Mapping of the human PAWR (par-4) gene to chromosome 12q21.
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Apoptosis Regulatory Proteins↗
Biomedical subjects
C Hansen
Publications and source records attributed to C Hansen.
Isolation of the human beaded-filament structural protein 1 gene (BFSP1) and assignment to chromosome 20p11.23-p12.1.
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Chromosome Mapping↗
[Bioequivalence of a combination of levothyroxine and iodine in comparison with levothyroxine only. A controlled double-blind study of bioavailability].
BACKGROUND: Iodine deficiency is the main cause of endemic goitre. Iodine supplementation and decrease of pituitary TSH are the therapeutical aims. In this study, bioavailability of levothyroxine combined with iodide and the same dose of levothyroxine alone were compared. PATIENTS AND METHODS: Fourty-eight subjects aged 18 to 40 years were randomly assigned for 6 days either 150 micrograms levothyroxine and 150 micrograms iodide (group A, n = 25) or 150 micrograms levothyroxine (group B, n = 23). Baseline TSH and thyroid hormones were measured 2 days before starting therapy as well as daily till day 6. TRH-test (delta TSH) and thyroid sonography were performed at day -2 and 6. RESULTS: During therapy baseline TSH decreased markedly from 1.26 to 0.35 mU/ml (median) in group A and from 1.37 to 0.39 to 0.39 mU/ml in group B (both p < 0.001), as well as delta TSH (A from 5.66 to 2.61 mU/ml; B from 6.3 to 2.95 mU/ml; p < 0.001). Difference of delta TSH (day -2 versus day 6) was negatively correlated to body surface (r = -0.307; p < 0.05). TT4 levels increased in both groups (A from 7.1 to 9.1 microU/dl; B from 7.2 to 9.4 microU/dl; p < 0.005). No significant differences were noted between both groups for thyroid-related parameters. In both groups, confidence intervals for baseline TSH and TT4 were in the expected range. CONCLUSION: In this study, similar bioavailability and bioequivalence for levothyroxine and the combination of levothyroxine with iodide were demonstrated.
Adolescent↗
Human rab11a: transcription, chromosome mapping and effect on the expression levels of host GTP-binding proteins.
Rab11a is a member of the rab-branch of the ras-like small GTP-binding protein superfamily that is associated with both constitutive and regulated secretory pathways. Using a direct procedure for cDNA cloning of small ras-related GTPases, that is based on the screening of eukaryotic cDNA expression libraries using [alpha-32P]GTP as a probe, we have isolated two cDNA clones encoding rab11a. Both clones share identical coding sequences, but differ in the length and sequence of their 3' untranslated regions (3'-UTR). Northern blot hybridisation analysis of various human tissues revealed indeed two mRNA species with lengths of 1.0 and 2.3 kb, respectively. Sequence analysis of the cDNAs identified two different putative polyadenylation signals (AATAAA) at positions 927 and 2302 of the larger transcript. In addition, the 3'-UTR of the larger transcript exhibited several AU-rich elements (ARE) that are believed to control gene expression by regulating the rate of mRNA degradation. Southern blots of human DNA digested with several rare restriction enzymes, and separated by pulse-field gel electrophoresis, yielded the same macro-restriction fragment pattern when hybridised with probes that discriminate between the two transcripts. Taken together, these findings imply that the two mRNA species originate from a single gene, which we have mapped to 15q21.3-q22.31, by the use of different polyadenylation sites. As expected, both rab11a-cDNAs yielded the same protein product when transiently expressed in COS-1 cells, and surprisingly, upregulated the proteome expression profile (de novo synthesis or posttranslational modification of preexisting proteins) of a few other, yet unknown GTP-binding proteins.
Amino Acid Sequence↗
[Individually dosed levothyroxine with 150 micrograms iodide versus 100 micrograms levothyroxine combined with 100 micrograms iodide. A randomized double-blind trial].
BASIC PROBLEM AND OBJECTIVE: Intrathyroid deficiency and the influence of thyroid stimulating hormone (TSH) are the main pathogenetic factors in the development of endemic euthyroid goitre. Goitre reduction is achieved with either administration of levothyroxine, which diminishes hypophyseal TSG production, or of iodide. Aim of this study was to compare the efficacy of treatment with a dose-fixed combination of levothyroxine plus iodide with that of an individualized dosage of levothyroxine plus iodide. PATIENTS AND METHODS: After randomization 49 patients with euthyroid goitre (24 women, 25 men, aged 20-43 years) were treated for 12 weeks in a double-blind trial. Patients in group A received levothyroxine in a weight-adapted dosage (75,100 or 150 micrograms) plus 150 micrograms iodide, while those in group B were given a fixed dosage of 100 micrograms levothyroxine plus 100 micrograms iodide. Basal TSH, thyroid hormones, iodide excretion, hyperthyroid score and sonographic volume of the thyroid were determined before treatment and after 12 weeks. RESULTS: Basal TSH levels were reduced in both groups (P < 0.0001), without significant difference between the two groups (median relative change: group A 78.1%, group B 52.8%). Thyroid volume was decreased independently of the form of treatment (P < 0.0001) (median relative reduction: group A 37.6%, group B 30.9%; difference not significant). Iodide excretion rose in both groups, without significant difference (group A 107%, group B 49%). There was hardly any change of the hyperthyroid score in both groups. There were no side effects. CONCLUSION: Both forms of medication were equally efficacious and well tolerated in the treatment of euthyroid goitre.
Adult↗
The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region.
Uptake of vitamin B12 (cyanocobalamin) is facilitated by the cobalamin-binder gastric intrinsic factor (IF), which recognizes a 460-kD receptor, cubilin, present in the epithelium of intestine and kidney. Surface plasmon resonance analysis of ligand-affinity-purified human cubilin demonstrated a high-affinity calcium- and cobalamin-dependent binding of IF-cobalamin. Complete cDNA cloning of the human receptor showed a 3597 amino acid peripheral membrane protein with 69% identity to rat cubilin. Amino-terminal sequencing of the receptor indicates that the cDNA sequence encodes a precursor protein undergoing proteolytic processing due to cleavage at a recognition site (Arg7-Glu8-Lys9-Arg) for the trans-Golgi proteinase furin. Using fluorescence in situ hybridization, radiation hybrid mapping, and screening of YAC clones, the human cubilin gene was mapped between the markers D10S1661 and WI-5445 on the short arm of chromosome 10. This is within the autosomal recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown recessive-gene locus of juvenile megaloblastic anemia caused by intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's disease). In conclusion, the present molecular and genetic information on human cubilin now provides circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular background of this hereditary form of megaloblastic anemia.
Amino Acid Sequence↗
Isolation of antiSLIP1-reactive boar sperm P68/62 and its binding to mammalian zona pellucida.
Single-step purification of boar sperm P68/62 that is cross-reactive with a polyclonal antibody against sulfolipidimmobilizing protein 1 (SLIP1) was achieved by chromatofocusing. This method is useful for obtaining P68/62 in quantity. The two proteins, P68 and P62, were antigenically related, since the antibody generated specifically against the 68-kDa band reacted with both the 68- and 62-kDa bands. Like rat testis SLIP1, purified boar sperm P68/62 bound to sulfogalactosylglycerolipid (SGG) and inhibited sperm-egg binding in a dose-dependent manner when added exogenously to sperm-egg coincubates. This inhibitory effect occurred at the level of the zona pellucida (ZP), and further studies showed that biotinylated boar sperm P68/62 bound to the ZP of unfertilized mouse eggs. Furthermore, biotinylated boar sperm P68/62 bound to isolated ZP of unfertilized eggs from other species, including pig, rat, cat, dog, and human, as well as to ZP of intact fertilized mouse eggs and preimplantation embryos of various developmental stages, although the degree of its binding to the ZP of intact eight-cell embryos, morulae, and blastocysts was much lower than that of fertilized eggs and two-cell embryos. These results suggest that P68/62 of capacitated sperm must act together with other sperm surface proteins/molecules that regulate zona binding specificity within homologous species and in unfertilized eggs. Together with our previous findings, we suggest that rather than being a true ZP receptor, sperm P68/62 may be involved in the initial step of sperm-ZP binding that is adhesive in nature.
Animals↗
Analysis of orbital T cells in thyroid-associated ophthalmopathy.
Thyroid-associated ophthalmopathy (TAO) has a major effect on the two compartments of the retro-orbital (RO) space, leading to enlargement of the extraocular muscles and other RO tissues. T lymphocyte infiltration of RO tissue is a characteristic feature of TAO and there is current interest in whether these T cells are specifically and selectively reactive to RO tissue itself. We recently established 18 T cell lines (TCL) from RO adipose/connective tissue of six patients with severe TAO by using IL-2, anti-CD3 antibodies and irradiated autologous peripheral blood mononuclear cells (PBMC) to maintain the growth of T cells reactive to autologous RO tissue protein fractions. Here we report on the phenotype characteristics and cytokine gene expression profiles of these orbital TCL and on their immunoreactivity to the organ-specific thyroid antigens thyrotropin receptor (TSH-R), thyroidal peroxidase (TPO) and thyroglobulin (TG). Flow cytometry revealed that 10 TCL were predominantly of CD4+ phenotype, three being mostly CD8+ and five neither CD4+ nor CD8+. Analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) of cytokine gene expression revealed both Th1- and Th2-like products in all TCL: IL-2 product (in 17 TCL), interferon-gamma (IFN-gamma) (n = 10), tumour necrosis factor-beta (TNF-beta) (n = 15), IL-4 (n = 12), IL-5 (n = 17), IL-6 (n = 13), TNF-alpha (n = 12) and IL-10 (n = 4). Reactivity to thyroid antigens was observed only in two TCL, the other 16 being uniformly unreactive. Although 10 out of 18 RO tissue-reactive TCL were predominantly CD4+ there were no significant relationships between TCL phenotype, cytokine gene profile, magnitude of reactivity to RO tissue protein or the (rare) occurrence of thyroid reactivity. The findings of both Th1- and Th2-like cytokine gene expression in all RO tissue-reactive TCL support the concept that TAO is a tissue-specific autoimmune disease, distinct immunologically from the thyroid, and involving both T cell and B cell autoimmune mechanisms in disease pathogenesis.
Adult↗
Muscarinic K+ channel in the heart. Modal regulation by G protein beta gamma subunits.
The membrane-delimited activation of muscarinic K+ channels by G protein beta gamma subunits plays a prominent role in the inhibitory synaptic transmission in the heart. These channels are thought to be heterotetramers comprised of two homologous subunits, GIRK1 and CIR, both members of the family of inwardly rectifying K+ channels. Here, we demonstrate that muscarinic K+ channels in neonatal rat atrial myocytes exhibit four distinct gating modes. In intact myocytes, after muscarinic receptor activation, the different gating modes were distinguished by differences in both the frequency of channel opening and the mean open time of the channel, which accounted for a 76-fold increase in channel open probability from mode 1 to mode 4. Because of the tetrameric architecture of the channel, the hypothesis that each of the four gating modes reflects binding of a different number of Gbeta gamma subunits to the channel was tested, using recombinant Gbeta1 gamma5. Gbeta1 gamma5 was able to control the equilibrium between the four gating modes of the channel in a manner consistent with binding of Gbeta gamma to four equivalent and independent sites in the protein complex. Surprisingly, however, Gbeta1 gamma5 lacked the ability to stabilize the long open state of the channel that is responsible for the augmentation of the mean open time in modes 3 and 4 after muscarinic receptor stimulation. The modal regulation of muscarinic K+ channel gating by Gbeta gamma provides the atrial cells with at least two major advantages: the ability to filter out small inputs from multiple membrane receptors and yet the ability to create the gradients of information necessary to control the heart rate with great precision.
Adenosine↗
Glycosaminoglycans in thyroid eye disease.
Orbital accumulation of hydrophilic, interstitial glycosaminoglycans (GAG) and subsequent expansion of retrobulbar tissue lead to the clinical manifestation of exophthalmos in patients with thyroid eye disease (TED). In order to analyze whether the alteration of distribution pattern and biochemical composition of GAG and proteoglycans play a role in the development of the disease, a highly specific high-pressure liquid chromatography (HPLC) method was developed. The concentration of total GAG, chondroitin sulfate A (CA), dermatan sulfate (DS), and hyaluronic acid (HA) was determined in patients and controls, revealing marked differences in urinary concentration of total GAG and HA, as well as an elevation of CA in patients versus controls. Method sensitivity was 0.86 for patients with active disease, and 0.87 for patients with untreated ophthalmopathy, whereas specificity was 1.0 for patients with inactive disease. Patients with increased GAG concentration responded well to steroids and/or orbital irradiation. Furthermore, distribution pattern of orbital extracellular matrix GAG exhibited a significant increase in the tissue fractions of CA and HA in patients with TED in comparison to controls. In conclusion, GAG polysaccharides not only play a major role in the pathogenesis of TED but have been successfully introduced as an activity marker of the disease.
Chondroitin Sulfates↗
Clinicopathologic significance of transitional cell carcinoma pattern in nonlocalized ovarian epithelial tumors (stages 2-4).
The transitional cell carcinoma (TCC) pattern has been associated with favorable outcome in patients with late-stage ovarian epithelial tumors who receive chemotherapy. We examined the clinicopathologic significance of TCC and explored other histopathologic prognostic indicators for patients with ovarian epithelial tumor. The surgical records of patients at the University of California at Davis Medical Center who underwent treatment for stages 2 to 4 ovarian epithelial tumor were studied retrospectively; the histopathologic features were correlated with outcome. The TCC pattern was identified in 32 of 136 ovarian epithelial tumors (23.5%): 18 (13.2%) as a predominant (> 50%) and 14 (10.3%) as a focal (< or = 50% but > 25%) histologic pattern. The other predominant histopathologic types were serous (65.4%), mucinous (11.7%), endometrioid (3.6%), clear cell (3.6%), and small cell (1.5%) carcinoma. Architectural grade was as follows: low malignant potential, 13 cases; grade I, 34 cases; grade II, 63 cases; grade III, 26 cases. Nuclear grade was as follows: low grade, 27 cases; high grade, 109 cases. One hundred seven patients had dominant ovarian tumors, and 29 had diffuse primary peritoneal epithelial tumor. One hundred twenty-three cases (90%) of peritoneal disease were invasive; 11 (10%) were noninvasive. Peritoneal disease histopathologic density was 50% or less cross-sectional involvement in 68 patients (50%) and greater than 50% in 68 (50%). Follow-up data were available for 118 patients: 46 patients had persistent disease that was unresponsive to chemotherapy; 36 of these patients died of disease at 0 to 41 months (mean, 15.6 months; median, 23.5 months). Ten patients were alive at 16 to 40 months (mean, 24.5 months; median, 20.5 months). Thirty-six patients had recurrent disease after 6 to 66 months (mean, 23.5 months; median, 18.5 months); 20 of these patients died of disease after 10 to 69 months (mean, 33.7 months; median, 30 months), and 16 were alive after 12 to 159 months (mean, 33.7 months; median, 30 months). Thirty-six patients had no evidence of disease at 12 to 159 months of follow-up (mean, 49.5 months; median, 31 months). The TCC pattern, either predominant or focal, was not associated with disease status or survival time (P > .05). Predictors of recurrent or persistent disease and survival, respectively, were invasive peritoneal disease (P < .05, P < .0001) and greater than 50% cross-sectional area histologic density of peritoneal disease (P < .01, P < .01). Grade, histologic type, and diffuse primary peritoneal vs ovarian location were not predictors of outcome. The TCC pattern was present in at least a focal (> 25%) component in 23% of epithelial tumors; however, this finding did not reach significance as a predictor of outcome in this study. The histologic pattern of the peritoneal disease (invasiveness and density) was a much stronger predictor of disease response and survival.
Brenner Tumor↗
Cognitive-behavioral treatment of school phobia.
OBJECTIVE: To conduct a controlled group outcome investigation of the efficacy of cognitive-behavioral treatment for school phobia. METHOD: Fifty-six children with school phobia were randomly assigned to 12 weeks of cognitive-behavioral therapy or an attention-placebo control condition. Pre- and posttreatment school attendance, self-reported anxiety and depression, and diagnostic status were compared. RESULTS: Both the experimental and control treatments were equally effective at returning children to school. Both treatments also were effective in reducing children's anxiety and depressive symptoms. Follow-up revealed no differences between groups when the children reentered school the next school year. CONCLUSIONS: Overall, results suggest that psychosocial treatments are effective at returning school-phobic children to school and that the highly structured cognitive-behavioral approach may not be superior to more traditional educational and supportive treatment methods.
Adolescent↗
Apolipoprotein E alleles in mothers of trisomy 18 conceptuses.
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Alleles↗
Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis.
BACKGROUND: Black tea is known to be a potent inhibitor of intestinal absorption of non-haem iron at least in healthy subjects. AIMS: To investigate this effect in patients with genetic haemochromatosis, and, more importantly, the effect of regular tea drinking on the accumulation of storage iron in these patients over one year. PATIENTS: Investigations were carried out on 18 patients with clinically proven genetic haemochromatosis. For the study of storage iron accumulation, they were separated into a group instructed to drink a particularly tannin rich tea regularly with meals and a control group. METHODS: Intestinal iron absorption from a test meal was measured using whole body counting. Body iron stores were evaluated quantitatively by exhaustive phlebotomy, using haemoglobin, saturation of serum iron binding capacity, and serum ferritin for the assessment of body iron status. RESULTS: A significant reduction in iron absorption was observed when the test meal was accompanied by drinks of tea instead of water. In the tea drinking group, the increase in storage iron was reduced by about one third compared with that of the control group. CONCLUSIONS: Regular tea drinking with meals reduces the frequency of phlebotomies required in the management of patients with haemochromatosis.
Adult↗
Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel.
The human intermediate-conductance, Ca2+-activated K+ channel (hIK) was identified by searching the expressed sequence tag database. hIK was found to be identical to two recently cloned K+ channels, hSK4 and hIK1. RNA dot blot analysis showed a widespread tissue expression, with the highest levels in salivary gland, placenta, trachea, and lung. With use of fluorescent in situ hybridization and radiation hybrid mapping, hIK mapped to chromosome 19q13.2 in the same region as the disease Diamond-Blackfan anemia. Stable expression of hIK in HEK-293 cells revealed single Ca2+-activated K+ channels exhibiting weak inward rectification (30 and 11 pS at -100 and +100 mV, respectively). Whole cell recordings showed a noninactivating, inwardly rectifying K+ conductance. Ionic selectivity estimated from bi-ionic reversal potentials gave the permeability (PK/PX) sequence K+ = Rb+ (1.0) > Cs+ (10.4) >> Na+, Li+, N-methyl-D-glucamine (>51). NH+4 blocked the channel completely. hIK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM.
Azepines↗
Predictors of severity of absenteeism in children with anxiety-based school refusal.
Examined possible relations among sociodemographic, clinical, and familial variables and level of school absenteeism in children with anxiety-based school refusal. These children exhibit a great deal of variability in the severity of school refusal, with some youngsters missing only an occasional day of school, whereas other exhibit pervasive school absenteeism. Participants were 76 children referred for treatment of anxiety-based school refusal. Children and a parent completed a structured clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children) and self-report measures that assess children's levels of fear (Fear Survey Schedule for Children-Revised), trait and somatic anxiety (Modified State-Trait Anxiety Inventory for Children), and depressive symptomatology (Children's Depression Inventory), as well as family environment characteristics (Family Environment Scale). Regression analyses revealed that older age, lower levels of fear, and less active families were primary predictors of greater levels of school absenteeism.
Absenteeism↗
[Combination therapy of endemic goiter with two different thyroxine/iodine combinations].
AIM: Of this study was to investigate the extent of thyrotropin (TSH) suppression and volume reduction in combination therapy of endemic goitre. We compared an individually adapted dose of thyroxine with a fixed dose. METHODS: 105 patients of a multicenter study (randomised, single blinded, controlled) received daily a weight-adjusted LT4-dose in combination with 150 micrograms iodide (group A) or a fixed combination of 100 micrograms LT4 plus 100 micrograms iodide (group B), respectively. At the beginning and after 12 weeks TSH-levels and goitre volume were examined. RESULTS: Although the amount of thyrotropin suppression showed no differences in both groups, there were more patients in the weight-adjusted treatment group with completely suppressed thyrotropin serum concentrations (p < 0.05). Both groups showed a reduction of goitre volume of 24% CONCLUSION: A weight-adjusted LT4-dose of 1.4 micrograms/kg body weight often leads to subclinical hyperthyroidism. To obtain low TSH-levels without complete suppression LT4-doses of 1.0 microgram/kg body weight plus 150 micrograms iodide are probably sufficient.
Adolescent↗
Ribozyme-mediated suppression of the G protein gamma7 subunit suggests a role in hormone regulation of adenylylcyclase activity.
Human HEK 293 cells present a simple and tractable system to directly test the hypothesis that the G protein gamma subunits contribute to the specificity of receptor signaling pathways in vivo. To begin to elucidate the functions of the individual gamma subunits in these cells, a ribozyme strategy was used to specifically inactivate the mRNA encoding the gamma7 subunit. A phosphorothioated DNA-RNA chimeric hammerhead ribozyme was constructed and analyzed for specificity toward the targeted gamma7 subunit. In vitro cleavage analysis of this ribozyme revealed a highly efficient cleavage activity directed exclusively toward the gamma7 RNA transcript. In particular, this ribozyme did not result in cleavage of the gamma12 RNA transcript, which is 75% identical to the gamma7 RNA transcript. Using a transient transfection assay, in vivo analysis of this ribozyme showed a specific reduction in both the mRNA and protein expression of the gamma7 subunit in HEK 293 cells. Coincident with this loss in gamma7 subunit, there was a specific reduction in the protein expression of the beta1 subunit, suggesting that the beta1 and gamma7 subunits may functionally interact to form a betagamma dimer in vivo. Functional analysis of the consequences of ribozyme-mediated suppression of the gamma7 subunit expression indicated that it was associated with significant attenuation of isoproterenol-, but not prostaglandin E1-, stimulated adenylylcyclase activity. Suppression of the gamma7 subunit expression had no effect on carbachol- and ATP-mediated stimulation of phosphatidylinositol turnover. Taken together, these results not only indicate the feasibility of using the ribozyme technology to determine the roles of individual gamma subunits in receptor-G protein-effector pathways in vivo, but they point to a specific role of the gamma7 subunit in the regulation of adenylylcyclase activity in response to isoproterenol.
Adenosine Triphosphate↗