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PubMed2001

Looking for important change/differences in studies of responsiveness. OMERACT MCID Working Group. Outcome Measures in Rheumatology. Minimal Clinically Important Difference.

The purpose of this paper is to describe a classification system for studies of responsiveness that was designed to help organize these studies, and identify those with the potential to provide information on minimal clinically important difference (MCID). We developed a 3 dimensional cube into which studies of responsiveness can be categorized based on their evaluation of 3 attributes: 1. individual or group setting; 2. which scores are contrasted; and 3. the type of change or difference being assessed. We present and discuss examples of studies that fit into categories in the classification cube. This classification system helps to focus attention on whether the literature is able to provide information on the specific type of change a person is interested in. It reinforces that the ability of an instrument to detect a certain category of discrimination within the cube does not mean it will necessarily be responsive to another category. The cube has been shown here as a means to separate out studies that address important change. These studies can then be examined as the source of information on MCID.

Clinical Trials as Topic↗
PubMed1991

Nuclear import substrates compete for a limited number of binding sites. Evidence for different classes of yeast nuclear import receptors.

A nuclear receptor likely involved in nuclear protein import is described. Purified ATP-depleted yeast nuclei show saturable high-affinity binding of the yeast nuclear protein Mcm1. The dissociation constant for the binding is 0.5 microM, and the number of binding sites is approximately 3,500 per nucleus, equivalent to 10-30 binding sites per nuclear pore. Mcm1 competes with other yeast nuclear proteins Ste12 and Swi5, but not with Rap1 or Nop1, indicating that there may be different types of import receptors. Bound Mcm1 is resistant to extraction by nucleases, salt, and non-ionic detergent, but can be released by 5 M urea, suggesting that Mcm1 binds to a yeast equivalent of the nuclear pore complex-lamina fraction of higher eukaryotes.

Binding Sites↗
PubMed1984

Import of rat liver mitochondrial malate dehydrogenase. Binding of the precursor to mitochondria, an intermediate step in import.

We have previously reported that the precursor of rat liver mitochondrial malate dehydrogenase, synthesized in vitro, is about 1,500 to 2,000 Mr larger than the mature enzyme and can be processed to the mature size by isolated mitochondria from Chinese hamster ovary cells (Chien, S.-M. and Freeman, K. B. (1984) J. Biol. Chem. 259, 3337-3342). Furthermore, binding, but not processing, was observed in the presence of an uncoupler. Binding was insensitive to temperature and was completed within 2.5 min at 0 degrees C. The role of binding in the overall process of import of the precursor is now further characterized. The precursor form, bound either in the presence of an uncoupler or at 0 degrees C, was sensitive to trypsin suggesting that binding occurs on the mitochondrial outer membrane. Saturation of binding was observed with a limited amount of mitochondria and an excess of in vitro translated rat liver proteins indicating that there is a finite number of binding sites. Furthermore, when the precursor was prebound to mitochondria at 0 degrees C for 5 min, the precursor was processed to the mature size and the rate of processing was independent of the volume of reaction mixture. In contrast, the rate of processing of unbound precursor was dependent on reaction volume. These results strongly suggest that binding of the precursor of malate dehydrogenase to the mitochondrial outer membrane is an intermediate step in its import.

Animals↗
PubMed2004

The importance of importance in OCD memory research.

Investigations of memory and associated phenomena in obsessive-compulsive disorder (OCD) can advance our understanding of this often debilitating problem. Theoretical models predict both the presence and absence of memory biases in favour of threat-relevant information in association with anxiety disorders generally, and with OCD specifically. Two previous experiments (one involving compulsive washing and another involving compulsive checking) that demonstrated such a memory bias are reviewed in the context of the existing literature. Additionally, a new experiment failing to demonstrate such a bias (in association with compulsive ordering and arranging) is presented. The results are discussed in terms of cognitive-behavioural and information processing approaches to understanding OCD. It is argued that experiments which utilize stimuli that are low in ecological validity are unlikely to detect explicit memory biases in OCD. As such, experimental paradigms that are perceived as particularly significant, relevant and important to participants with OCD are encouraged.

Adult↗
PubMed1995

Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import.

We have fluorescently labeled one of the eight genomic segments of influenza virus RNA and a recombinant influenza viral protein, the nucleoprotein (NP), to investigate the requirement for their uptake into nuclei of digitonin-permeabilized cells. We found that the influenza viral NP behaves like a nuclear localization sequence (NLS) containing protein. Thus, at 0 degrees C it docks at the nuclear envelope only in the presence of the heterodimeric karyopherin (either karyopherin alpha 1 beta or karyopherin alpha 2 beta), and docking is competitively inhibited by an unlabeled NLS containing substrate. Like other NLS-containing proteins, at 20 degrees C NP is imported into the nucleus after further addition of the GTPase Ran and of p10. In contrast, the fluorescently labeled, 890-nucleotide-long viral RNA segment does not dock to the nuclear envelope or enter the nucleus either in the presence of exogenous cytosol or of karyopherin heterodimer, Ran, and p10. However, in the presence of NP the RNA is able to dock and enter the nucleus with transport requirements indistinguishable from those for docking and entry of NP. These data indicate that uptake of the influenza virus RNA segment is not via a signal in the RNA but via an NLS of a viral protein such as NP.

Animals↗
PubMed1999

Nup124p is a nuclear pore factor of Schizosaccharomyces pombe that is important for nuclear import and activity of retrotransposon Tf1.

The long terminal repeat (LTR)-containing retrotransposon Tf1 propagates within the fission yeast Schizosaccharomyces pombe as the result of several mechanisms that are typical of both retrotransposons and retroviruses. To identify host factors that contribute to the transposition process, we mutagenized cultures of S. pombe and screened them for strains that were unable to support Tf1 transposition. One such strain contained a mutation in a gene we named nup124. The product of this gene contains 11 FXFG repeats and is a component of the nuclear pore complex. In addition to the reduced levels of Tf1 transposition, the nup124-1 allele caused a significant reduction in the nuclear localization of Tf1 Gag. Surprisingly, the mutation in nup124-1 did not cause any reduction in the growth rate, the nuclear localization of specific nuclear localization signal-containing proteins, or the cytoplasmic localization of poly(A) mRNA. A two-hybrid analysis and an in vitro precipitation assay both identified an interaction between Tf1 Gag and the N terminus of Nup124p. These results provide evidence for an unusual mechanism of nuclear import that relies on a direct interaction between a nuclear pore factor and Tf1 Gag.

Alleles↗
PubMed2005

Identification of nuclear import and export signals within Fli-1: roles of the nuclear import signals in Fli-1-dependent activation of megakaryocyte-specific promoters.

The Ets factor Friend leukemia integration 1 (Fli-1) is an important regulator of megakaryocytic (Mk) differentiation. Here, we demonstrate two novel nuclear localization signals (NLSs) within Fli-1: one (NLS1) is located at the N terminus, and another (NLS2) is within the Ets domain. Nuclear accumulation of Fli-1 reflected the combined functional effects of the two discrete NLSs. Each NLS can independently direct nuclear transport of a carrier protein, with mutations within the NLSs affecting nuclear accumulation. NLS1 has a bipartite motif, whereas the NLS2 region contains a nonclassical NLS. Both NLSs bind importin alpha (IMPalpha) and IMPbeta, with NLS1 and NLS2 being predominantly recognized by IMPalpha and IMPbeta, respectively. Fli-1 also contains one nuclear export signal. Leptomycin B abolished its cytoplasmic accumulation, showing CRM1 dependency. We demonstrate that Ets domain binding to specific target DNA effectively blocks IMP binding, indicating that the targeted DNA binding plays a role in localizing Fli-1 to its destination and releasing IMPs for recycling back to the cytoplasm. Finally, by analyzing full-length Fli-1 carrying NLS1, NLS2, and combined NLS1-NLS2 mutations, we conclude that two functional NLSs exist in Fli-1 and that each NLS is sufficient to target Fli-1 to the nucleus for activation of Mk-specific genes.

Active Transport, Cell Nucleus↗
PubMed1990

[Importance and function of the melanocyte-stimulating hormone in malignant melanoma. Importance of MSH].

According to the present state of findings there are melanocyte-stimulating hormones (MSH) alpha, beta, gamma and delta with hormone alpha-MSH special physiological importance for man. Our study of special literature shows that the secretion of MSH is affected by exogene factors, different biorhythms and some diseases. Numerous investigation with melanocytes and melanoma cell cultures clearly show the impact of MSH on the function, regulation and the proliferation of pigment cells. The results presented contribute to the discussion of possibilities of improving diagnostics or therapy of malignant melanoma.

Biomarkers, Tumor↗
PubMed1982

Import of proteins into mitochondria. Extramitochondrial pools and post-translational import of mitochondrial protein precursors in vivo.

Extramitochondrial pools of mitochondrial precursor polypeptides can be detected in yeast spheroplasts which had been pulse-labeled for 3 min in the absence of inhibitors or for 10 min in the presence of an uncoupler of oxidative phosphorylation. In either case, these precursors can be post-translationally converted to the mature forms during a subsequent chase. Post-translational maturation of the precursor to F1-ATPase beta-subunit is accompanied by uptake of the polypeptide into mitochondria. Pools of precursor polypeptides are also found in pulse-labeled intact yeast cells, the pool sizes depending on the metabolic status of the cells. For example, if the rate of protein synthesis is lowered by cycloheximide, the precursor pool size decreases. This indicates that living yeast cells can, and apparently do, import polypeptides into mitochondria post-translationally.

Biological Transport↗
PubMed1997

[Bionomy, occurrence and importance of the giant liver fluke (Fascioloides magna), an important parasite of free-living ruminants].

The paper summarizes the most important knowledge of the giant liver fluke of ruminants, Fascioloides magna, with respect to its occurrence throughout the Northern Hemisphere, its fenotypic and genetic discriminative characteristics, its pathogenicity in various obligatory and facultative hosts and possible prophylaxis and medical control. The paper emphasizes the fact that new natural foci with heavy F. magna infections of deer regularly occur in Europe.

Animals↗
PubMed1994

Hepatitis E--an important cause of imported non-A, non-B hepatitis among migrant workers in Qatar.

In 1985, Glynn et al. [Journal of Medical Virology 17:371-375] reported on epidemic viral hepatitis in Qatar and concluded that 72% (91/126) had acute enterically transmitted non-A, non-B viral hepatitis (ET-NANBH). Most of the patients (98%) presented within 8 weeks of arrival in Qatar and were migrant workers from the Indian subcontinent. The data was reanalysed for evidence of infection with hepatitis E virus (HEV). Seventy-eight of 91 (86%) of stored sera were still suitable for analysis since collection in 1981. A newly described enzyme immunoassay (EIA) for both IgG and IgM anti-HEV was used (Abbott Laboratories, Delkenheim, Germany); 59/78 (76%) were positive for either or both assays. All but two were from the Indian subcontinent. The data suggest that HEV was the major cause of ET-NANBH in Qatar in 1981, particularly among newly arrived migrant workers from the Indian subcontinent.

Adult↗
PubMed2006

Embryo quality is more important for younger women whereas age is more important for older women with regard to in vitro fertilization outcome and multiple pregnancy.

OBJECTIVE: To determine the efficiency of embryo scoring systems for multiple pregnancy in women undergoing IVF procedures. DESIGN: Retrospective record analysis. SETTING: University hospital, tertiary medical center. PATIENT(S): Three hundred one patients undergoing controlled ovarian stimulation, IVF/intracytoplasmic sperm injection (ICSI), and day 3 embryo transfer. INTERVENTION(S): IVF/ICSI and embryo transfer. MAIN OUTCOME MEASURE(S): Rate of pregnancy and rate of multiple pregnancy. RESULT(S): The score of the best three embryos (Top3) was more correlated with IVF outcome than were the number of good embryos (P=.009) or the cumulative embryo score (P=.038). In the logistic regression model, Top3 was more relevant to IVF outcome and multiple pregnancy for younger patients than was age (P<.05). For older patients, age was more correlated with IVF outcome and multiple pregnancy than was embryo morphology (P<.05). CONCLUSION(S): The embryo morphology criteria can help reduce the number of embryos transferred into younger patients. We could use the age of patients as an indicator to determine the number of embryos transferred into older patients.

Adult↗
PubMed2004

"Important to test, important to support": attitudes toward disability rights and prenatal diagnosis among leaders of support groups for genetic disorders in Israel.

To situate the North American, and to some extent, European debate regarding disability rights and prenatal diagnosis in a social and cross-cultural context, this pilot study explored the views of leaders of organizations for disability rights and support groups for people with genetic conditions in Israel, where a similar debate has not emerged. Unlike many of their counterparts in North America, Israeli respondents were generally in favor of prenatal genetic testing as well as selective abortion, while at the same time expressing their commitment for already-born disabled individuals. The religious, legal, economic and socio-cultural context of this two-fold view of disability--which separates prenatal (preventive testing) and postnatal (supporting disability)--is discussed in order to further situate the debate in cross-cultural perspective. It is hypothesized that prenatal diagnosis and selective abortion are supported in secular Israeli society independently of the rabbinical stance, which forbids selective abortion, and in a way that reflects society's non-acceptance of congenital disability, veneration of the healthy body, and medical directiveness.

Abortion, Eugenic↗
PubMed1998

Site-directed mutagenesis of the A-factor receptor protein: Val-41 important for DNA-binding and Trp-119 important for ligand-binding.

The A-factor receptor protein (ArpA) plays a key role in the regulation of secondary metabolism and cellular differentiation in Streptomyces griseus. ArpA binds the target DNA site forming a 22 bp palindrome in the absence of A-factor, and exogenous addition of A-factor to the ArpA-DNA complex immediately releases ArpA from the DNA. An amino acid (aa) replacement at Val-41 to Ala in an alpha-helix-turn-alpha-helix (HTH) motif at the N-terminal portion of ArpA abolished DNA-binding activity but not A-factor-binding activity, suggesting the involvement of this HTH in DNA-binding. On the other hand, an aa replacement at Trp-119 to Ala generated a mutant ArpA that was unable to bind A-factor, thus resulting in an A-factor-insensitive mutant that bound normally to its target DNA in both the presence and absence of A-factor. These data suggest that ArpA consisting of two functional domains, one for HTH-type DNA-binding at the N-terminal portion and one for A-factor-binding at the C-terminal portion, is a member of the LacI family. Consistent with this, two ArpA homologues, CprA and CprB, from Streptomyces coelicolor A3(2), each of which contains a very similar aa sequence of the HTH to that of ArpA, also recognized and bound the same DNA target. However, neither CprA nor CprB recognized A-factor, probably due to much less similarity in the C-terminal domains.

4-Butyrolactone↗
PubMed2005

The importance of imported infections in maintaining hepatitis B in The Netherlands.

In The Netherlands, in May 1999 an enhanced surveillance of hepatitis B was begun to collect detailed information of patients with acute hepatitis B virus (HBV) infection. The objective was to gain insight in transmission routes and source of infection of new HBV cases. Through public health services, patients were interviewed on risk factors. It appeared that the majority (59%) acquired the infection through sexual contact; 52% of these by homosexual and 48% by heterosexual contact. In 60% of the heterosexual cases, the source of infection was a partner originating from a hepatitis B-endemic region. Sexual transmission is the most common route of transmission of acute hepatitis B in The Netherlands and introduction of infections from abroad plays a key role in the current epidemiology of HBV. As well as prevention programmes targeted at sexual high-risk groups, prevention efforts should focus more on the heterosexual transmission from HBV carriers.

Adult↗