found in 3 unrelated Iraqi-Jewish families that consists of an 11.2-kb deletion between an Alu repeat in intron 9 and exon 13 of the GPIIIa gene. The mutant DNA is transcribed into mRNA in which exons 10 through 13 are absent. Splicing of exon 9 directly to exon 14 leads to a shift in the reading frame resulting in a stop codon. The predicted protein is truncated in the middle of the third cysteine-rich domain before the transmembrane domain. Simple DNA-based methods were devised for identification of both mutations in Iraqi Jews for the purpose of carrier detection and prenatal diagnosis enabling prevention of GT. A survey of the general Iraqi-Jewish population for the first 11-bp deletion and the second 11.2-kb deletion disclosed that the allele frequency of the first mutation was 0.0043, whereas none of 700 individuals examined bore the second mutation (allele frequency <0.0007). Among 40 GT patients of Iraqi-Jewish origin 31 were homozygous for the first mutation, 4 were compound heterozygotes for the first and second mutations, and 2 were homozygous for the second mutation. Haplotype analyses using 4 polymorphic markers in the GPIIIa gene showed that each mutation originated in a distinct founder.
Adult↗
Platelets mediate tumor cell adhesion to the subendothelium under flow conditions: involvement of platelet GPIIb-IIIa and tumor cell alpha(v) integrins.
The aim of our study was to explore the role of platelets and their specific integrin receptors in mediating the interaction of 4 human tumor cell lines (3 melanoma and 1 carcinoma) with the extracellular matrix (ECM) under static and arterial flow conditions. Under static conditions, all 4 cell lines adhered to the ECM. The adhesion capacity of all 4 cell lines was virtually abolished by application of flow during incubation with the ECM. Under static conditions, tumor cell adhesion was not affected by adding platelets to the cell suspension and was slightly reduced by pre-coating the ECM with platelets prior to the addition of tumor cells. In contrast, under flow conditions, platelets significantly increased tumor cell adhesion to the ECM, the enhancing effect being more pronounced when platelets were pre-incubated with the ECM prior to the addition of tumor cells than when incubated simultaneously with the cells. Platelet-mediated tumor cell adhesion under flow was markedly inhibited by blockade of the platelet GPIIb-IIIa or of the tumor cell alpha(v) integrins. Platelets of a Glanzmann thrombastenia (GT) patient were unable to support tumor cell adhesion to the ECM under flow. Our results suggest that the interaction of tumor cells with subendothelium-bound platelets under flow conditions is mediated by platelet GPIIb-IIIa and by tumor cell alpha(v) integrins independently of the nature of the beta subunit.
Animals↗
Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1.
RIN1 was originally identified by its ability to physically bind to and interfere with activated Ras in yeast. Paradoxically, RIN1 potentiates the oncogenic activity of the BCR-ABL tyrosine kinase in hematopoietic cells and dramatically accelerates BCR-ABL-induced leukemias in mice. RIN1 rescues BCR-ABL mutants for transformation in a manner distinguishable from the cell cycle regulators c-Myc and cyclin D1 and the Ras connector Shc. These biological effects require tyrosine phosphorylation of RIN1 and binding of RIN1 to the Abl-SH2 and SH3 domains. RIN1 is tyrosine phosphorylated and is associated with BCR-ABL in human and murine leukemic cells. RIN1 exemplifies a new class of effector molecules dependent on the concerted action of the SH3, SH2, and catalytic domains of a cytoplasmic tyrosine kinase.
Adaptor Proteins, Signal Transducing↗