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Biomedical subjects

A L Nielsen

Publications and source records attributed to A L Nielsen.

At least 19 recordsLinked to original sources
PubMed2001

Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins.

Members of the heterochromatin protein 1 (HP1) family are silencing nonhistone proteins. Here, we show that in P19 embryonal carcinoma (EC) nuclei, HP1 alpha, beta, and gamma form homo- and heteromers associated with nucleosomal core histones. In vitro, all three HP1s bind to tailed and tailless nucleosomes and specifically interact with the histone-fold of histone H3. Furthermore, HP1alpha interacts with the linker histone H1. HP1alpha binds to H3 and H1 through its chromodomain (CD) and hinge region, respectively. Interestingly, the Polycomb (Pc1/M33) CD also interacts with H3, and HP1alpha and Pc1/M33 binding to H3 is severely impaired by CD mutations known to abrogate HP1 and Polycomb silencing in Drosophila. These results define a novel function for the conserved CD and suggest that HP1 self-association and histone binding may play a crucial role in HP1-mediated heterochromatin assembly.

Amino Acid Sequence↗
PubMed2001

Creutzfeldt-Jakob disease segregating in a three generation Danish family.

A three generation family is presented in which rapidly progressive, early-onset Creutzfeldt-Jakob disease without typical EEG changes segregates as an autosomal dominant disease. An aspartic acid to asparagine mutation at codon 178 of the prion gene, PRNP, co-segregates with the disease. As expected, the disease allele also carries the valine codon of the polymorphic valine/methionine codon 129 of the gene. In family members homozygous for this valine codon the disease was more rapidly progressive than in a heterozygous family member, who had a variant clinical phenotype. Definite neuropathological diagnosis required prion staining with specific antibodies.

Adult↗
PubMed2001

Drinking patterns among Hispanic adolescents: results from a national household survey.

OBJECTIVE: This is one of the first studies to examine and compare alcohol use for adolescent Cubans, Mexican Americans, Puerto Ricans and other Hispanics. METHOD: The data come from the 1993 National Household Survey on Drug Abuse (NHSDA), a national probability sample of the U.S. household population. The sample examined here (N = 1,865, 52% male) comprises 200 Cubans, 1,133 Mexican Americans, 255 Puerto Ricans and 277 Central/South Americans who were 12 to 17 years old. Drinking patterns are measured using a quantity-frequency index, and analyses are conducted using Stata. RESULTS: In the cross-tabulations, no ethnic differences in drinking patterns are found for males or females, nor is there evidence of gender differences within ethnic groups, although there are some age differences in alcohol use. In the logistic regression analyses, two ethnic differences emerge, although the factors most consistently associated with drinking behaviors in these analyses are age, Spanish language use and urban residence. Additional analyses using the 1998 NHSDA suggest that ethnic differences in alcohol use may emerge in late adolescence/early adulthood. CONCLUSIONS: Given the established findings of ethnic and gender differences in drinking among adult Hispanics, it is surprising that few differences are evidenced in adolescence. Future research should explore whether such differences emerge during the transition into adulthood and, if so, identify factors that produce them. In addition, to increase understanding of these ethnic groups' drinking patterns, future research should further investigate the factors associated with Hispanic adolescents' alcohol use, including both consideration of whether the predictors are the same across groups and of the role of sociocultural factors.

Acculturation↗
PubMed2001

Drinking in adulthood: similarities and differences in effects of adult roles for Hispanic ethnic groups and Anglos.

OBJECTIVE: This study examines whether the adult social roles perspective. an approach that explains drinking behaviors for Anglos, similarly affects alcohol use by Cubans, Mexican Americans, Puerto Ricans and Other Hispanics (Central and South Americans). METHOD: The 1993 National Household Survey on Drug Abuse, a national probability sample of the household population in the United States, is used. The sample utilized here (N= 13,822; 56.2% female) consisted of 9,388 Anglos, 611 Cubans, 2,459 Mexican Americans, 611 Puerto Ricans and 753 Central/South Americans age 18 and older. The outcome measures include past-year drinking, and for drinkers, heavy drinking and alcohol-related problems. Logistic regression analyses are conducted using Stata. RESULTS: The results show that there are some ethnic differences in the effects of the adult social roles. Of particular importance is the finding that being married has anomalous effects for Cubans (heavy drinking), Mexican Americans (problems) and Other Hispanics (problems) compared with Anglos and the other Hispanic ethnic groups. CONCLUSIONS: The adult social roles perspective has some utility for explaining Hispanic drinking patterns. Future research should consider not only traditional predictors of drinking but also such socio-cultural factors as acculturation and familism, to better understand adult alcohol use by members of Hispanic ethnic groups.

Adolescent↗
PubMed2000

Examining drinking patterns and problems among hispanic groups: results from a national survey.

OBJECTIVE: This study examines and compares the drinking patterns and problems of members of four Hispanic groups (Cubans, Mexican Americans, Puerto Ricans and other Hispanics) in the United States, with information presented by gender and age. METHOD: The 1993 National Household Survey on Drug Abuse, a recent national probability sample of the household population aged 18 and over in the United States, is used. Data are obtained through in-person interviews. The sample includes 4,462 Hispanics of Cuban (n = 620), Mexican (n = 2,467), Puerto Rican (n = 619) and Central and South American (n = 756) origin. Analyses are conducted using SUDAAN. RESULTS: There are significant differences across the Hispanic groups in their drinking patterns and problems. Among men, Mexican Americans report the most frequent and heavy drinking, and the greatest prevalence of drunkenness and alcohol-related problems. Cubans report the lowest percentages of such respondents, and Puerto Ricans and other Hispanics are in between the other two groups. For women, fewer ethnic differences are evidenced than for men. In general, Puerto Ricans and Mexican Americans drink more often and heavily and experience more problems than the other groups. Even after controlling for predictors of adult alcohol use, some ethnic differences in drinking persist. CONCLUSIONS: The four Hispanic groups have different drinking patterns. More research is necessary to determine the factors associated with differences in drinking across Hispanic groups.

Adolescent↗
PubMed1999

Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family.

Mammalian TIF1alpha and TIF1beta (KAP-1/KRIP-1) are related transcriptional intermediary factors that possess intrinsic silencing activity. TIF1alpha is believed to be a euchromatic target for liganded nuclear receptors, while TIF1beta may serve as a co-repressor for the large family of KRAB domain-containing zinc finger proteins. Here, we report an association of TIF1beta with both heterochromatin and euchromatin in interphase nuclei. Co-immunoprecipitation of nuclear extracts shows that endogenous TIF1beta, but not TIF1alpha, is associated with members of the heterochromatin protein 1 (HP1) family. However, in vitro, both TIF1alpha and TIF1beta interact with and phosphorylate the HP1 proteins. This interaction involves a conserved amino acid motif, which is critical for the silencing activity of TIF1beta but not TIF1alpha. We further show that trichostatin A, an inhibitor of histone deacetylases, can interfere with both TIF1 and HP1 silencing. The silencing activity of TIF1alpha appears to result chiefly from histone deacetylation, whereas that of TIF1beta may be mediated via both HP1 binding and histone deacetylation.

Amino Acid Sequence↗
PubMed1999

Phase II study of gemcitabine and vindesine in patients with previously untreated non-resectable non-small-cell lung cancer.

Because both vindesine and gemcitabine are active drugs in advanced non-small-cell lung cancer (NSCLC), with different modes of action and only partly overlapping toxicity, a phase II study was performed. Gemcitabine 1000 mg m(-2) was given on days 1, 8 and 15 every 4 weeks, while vindesine 3 mg m(-2) was administered weekly for 7 weeks, then every 2 weeks. A total of 42 patients with nonresectable NSCLC were included. The median age of patients was 56 years; 57% were men, 52% had adenocarcinoma, 31% squamous cell carcinoma and 17% had large-cell carcinoma. The performance status ranged from 0 to 2 with 83% in performance status 1. The majority (55%) had stage IV disease, while 40% had stage III B and 5% stage III A disease. WHO grade 3-4 leucopenia occurred in five patients (12%) and 9% had grade 4 neutropenia. Thrombocytopenia grade 3-4 was observed in six patients (15%). There were no septic death or bleeding episodes. One patient had a transient WHO grade 4 increase in bilirubin, and four patients had a decrease in glomerular filtration rate below the normal limit; one of these patients developed a non-reversible renal insufficiency. Ten patients (24%) complained of dyspnoea of uncertain mechanism, possibly involving bronchoconstriction. There were one complete and seven partial responses among 40 assessable patients (20%, 95% confidence limits 9-36%). Median response duration was 31 weeks (range 11-83 weeks) and median survival time 31 weeks (range 2-171 weeks). The current combination of gemcitabine and vindesine does not appear to be promising for further examination because of the toxicity and somewhat disappointing activity.

Adult↗
PubMed1999

Assessment of pH and oxygen status during hemodialysis using the arterial blood line in patients with an arteriovenous fistula.

BACKGROUND: In patients with arteriovenous fistulas, assessment of pH and oxygen status during hemodialysis (HD) using the extracorporeal dialysis arterial blood line is widely used both in daily routine and in most studies investigating hypoxia during HD. We designed this study to evaluate whether results of blood gas samples drawn from the extracorporeal arterial line were clinically acceptable in assessing oxygen status. METHODS: We compared samples drawn from the extracorporeal arterial line with conventionally arterial punctures during 18 routine HD sessions. The samples were drawn simultaneously and analyzed immediately for blood gases, pH and hemoximetry values. RESULTS: No significant difference was found between the values from the radial artery and the extracorporeal arterial blood line except for FMetHb. CONCLUSION: Thus, obtaining samples from the extracorporeal dialysis arterial blood line to evaluate the parameters of the oxygen status (pH, pO(2), pCO(2), ctHb, sO(2), FCOHb and ctO(2)) during routine HD is a clinically convenient and accurate sampling approach.

Arteriovenous Shunt, Surgical↗
PubMed1998

TIF1alpha: a possible link between KRAB zinc finger proteins and nuclear receptors.

Ligand-induced gene activation by nuclear receptors (NRs) is thought to be mediated by transcriptional intermediary factors (TIFs), that interact with their ligand-dependent AF-2 activating domain. Included in the group of the putative AF-2 TIFs identified so far is TIF1alpha, a member of a new family of proteins which contains an N-terminal RBCC (RING finger-B boxes-coiled coil) motif and a C-terminal bromodomain preceded by a PHD finger. In addition to these conserved domains present in a number of transcriptional regulatory proteins, TIF1alpha was found to contain several protein-protein interaction sites. Of these, one specifically interacts with NRs bound to their agonistic ligand and not with NR mutants that are defective in the AF-2 activity. Immediately adjacent to this 'NR box', TIF1alpha contains an interaction site for members of the chromatin organization modifier (chromo) family, HP1alpha and MOD1, which both are heterochromatinic proteins. Finally, TIF1alpha also has a binding site for KRAB silencing domains of C2H2 zinc finger proteins. TIF1beta, another member of the TIF1 gene family, has some interacting partners in common with TIF1alpha. TIF1beta can interact with HP1alpha, MOD1 and KRAB domains, but apparently not with NRs. Both TIF1alpha and TIF1beta repress transcription when fused to a DNA binding domain in transiently transfected mammalian cells. A model discussing the potential function(s) of TIF1s in the control of transcription at the level of the chromatin template will be presented.

Animals↗
PubMed1998

Oxygen and 2,3 biphosphoglycerate (2,3-BPG) during haemodialysis.

Eleven patients with chronic renal failure who were being treated with haemodialysis three times a week were monitored for a total of 34 haemodialysis sessions. Erythrocyte 2,3-biphosphoglycerate (2,3-BPG) concentration was analysed immediately before initiation of bicarbonate haemodialysis and 1 h afterwards. The 2,3-BPG concentration was expressed relative to the haemoglobin tetramer (Hb4) concentration as the 2,3-BPG/Hb4 ratio and compared with blood gas analyses and biochemical variables important for characterizing uraemia. During the first hour of haemodialysis the 2,3-BPG/Hb4 ratio decreased (p < 0.002), but the magnitude of the decrease did not significantly correlate with the 2,3-BPG/Hb4 ratio measured before haemodialysis (p=0.104). The decrease is most likely to be caused by the haemodialysis procedure itself. Mechanical stress on the erythrocytes is believed to cause the 2,3-BPG to escape; it is then removed by haemodialysis. Physiologically, an increase in 2,3-BPG would be expected to counteract the hypoxia which is frequently observed during haemodialysis. However, the present results show the opposite, a decrease in 2,3-BPG. No significant correlation was shown between the haemoglobin concentration and the 2,3-BPG/Hb4 ratio before dialysis (p=0.414). The pH showed a significant positive correlation with the 2,3-BPG/Hb4 ratio before dialysis, whereas the arterial pO2 and the 2,3-BPG/Hb4 ratio before dialysis were insignificantly negatively correlated. The concentrations of calcium, phosphate, creatinine, urea and albumin did not correlate significantly with the change in 2,3-BPG/Hb4-ratio after 1 h. The 2,3-BPG/Hb4 ratio (p=0.03) sampled just before dialysis correlated significantly and positively with the total weekly dosage of erythropoietin given to the patients.

2,3-Diphosphoglycerate↗
PubMed1997

[The prognostic significance of progesterone receptor level in endometrial cancer].

Oestrogen receptor (ER) and progesterone receptor (PR) contents were determined by biochemical (dextran charcoal-coated (DCC) assay) and immunohistochemical (ICA) methods in biopsies from 145 primary endometrial adenocarcinomas. Correlations between receptor contents and cancer specific survival were examined in a multivariate analysis including histopathological characteristics. Median patient follow-up time was 67 months with 18 cancer deaths. "High" PR levels correlated significantly (p = 0.004) with survival, independently of stage risk group (stages Ia-Ib vs Ic-IV). Patient age and histological grade were prognostic factors in a univariate setting but these parameters were eliminated in the multivariate model. The association between PR contents and cancer survival suggests that determination of PR can be of importance in the evaluation of endometrial cancer.

Adult↗
PubMed1997

Comparison of the reproducibility of the WHO classifications of 1975 and 1994 of endometrial hyperplasia.

In a blinded, randomized design, six histopathologists with an interest in gynecological pathology examined the inter- and intraobserver variation of the histopathological diagnosis of endometrial hyperplasia according to the World Health Organization (WHO) classification of 1975 and the new WHO classification of 1994. On four occasions, the pathologists assessed hematoxylin/eosin-stained slides from 128 cases originally diagnosed and coded in the Snomed system as endometrial hyperplasia. In the first and third rounds, the slides were classified according to the 1975 classification and in the second and fourth rounds according to the 1994 classification. The overall interobserver agreement in the two rounds where the 1975 classification was used was 0.47 and 0.51, and the kappa values 0.24 [95% confidence interval (CI) 0.21-0.27] and 0.30 (95% CI 0.27-0.33). The overall interobserver agreement in the two rounds using the 1994 classification was 0.45 and 0.41 and the kappa values 0.25 (95% CI 0.23-0.28) and 0.20 (95% CI 0.17-0.22). Reducing the classification to two categories with clinical significance (atypical endometrial hyperplasia versus others in the 1975 classification, and atypical endometrial hyperplasia, complex versus others in the 1994 classification) increased the overall agreement of the 1975 classification in both rounds to 0.91 and of the 1994 classification to 0.92 and 0.90. The kappa values increased to 0.54 (95% CI 0.49-0.58) and 0.49 (95% CI 0.45-0.54) in the 1975 classification and to 0.59 (95% CI 0.54-0.63) and 0.42 (95% CI 0.37-0.46) in the 1994 classification. The intraobserver overall agreement for the 1975 classification ranged from 0.80 to 0.55 and the kappa values from 0.70 (95% CI 0.58-0.81) to 0.28 (95% CI 0.17-0.39). The intraobserver overall agreement for the 1994 classification ranged from 0.71 to 0.46 and the kappa values from 0.60 (95% CI 0.51-0.70) to 0.20 (95% CI 0.09-0.30). It is concluded that there is considerable inter- and intraobserver variation using both the 1975 and the 1994 classifications of endometrial hyperplasia. We propose that there is need for a specification and for a simplification of the classification.

Double-Blind Method↗
PubMed1996

E-box sequence and context-dependent TAL1/SCL modulation of basic helix-loop-helix protein-mediated transcriptional activation.

TAL1/SCL is a basic helix-loop-helix (bHLH) oncoprotein that is expressed in several cell lines including many hematolymphoid cells, but not in T- and B-lineage cells. The TAL1 gene was originally discovered as being transcriptionally activated by chromosomal rearrangements in T-cell acute lymphoblastic leukemia (T-ALL). Here we have shown that TAL1 and the ubiquitously expressed murine bHLH transcription factor ALF1 formed heterodimers that, compared with ALF1 homodimers, had a more restricted E-box specificity and bound preferentially to the glucocorticoid-responsive E-box (Egre) motif (AACAGATGGT). Overexpression of the dominant inhibitory HLH protein Id1 in NIH3T3 cells reduced the transcriptional activity mediated by ALF1 homodimers, whereas the transcriptional activity mediated by TAL1/ALF1 heterodimers was resistant to Id overexpression. Our results show that ALF1 may serve as a dimerization partner for the bHLH oncoprotein TAL1 and form a complex with a distinctive DNA binding property. These findings support the hypothesis that the leukemic characteristics of the TAL1 oncoprotein could be mediated by activation of a set of target genes as heterodimeric complexes with ubiquitously expressed bHLH transcription factors such as ALF1 and that a principal role of TAL1 might be to neutralize an Id-mediated inactivation.

3T3 Cells↗
PubMed1996

A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors.

Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate complex effects on development, differentiation and homeostasis. They regulate the transcription of their target genes through binding to cognate DNA sequences as homodimers or heterodimers. The molecular mechanisms underlying transcriptional activation by NRs are still poorly understood, although intermediary factors (mediators) appear to be involved in mediating the transactivation functions of NRs. TIF1 has been identified previously as a protein that interacts specifically with the ligand binding domain of several nuclear receptors, both in yeast and in vitro. The characteristics of these interactions have led us to suggest that TIF1 might be a mediator of the NR ligand-inducible activation function AF-2. Using a two-hybrid screening in yeast, we have now identified two TIF1-binding proteins, mHP1 alpha and mMOD1, that are mouse homologues of the Drosophila heterochromatinic protein 1. Using mHP1 alpha as a bait in a second two-hybrid screening, we have isolated cDNAs encoding proteins that are also very likely to be involved in chromatin structure and function, as well as a protein structurally and functionally related to TIF1 (renamed TIF1 alpha), which was named TIF1 beta. Here we discuss how the function of members of the TIF1 family in the control of transcription could be exerted at the level of the structure of the chromatin template.

Amino Acid Sequence↗
PubMed1996

The combination of p53 and age predict cancer specific death in advanced stage (FIGO Ic-IV) of endometrial carcinoma of endometrioid type. An immunohistochemical examination of growth fraction: Ki-67, MIB-1 and PC10; suppressor oncogene protein: p53; oncogene protein: p185 and age, hormone treatment, stage, and histologic grade.

OBJECTIVE: Early surgical stage (FIGO Ia + b) is an excellent predictor of survival in endometrial carcinoma of endometrioid type (EC), in contrast to advanced stage which only predict cancer specific death (CSD) in approximately 20-30% of the patients. The value of growth fraction, p53 and p185 as predictor of CSD in EC was studied. STUDY DESIGN: One hundred and eleven patients (45% hormone-users) with EC were entered prospectively and consecutively into an immunohistochemical study of growth fraction (Ki-67, MIB-1 and PC10), suppressor oncogene protein (p53) and oncogene protein (p185). RESULTS: All markers except p185 intercorrelated significantly, although weakly, however, marked differences were found in median values of the markers of growth fraction (GF). It was shown that immunohistochemical demonstration of p53 and p185 proteins and stage correlates independently with CSD in EC. CONCLUSION: The study indicates that the markers of GF do not give exact information about the proliferative compartment of the EC, and it is shown that p53 correlate to CSD, while stage indicate crude death.

Age Factors↗