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At least 1,207 records · Page 67Linked to original sources
PubMed2004

Electromechanical coupling, uncoupling, and ventricular function in patients with bundle branch block: a tissue-Doppler echocardiographic study.

BACKGROUND: Left bundle branch block (LBBB) is associated with impaired left ventricular (LV) function and increased morbidity and mortality, especially in patients with structural heart diseases. The mechanisms are poorly understood. SUBJECTS AND METHODS: Subjects with isolated LBBB (n=20), right bundle branch block (RBBB, n=20), and controls (C, n=20) were studied with standard two-dimensional (2D), and color-encoded tissue-Doppler echocardiography (TDE). Inter- and intraventricular systolic and diastolic coordination were assessed from the TDE velocity profiles. LV function was assessed by 2D echocardiography, by TDE-derived peak systolic velocities, and the atrioventricular (AV) plane displacement. RESULTS: Subjects with LBBB had longer electromechanical delays and longer isovolumic relaxation times than did the C and RBBB groups (P <0.001). For the LBBB subjects compared with the RBBB and C groups, ejection times were shorter, peak systolic velocities and AV plane displacements were lower, they had larger LV end-systolic volumes and lower LV ejection fraction (all P <0.001), and the atrial contribution to A-V plane displacement was higher (P <0.01). There were no differences in diastolic or filling times among the groups. CONCLUSIONS: In patients with LBBB, delayed regional electromechanical coupling and uncoupling leads to generalized intra- and interventricular asynchrony, thereby explaining the depressed regional and global LV functions. Assessment of the electromechanical coupling and uncoupling processes and their consequences on cardiac function in patients with BBB and structural heart diseases may be possible using TDE.

Analysis of Variance↗
PubMed2006

GFAP-expressing cells in the postnatal subventricular zone display a unique glial phenotype intermediate between radial glia and astrocytes.

Neural stem cells in the adult subventricular zone (SVZ) derive from radial glia and express the astroglial marker glial fibrillary acidic protein (GFAP). Thus, they have been termed astrocytes. However, it remains unknown whether these GFAP-expressing cells express the functional features common to astrocytes. Using immunostaining and patch clamp recordings in acute slices from transgenic mice expressing green fluorescent protein (GFP) driven by the promoter of human GFAP, we show that GFAP-expressing cells in the postnatal SVZ display typical glial properties shared by astrocytes and prenatal radial glia such as lack of action potentials, hyperpolarized resting potentials, gap junction coupling, connexin 43 expression, hemichannels, a passive current profile, and functional glutamate transporters. GFAP-expressing cells express both GLAST and GLT-1 glutamate transporters but lack AMPA-type glutamate receptors as reported for dye-coupled astrocytes. However, they lack 100 microM Ba2+-sensitive inwardly rectifying K+ (K(IR)) currents expressed by astrocytes, but display delayed rectifying K+ currents and 1 mM Ba2+-sensitive K+ currents. These currents contribute to K+ transport at rest and maintain hyperpolarized resting potentials. GFAP-expressing cells stained positive for both K(IR)2.1 and K(IR)4.1 channels, two major K(IR) channels in astrocytes. Ependymal cells, which also derive from radial glia and express GFAP, display typical glial properties and K(IR) currents consistent with their postmitotic nature. Our results suggest that GFAP-expressing cells in concert with ependymal cells can perform typical astrocytic functions such as K+ and glutamate buffering in the postnatal SVZ but display a unique set of functional characteristics intermediate between astrocytes and radial glia.

Amino Acid Transport System X-AG↗
PubMedDate not supplied

Modulation of biological functions of Naegleria fowleri amoebae by growth medium.

Two strains of Naegleria fowleri amoebae were studied when the amoebae were maintained in the same growth medium or in two different media. A weakly pathogenic strain of N. fowleri, LEE, and a highly pathogenic strain, LEEmpC1, were compared for growth properties, the presence or absence of surface structures termed food cups, cytopathogenicity, cellular locomotion, susceptibility to complement-mediated lysis and immunological relatedness by western immunoblot analysis when grown in Nelson medium or in Cline medium. The two different strains of N. fowleri, LEE and LEEmpC1, were more similar in protein profiles and functional activity when both strains were grown in the same nutritional medium. Differences in growth, proteins synthesized, cytopathogenicity, susceptibility to complement lysis and rate of locomotion were noted when the same strain was grown in different media. Naegleria fowleri grown in Cline medium demonstrated an increased rate of growth, an increase in its rate of locomotion, an increased resistance to complement lysis, and destroyed target nerve cells by contact-dependent lysis. In contrast, the same strain of amoeba grown in Nelson medium showed slower growth, destroyed target cells by trogocytosis, and was less resistant to complement-mediated lysis.

Animals↗
PubMed2006

In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel inhaled beta(2) adrenoceptor agonist with a 24-h duration of action.

Here, we describe the preclinical pharmacological profile of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel, chirally pure inhaled beta(2) adrenoceptor agonist, in comparison with marketed drugs. Indacaterol is close to a full agonist at the human beta(2) adrenoceptor (E(max) = 73 +/- 1% of the maximal effect of isoprenaline; pEC(50) = 8.06 +/- 0.02), whereas salmeterol displays only partial efficacy (38 +/- 1%). The functional selectivity profile of indacaterol over beta(1) human adrenoceptors is similar to that of formoterol, whereas its beta(3) adrenoceptor selectivity profile is similar to that of formoterol and salbutamol. In isolated superfused guinea pig trachea, indacaterol has a fast onset of action (30 +/- 4 min) similar to formoterol and salbutamol, and a long duration of action (529 +/- 99 min) comparable with salmeterol. In the conscious guinea pig, when given intratracheally as a dry powder, indacaterol inhibits 5-hydroxytryptamine-induced bronchoconstriction for at least 24 h, whereas salmeterol, formoterol, and salbutamol have durations of action of 12, 4, and 2 h, respectively. When given via nebulization to anesthetized rhesus monkeys, all of the compounds dose-dependently inhibit methacholine-induced bronchoconstriction, although indacaterol produces the most prolonged bronchoprotective effect and induces the lowest increase in heart rate for a similar degree of antibronchoconstrictor activity. In conclusion, the preclinical profile of indacaterol suggests that this compound has a superior duration of action compatible with once-daily dosing in human, together with a fast onset of action and an improved cardiovascular safety profile over marketed inhaled beta(2) adrenoceptor agonists.

Administration, Inhalation↗
PubMed2006

The FunGenES consortium: functional genomics in engineered embryonic stem cells.

Although the complete sequence of a mammalian genome defines the information content of each cell, understanding the selective usage of this information during the development of specific cell types is limited. The fundamental questions that remain to be answered includes, which are the gene subsets that define the pluripotential self-renewing state of embryonic stem (ES) cells, partially and terminally differentiated developmental states, and how are transitions between these states regulated (lineage commitment)? The FunGenES consortium has been formed to address this challenge by mapping the gene subsets involved in pluripotent, lineage committed, and selected differentiated cell types using gene expression profiling and functional screens. They create an atlas of mammalian genome participating in early and late developmental processes. To fulfil the aim, mouse ES cells were used as an in vitro developmental model system that is very close to the human as they are pluripotent. They can be differentiated through the three major developmental pathways ecto-, meso-, and endoderm into many committed cell types and can be genetically engineered with relative ease. Knowledge of genetic pathways in mouse ES cell differentiation and development might be translated to human ES cells and the potential development of stem cell-based therapies.

Animals↗
PubMed2006

Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII.

Wide variation in glucocorticoid (Gc) sensitivity exists between individuals which may influence susceptibility to, and treatment response of, inflammatory diseases. To determine a genetic fingerprint of Gc sensitivity 100 healthy human volunteers were polarized into the 10% most Gc-sensitive and 10% most Gc-resistant following a low dose dexamethasone (0.25 mg) suppression test. Gene expression profiling of primary lymphocytes identified the 98 most significantly Gc regulated genes. These genes were used to build a subnetwork of Gc signaling, with 54 genes mapping as nodes, and 6 non-Gc regulated genes inferred as signaling nodes. Twenty four of the 98 genes showed a difference in Gc response in vitro dependent on the Gc sensitivity of their donor individuals in vivo. A predictive model was built using both partial least squares discriminate analysis and support vector machines that predicted donor glucocorticoid sensitivity with 87% accuracy. Discriminating genes included bone morphogenetic protein receptor, type II (BMPRII). Transfection studies showed that BMPRII modulated Gc action. These studies reveal a broad base of gene expression that predicts Gc sensitivity and determine a Gc signaling network in human primary T lymphocytes. Furthermore, this combined gene profiling, and functional analysis approach has identified BMPRII as a modulator of Gc signaling.

Adult↗
PubMed2006

Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells.

BACKGROUND: The latent reservoir of human immunodeficiency virus type 1 (HIV-1) in resting CD4+ T cells is a major obstacle to the clearance of infection by highly active antiretroviral therapy (HAART). Recent studies have focused on searches for adjuvant therapies to activate this reservoir under conditions of HAART. Prostratin, a non tumor-promoting phorbol ester, is a candidate for such a strategy. Prostratin has been shown to reactivate latent HIV-1 and Tat-mediated transactivation may play an important role in this process. We examined resting CD4+ T cells from healthy donors to determine if prostratin induces Cyclin T1/P-TEFb, a cellular kinase composed of Cyclin T1 and Cyclin-dependent kinase-9 (CDK9) that mediates Tat function. We also examined effects of prostratin on Cyclin T2a, an alternative regulatory subunit for CDK9, and 7SK snRNA and the HEXIM1 protein, two factors that associate with P-TEFb and repress its kinase activity. RESULTS: Prostratin up-regulated Cyclin T1 protein expression, modestly induced CDK9 protein expression, and did not affect Cyclin T2a protein expression. Although the kinase activity of CDK9 in vitro was up-regulated by prostratin, we observed a large increase in the association of 7SK snRNA and the HEXIM1 protein with CDK9. Using HIV-1 reporter viruses with and without a functional Tat protein, we found that prostratin stimulation of HIV-1 gene expression appears to require a functional Tat protein. Microarray analyses were performed and several genes related to HIV biology, including APOBEC3B, DEFA1, and S100 calcium-binding protein genes, were found to be regulated by prostratin. CONCLUSION: Prostratin induces Cyclin T1 expression and P-TEFb function and this is likely to be involved in prostratin reactivation of latent HIV-1 proviruses. The large increase in association of 7SK and HEXIM1 with P-TEFb following prostratin treatment may reflect a requirement in CD4+ T cells for a precise balance between active and catalytically inactive P-TEFb. Additionally, genes regulated by prostratin were identified that have the potential to regulate HIV-1 replication both positively and negatively.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs.

D(2)-like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D(2)-like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-n-propyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D(2)-producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems, effects blocked by D(2), but not D(1), antagonists. In the MN9D cells, quinpirole and R-(-)-N-propylnorapomorphine (NPA) also inhibited the K(+)-stimulated release of [(3)H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K(+)-stimulated [(3)H]dopamine release, although they antagonized the effects of quinpirole. S-(+)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D(2L) receptors coupled to inhibition of dopamine release, but a weak partial agonist at D(2L) receptor-mediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D(2) receptors coupled to G protein-coupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D(2) receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D(2L) receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".

Animals↗
PubMed1999

In vitro characterisation of two naturally occurring mutations in the thrombin-sensitive region of anticoagulant protein S.

The molecular consequences of two naturally occurring mutations in the thrombin-sensitive region of protein S were investigated using a combination of recombinant protein expression, functional analysis and molecular modelling. Both mutations (R49H and R70S) have been found in thrombosis patients diagnosed as having type I protein S deficiency. Molecular modelling analysis suggested the R49H substitution not to disrupt the structure of thrombin-sensitive region, whereas the R70S substitution could affect the 3D structure mildly. To elucidate the molecular consequences of these substitutions experimentally, site directed mutagenesis of protein S cDNA and expression in mammalian cells created the two mutants. The secretion profiles and functional anticoagulant activities of the protein S mutants were characterised. Secretion of the R49H mutant was similar to that of wild type protein S, whereas the R70S mutant showed moderately decreased expression. Neither of the mutants showed any major functional defects as cofactors to activated protein C (APC) in an APTT-based assay or in degradation of factor Va. However, both mutants demonstrated decreased activity in a factor VIIIa degradation assay, which in addition to APC and protein S also included factor V as synergistic APC cofactor. In conclusion, the R49H substitution did not produce a quantitative abnormality in vitro, raising doubts as to whether it caused the type I deficiency. In contrast, the experimental data obtained for the R70S mutant agrees well with the observed type I deficiency. Our study illustrates that in vitro experimental characterisation together with computer-based structural analysis are useful tools in the analysis of the relationship between naturally occurring mutations and clinical phenotypes.

Binding Sites↗
PubMed2005

Hygrothermal degradation of (3-glycidoxypropyl)trimethoxysilane films studied by neutron and X-ray reflectivity and attenuated total reflection infrared spectroscopy.

Thin films of organosilanes have great technological importance in the areas of adhesion promotion, durability, and corrosion resistance. However, it is well-known that water can degrade organosilane films, particularly at elevated temperatures. In this work, X-ray and neutron reflectivity (XR and NR) were combined with attenuated total reflection infrared (ATR-IR) spectroscopy to study the chemical and structural changes within thin films of (3-glycidoxypropyl)trimethoxysilane (GPS) after exposure for various periods of time to air saturated with either D2O or H2O at 80 degrees C. For NR and XR, ultrathin (approximately 100 A) films were prepared by spin-coating. Both D2O and H2O provide neutron scattering contrast with GPS. Variations in the neutron scattering length density (SLD) profiles (a function of mass density and atomic composition) with conditioning time were measured after drying the samples out and also swelled with H2O or D2O vapor at room temperature. For samples that were dried out prior to measurement, little or no change was observed for H2O conditioning up to 3.5 days, but large changes were observed after 30 days of conditioning. The range of conditioning time for this structural change was narrowed to between 4 and 10 days with XR. The SLD profiles indicated that the top portion of the GPS film was transformed into a thick low-density layer after conditioning, but the bottom portion showed little structural change. A previous NR study of as-prepared GPS films involving swelling with deuterated nitrobenzene showed that the central portion of the film has much lower cross-link density than the region nearest the substrate. The present data show that the central portion also swells to a much greater extent with water and hydrolyzes more rapidly. The chemical degradation mechanism was identified by IR as hydrolysis of siloxane bonds. For ATR-IR, GPS films were prepared by dip-coating, which resulted in a greater and more variable thickness than for the spin-coated samples. The IR spectra revealed an increase in vicinal silanol generation over the first 3 days of conditioning followed by geminal silanol generation. Thus, the structural change detected by NR and XR roughly coincided with the onset of geminal silanol generation. Finally, little change in the reflectivity data was observed for films conditioned with D2O at 80 degrees C for 1 month. This indicates that hydrolysis of Si-O-Si is much slower with D2O than with H2O.

Journal Article↗
PubMed2004

Effects of white and red wine on endothelial function in subjects with coronary artery disease.

BACKGROUND: Levels of anti-oxidant polyphenols are higher in red than in white wine and are thought to contribute to the reduced cardiovascular risk associated with moderate consumption of wine observed in epidemiological studies. AIM: To compare the acute effects of acute ingestion of white and red wine on endothelial function in subjects with coronary artery disease (CAD). METHODS: Fourteen subjects with proven CAD were randomised to consume white and red wine with a light meal in a single blind cross-over study. Flow-mediated dilatation (FMD) of the brachial artery was measured using high-resolution ultrasonography. Endothelial function, lipid profile, plasma alcohol and polyphenols were measured at baseline, 60 and 360 min after wine consumption. RESULTS: At baseline, FMD was similar (white wine 1.6 +/- 1.9%, red wine 1.8 +/- 1.7%). At 360 min after ingestion of wine there was no difference in FMD, which improved nearly threefold after both wines (white wine 4.7 +/- 2.2%, red wine 3.4 +/- 2.9%; P = 0.002). There was no detectable change in plasma polyphenol levels after either wine. CONCLUSIONS: These data suggest that wine acutely improves endothelial function in patients with CAD. This improved endothelial function might contribute to a reduced risk of cardiovascular events.

Adult↗
PubMed2004

Successful steroid withdrawal in lung transplant recipients: result of a pilot study.

OBJECTIVE: Corticosteroids play a key role in immunosuppression after transplantation. However, because chronic steroid treatment may cause significant morbidity and mortality, steroid-free immunosuppression remains a desirable goal. To the best of our knowledge, there are no reports on successful steroid withdrawal (SW) in lung transplant recipients. METHODS: The study group included 35 patients who underwent heart-lung, double-lung or single-lung transplantation. Criteria for initiation of SW were stable pulmonary function tests and absence of clinical or bronchoscopic evidence of acute or chronic rejection in the last 6 months. Pulmonary function, blood pressure and metabolic parameters were compared between the patients who underwent SW and those who did not. RESULTS: Eight patients (23%) underwent SW. Median follow-up was 19 months (range 11-23 months). Compared to the non-withdrawal group, the withdrawal group was older (60+/-6 vs. 52+/-13 years, P=0.01, r=0.49), had higher rates of emphysema (88% vs. 18%, P=0.01) and use of a cyclosporine-based regimen (62% vs. 26%, P=0.0001), and had longer time from transplantation to the withdrawal attempt (70+/-13 vs. 29+/-26 months, P=0.0002). The SW group showed no adverse effects in graft function and no deterioration on pulmonary function tests. SW had a beneficial metabolic effect, with a decrease in mean cholesterol level from 229+/-45 to 194+/-25 mg/dl (P=0.02) and no significant change in weight, systolic blood pressure or glucose level. In the non-withdrawal group, mean cholesterol levels increased from 175+/-34 to 209+/-57 mg/dl (P=0.0005), weight increased from 72+/-15 to 80+/-14 kg (P=0.0001), and systolic blood pressure increased from 125+/-15 to 139+/-16 mmHg (P=0.001); glucose levels did not change. There was a significant correlation between total cholesterol level and weight in both groups (P=0.0006, r=-0.56 and P=0.01, r=-0.46, respectively). CONCLUSIONS: Late SW is safe in stable patients after lung transplantation. There was no evidence of rejection or a deterioration in pulmonary function. Lipid profile improvement and blood pressure stabilization accompanied the termination of steroid therapy.

Aged↗
PubMed2004

[Gene expression profile of yolk sac and fetal liver in mouse].

OBJECTIVE: To better understand the mechanisms of the fetal hematopoiesis turn over from primitive to definitive hematopoiesis through the expression level of c-kit(+) and sca-1(+), and major characters of gene expression profile of these cells. METHODS: c-kit and sca-1 expression level were monitored with fluorescence activated cell sorting (FACS) of the mononuclear cells from mouse yolk sac and fetal liver, while gene expression profile was carried out with EST sequencing strategy. RESULTS: The Sca-1(+) cells were increased while the c-kit(+) cells decreased with the embryonic development. Through profiling the functionally identified known genes, most of the highly expressed were globin genes, especially of embryonic types. CONCLUSION: The erythropoiesis played a key role in early fetal hematopoiesis in mammalian.

Animals↗
PubMed2004

Study on furundu, a traditional Sudanese fermented roselle (Hibiscus sabdariffa L.) seed: effect on in vitro protein digestibility, chemical composition, and functional properties of the total proteins.

Furundu, a meat substitute, is traditionally prepared by cooking the karkade (Hibiscus sabdariffa L.) seed and then fermenting it for 9 days. Physicochemical and functional properties of raw and cooked seed and of furundu ferments were analyzed. Furundu preparation resulted in significant changes in karkade seed major nutrients. Total polyphenols and phytic acid were also reduced. The increase in total acidity and fat acidity coupled with a decrease in pH indicates microbial hydrolysis of the major nutrients; proteins, carbohydrates, and fats. In vitro digestibility of the seed proteins reached the maximum value (82.7%) at the sixth day of fermentation, but thereafter it significantly decreased. The effect of furundu preparation on N solubility profiles and functional properties, such as emulsification and foaming properties and other related parameters, is investigated in water and in 1 M NaCl extracts from defatted flour samples. The results show that cooking followed by fermentation affects proteins solubility in water and 1 M NaCl. The foaming capacity (FC) from the flour of raw seed decreased as a result of cooking. Fermentation for 9 days significantly increased the FC of the cooked seed, restoring the inherent value. Foam from fermented samples collapsed more rapidly during a period of 120 min as compared to the foam from raw and cooked karkade seeds; stability in 1 M NaCl was lower as compared to those in water. In water, the emulsion stability (ES) from the fermented samples was significantly higher than that of the raw seed flour. Addition of 1 M NaCl significantly decreased the ES of the fermented samples.

Chemical Phenomena↗
PubMed2005

Significance of chemokine receptor expression in aggressive NK cell leukemia.

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.

Adult↗
PubMed2003

Active influx transport is mediated by members of the organic anion transporting polypeptide family in human epidermal keratinocytes.

Normal human epidermal keratinocytes have been shown to express a cell-type-specific pattern of extrahepatic cytochrome P450 enzymes and efflux transport proteins showing that these cells metabolize and excrete a variety of xenobiotics. Recently transport proteins involved in the uptake of xenobiotics have been detected and here we analyzed the mRNA and protein expression profiles and functional activities of these proteins in human keratinocytes in comparison to primary liver cells. The transporters studied included the subtypes A, B, C, D, and E of the organic anion transporting polypeptide (OATP) family, which are responsible for the uptake of various anionic and neutral molecules and especially organic cations - including drugs. Constitutive expression of OATP-B, OATP-D, and OATP-E was shown for the first time in normal human epidermal keratinocytes on a molecular level using reverse transcription polymerase chain reaction and northern blot analysis, as well as in human skin tissue shown by tissue blot hybridization and immunohistochemistry. Expression of OATP-A and OATP-C was not detected in any of the keratinocyte samples. In contrast, liver tissue showed a significant expression of OATP-A and OATP-B as well as OATP-C, a weak expression of OATP-D, and no expression of OATP-E. These data revealed that normal human epidermal keratinocytes express a specific profile of transporters involved in drug influx. Using a newly developed uptake-transport assay, uptake of known and well-characterized OATP substrates like estradiol-17beta-glucuronide and estrone sulfate was inhibited in normal human epidermal keratinocytes by specific inhibitors such as taurocholate, verifying the functional capacity of the expressed OATPs. Human dermal fibroblasts seem to have a lower influx transport activity for estradiol-17beta-glucuronide, which correlates with the immunohistologic data. Even though the substrate specificity of the OATP isoforms is only partially known until now, our findings support the concept that uptake of large organic cations like drugs in keratinocytes is an active transport process mediated by members of the OATP family.

Biological Transport, Active↗
PubMed2006

Towards a molecular definition of worker sterility: differential gene expression and reproductive plasticity in honey bees.

We show that differences in the reproductive development of honey bee workers are associated with locus-specific changes to abundance of messenger RNA. Using a cross-fostering field experiment to control for differences related to age and environment, we compared the gene expression profiles of functionally sterile workers (wild-type) and those from a mutant strain in which workers are reproductively active (anarchist). Among the set of three genes that are significantly differentially expressed are two major royal jelly proteins that are up-regulated in wild-type heads. This discovery is consistent with sterile workers synthesizing royal jelly as food for developing brood. Likewise, the relative underexpression of these two royal jellies in anarchist workers is consistent with these workers' characteristic avoidance of alloparental behaviour, in favour of selfish egg-laying. Overall, there is a trend for the most differentially expressed genes to be up-regulated in wild-type workers. This pattern suggests that functional sterility in honey bee workers may generally involve the expression of a suite of genes that effectively 'switch' ovaries off, and that selfish reproduction in honey bee workers, though rare, is the default developmental pathway that results when ovary activation is not suppressed.

Animals↗
PubMed2003

The validation of the Subjective Index of Physical and Social Outcome (SIPSO).

OBJECTIVE: To validate the Subjective Index of Physical and Social Outcome (SIPSO) in its final 10-item version as a measure of reintegration to pre-stroke lifestyle. DESIGN: Postal and interview administration of questionnaires. MEASURES: SIPSO, Functional Limitations Profile (FLP), Reintegration to Normal Living Index (RNLI). SETTING: Community setting, Bath, UK. SUBJECTS: Two hundred and sixty-one survivors of stroke discharged from a district general hospital. RESULTS: Internal consistency (item-total correlations >0.6) and test-retest reliability (intraclass correlation coefficient (ICC) = 0.96) of the measure were confirmed. Construct validity was confirmed through significant correlations with the six subsections of the FLP and the RNLI. Confirmatory factor analysis of the measure found that the first five items form a robust subscale that clearly relates to physical function. The items within the second subscale (questions 6-10) measure several domains (social, leisure, self-image) and do not form a homogeneous group. The SIPSO was able to detect an improvement in integration within a sample of patients over a three-month period soon after discharge (effect size = 0.26). The hypothesis that the degree of improvement experienced by patients following discharge from hospital would be small, but should be detectable was confirmed. The agreement between proxy and patient on the SIPSO was acceptable for individual items (kappa value range = 3.1-5.8) and total score (ICC = 0.96). CONCLUSIONS: The SIPSO is a brief self-complete measure, with proven validity and reliability, which addresses both quantitative and qualitative aspects of activities and interaction. It provides a useful measure for evaluating rehabilitation programmes that aim to reintegrate patients to their pre-stroke lifestyle. The authors suggest that the SIPSO should be used as a 10-item measure.

Aged↗