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PubMed1999

HLA-A, -B, -C genotyping and expression in human nonlymphoid tumor cell lines.

A combination of molecular genotyping and protein biochemistry methods was used to assess the HLA-A, -B, -C genotyping and expression of six tumor cell lines. Four cell lines had been previously HLA typed by conventional serologic methods. Two could not be typed by serology because deficient in the surface expression of HLA-A, -B, -C molecules. As shown herein, all the 25 alleles carried by the six tested cell lines were typed at the DNA level. In addition, discrepancies between the previous serologic and the present DNA typing results were detected in 9 of the 21 tested serologic specificities. Typing at the protein level by isoelectric focusing and allele-specific monoclonal antibodies confirmed the DNA typing data. Our results exemplify the limits of the serologic typing procedures and demonstrate that molecular methods are highly desirable to conduct functional experiments and identify HLA losses in neoplastic cells at single allele level.

Alleles↗
PubMed2005

Family health and characteristics in chronic fatigue syndrome, juvenile rheumatoid arthritis, and emotional disorders of childhood.

OBJECTIVE: To compare family health and characteristics in children with chronic fatigue syndrome (CFS), in juvenile rheumatoid arthritis (JRA), and emotional disorders. METHOD: Parents of 28 children and adolescents aged 11 to 18 years with CFS, 30 with JRA, and 27 with emotional disorders (i.e., anxiety and/or depressive disorders) were recruited from specialty clinical settings and completed interviews and questionnaires assessing family health problems, parental mental distress, illness attitudes, and family burden of illness. RESULTS: Parents of children with CFS were significantly more likely than those of children with JRA to report a history of CFS-like illness, high levels of mental distress, and a tendency to experience functional impairment in response to physical symptoms. Families of children with CFS were characterized by significantly greater emotional involvement and reported greater family burden related to the child's illness in comparison with families of children with JRA. CONCLUSIONS: CFS in childhood and adolescence is associated with higher levels of parental CFS-like illness, mental distress, emotional involvement, and family illness burden than those observed in association with JRA, a chronic pediatric physical illness.

Adolescent↗
PubMed2000

The differential time courses of the vasodilator effects of various 1,4-dihydropyridines in isolated human small arteries are correlated to their lipophilicity.

OBJECTIVES: To investigate a possible relationship between the time courses of action of various calcium antagonists and their lipophilicity, characterized as log P-values. METHODS: The functional experiments were performed in vitro in human small subcutaneous arteries (internal diameter 591 +/- 51 microm, n = 7 for each concentration), obtained from cosmetic surgery (mamma reduction and abdominoplasty). The vessels were investigated in an isometric wire myograph. The vasodilator effect of the calcium antagonists was quantified by means of log IC50-values, and the onset of the vasodilator effect for each concentration studied was expressed as time to Eeq90-values (time to reach 90% of the maximal effect). RESULTS: Log IC50-values were -8.46 +/- 0.09, -8.33 +/- 0.25 and -8.72 +/- 0.16 for nifedipine, felodipine and (S)-lercanidipine, respectively (not significant). On average, nifedipine reached time to Eeq90 in 11 +/- 1 min. For felodipine and (S)-lercanidipine the corresponding values were 60 +/- 11 min and 99 +/- 9 min, respectively. The differences between these values were statistically significant (P< 0.01). In spite of these differences in the in-vitro human vascular model, the three calcium antagonists are equipotent with regard to their vasodilator effects. Linear regression analysis of the correlation between the logarithm of the membrane partition coefficient (log P-values) of the calcium antagonists tested [2.50, 4.46 and 6.88 for nifedipine, felodipine and (S)-lercanidipine, respectively] and their respective values found for time to Eeq90 was highly significant. CONCLUSIONS: It appears that a higher log P-value is correlated with a slower onset of action.

Adipose Tissue↗
PubMed2003

Involvement of the beta3 adrenoceptor in nebivolol-induced vasorelaxation in the rat aorta.

Nebivolol is a highly selective beta(1) adrenoceptor blocker with additional vasodilating properties. Although it has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) and cGMP dependent, the receptor that mediates these actions remains controversial, and serotonergic as well as beta-adrenergic pathways may be involved. Therefore, functional experiments investigating the receptor involved in nebivolol-induced vasorelaxation were performed in the rat aorta. Isolated aortic rings were exposed to cumulative concentrations of nebivolol. Nebivolol concentrations of 3 micromol/L and higher caused vasorelaxation, which was inhibited by the presence of the NO synthase inhibitor l-NNA (100 micromol/L), or by mechanical removal of the endothelium. Exposure of the vessel rings to the selective 5-HT(1A) antagonist NAN-190 (1 micromol/L) or the 5-HT(1/2) antagonist methysergide (1 micromol/L) did not influence nebivolol-induced vasorelaxation. Similarly, the incubation with the beta(2)-adrenoceptor antagonist butoxamine (50 micromol/L) did not prevent vasorelaxation. The selective beta(3)-adrenoceptor antagonist S-(-)-cyanopindolol (1 micromol/L), however, significantly counteracted the nebivolol-induced vasorelaxation. Furthermore, exposure of the aortic rings to cumulative concentrations of the beta(3) selective adrenoceptor agonist BRL37344 caused, like nebivolol, NO-dependent vasorelaxation that was antagonized by S-(-)-cyanopindolol. The results suggest that nebivolol-induced NO-dependent vasorelaxation is, at least in part, caused by a beta(3)-adrenoceptor agonistic effect.

Animals↗
PubMed2004

Antioxidant activity of nebivolol in the rat aorta.

The beta-blocker nebivolol is a racemic mixture of D- and L- enantiomers that displays negative inotropic as well as direct vasorelaxant activity. In addition, it has been proposed that nebivolol exerts endothelium-protective effects caused by its antioxidant properties. In the present study we investigated the effect of D-, L-, and d/l-nebivolol on reactive oxygen species (ROS)-induced endothelial damage and compared it with carvedilol and metoprolol. Isolated rat aortic rings were exposed to ROS by electrolysis of the organ bath medium. Before and after electrolysis, endothelial function was measured by preconstricting the vessels with phenylephrine followed by the addition of methacholine. Carvedilol and nebivolol protected against ROS-induced endothelial damage, whereas metoprolol did not. The protective effect of nebivolol proved not to be stereoselective. Furthermore, we attempted to determine whether nebivolol acts a scavenger itself or whether another mechanism is involved. By means of HPLC measurements it was shown that nebivolol concentrations were decreased after exposure to electrolysis-induced ROS, thus indicating that nebivolol is degraded by its reaction with ROS. Functional experiments, in the rat aorta, demonstrated that exposure of nebivolol to ROS also affects its vasodilator activity. In conclusion, the present study demonstrates that nebivolol alleviates ROS-induced impairment of endothelium-dependent vasorelaxation. This protective effect is very likely the result of a direct ROS-scavenging action by the nebivolol molecule itself.

Adrenergic beta-Antagonists↗
PubMed1989

Using composite health status measures to assess the nation's health.

Research in progress at the National Center for Health Statistics for evaluating the usefulness of composite measures of health status for assessing the nation's health is described. Three measures suitable for use in the general population, the Health Insurance Experiment-Functional Limitations (HIE-FL), the Health Utility Index (HUI), and the Quality of Well-being (QWB) scale, have been mapped to data collected in the 1980 National Health Interview Survey (NHIS). Analysis using current algorithms for making composite function status measures according to the QWB methods suggests that traditional single indicators of health tend to overestimate the level of health by about 10%. When symptoms and problems are added to the composite function score, the overestimate as measured by the single indicator is at least 50%. The authors are continuing to validate these algorithms, to develop similar ones for the HIE-FL and HUI, and to extend the analysis to data collected in 1977, 1979, and 1984. Current results indicate that to realize fully the benefits of composite measures, well-established, valid, and reliable measures of health-related quality of life should be included as part of the regular NHIS data collection procedures.

Activities of Daily Living↗
PubMedDate not supplied

Effect of inactivity and undernutrition after acute ischemic stroke in a rat hindlimb muscle model.

BACKGROUND: Stroke patients experience functional changes resulting from muscle atrophy related to disuse, lack or limited neuronal stimulation, and undernutrition. Acute ischemic stroke is assumed to induce muscle atrophy. However, there is little information regarding muscle changes after acute stroke. OBJECTIVE: The purpose of this study was to examine the effect of inactivity and undernutrition after acute stroke on mass, myofibrillar protein content, and Types I and II fiber cross-sectional areas of rat hindlimb muscles. METHODS: Adult male Sprague-Dawley rats (body weight, 240-270 g) were randomly assigned to one of three groups: a stroke group (n = 7) that had occlusion of the right middle cerebral artery, a control group (n = 7) that underwent a sham right middle cerebral artery procedure, and an undernourished group (n = 9) that was pair-fed to match the intake of stroke rats. Food and water intake as well as body weight were measured daily. The rats were anesthetized 7 days after occlusion or sham occlusion, after which the soleus (Type I), plantaris (Type II), and gastrocnemius (Type II) muscles were dissected from both the affected and unaffected sides. The brain was sectioned to identify cerebral infarction in the stroke group. Body weight, food intake, muscle weight, fiber type distribution, cross-sectional area, and myofibrillar protein content of the dissected muscles were determined. RESULTS: The stroke group at 7 days after ischemic stroke showed significant decreases (p <.05), as compared with the control rats, in diet intake and body weight, muscle weight of affected gastrocnemius, Type I fiber cross-sectional area of the affected soleus muscle, Types I and II fiber cross-sectional areas and Type II fiber distribution of the unaffected soleus muscle, and myofibrillar protein content of both the affected and unaffected soleus muscles. As compared with the control group, the undernourished group showed significant decreases (p <.05) in diet intake and body weight, Type I fiber cross-sectional area of the affected soleus muscle, Types I and II fiber cross-sectional areas and Type II fiber distribution of the unaffected soleus muscle, Type I fiber distribution of the affected gastrocnemius muscle, and myofibrillar protein content of both the affected and unaffected soleus muscles. As compared with the undernourished group, the stroke group showed significant decreases (p <.05) in muscle weight and Type II fiber distribution of the affected gastrocnemius muscle. There were no differences in muscle characteristics between the affected and unaffected hindlimb muscles at 7 days after ischemic stroke. CONCLUSIONS: Hindlimb muscle atrophy occurs in both affected and unaffected sides after acute stroke, with Type I muscle changes more apparent than Type II changes.

Analysis of Variance↗
PubMedDate not supplied

Nursing leadership succession planning in Veterans Health Administration: creating a useful database.

An electronic database was developed for succession planning and placement of nursing leaders interested and ready, willing, and able to accept an assignment in a nursing leadership position. The tool is a 1-page form used to identify candidates for nursing leadership assignments. This tool has been deployed nationally, with access to the database restricted to nurse executives at every Veterans Health Administration facility for the purpose of entering the names of developed nurse leaders ready for a leadership assignment. The tool is easily accessed through the Veterans Health Administration Office of Nursing Service, and by limiting access to the nurse executive group, ensures candidates identified are qualified. Demographic information included on the survey tool includes the candidate's demographic information and other certifications/credentials. This completed information form is entered into a database from which a report can be generated, resulting in a listing of potential candidates to contact to supplement a local or Veterans Integrated Service Network wide position announcement. The data forms can be sorted by positions, areas of clinical or functional experience, training programs completed, and geographic preference. The forms can be edited or updated and/or added or deleted in the system as the need is identified. This tool allows facilities with limited internal candidates to have a resource with Department of Veterans Affairs prepared staff in which to seek additional candidates. It also provides a way for interested candidates to be considered for positions outside of their local geographic area.

Career Mobility↗
PubMed1985

The bone mineral content of the lumbar spine in patients with chronic low-back pain.

The bone mineral content (BMC) of the third lumbar vertebra was determined in 43 patients with chronic low-back pain. No correlation was found to sex, height, pain experience, functional disability, or alcohol consumption. A positive correlation was found between the BMC and body weight and between the BMC and smoking in men (but not in women). A statistically significant negative correlation was found between the BMC and the overall duration of the back problem, ie, the longer duration the lower the BMC.

Adult↗
PubMed2004

The role of selective salpingography and tubal catheterization in the management of the infertile couple.

PURPOSE OF REVIEW: This review is intended to update the reader about recent developments in the field of selective salpingography and tubal catheterization, to offer an interpretation of the information presented and to suggest further research links. RECENT FINDINGS: The measurement of tubal perfusion pressures at selective salpingography and tubal catheterization has offered a new dimension in the evaluation of the fallopian tube. A classification of infertile women based on tubal perfusion pressures is presented, and this is correlated with the possibility of spontaneous fertility, thus giving selective salpingography and tubal catheterization a prognostic profile in addition to diagnostic and therapeutic functions. Experience derived from the use of the technique in unselected infertile women (i.e. not with proximal tubal blockage) is presented. The use of selective tube catheterization for sterilization purposes joins the mainstream with the publication of the encouraging results of a multinational trial. The debate on the validity of the diagnosis of proximal tubal blockage is enriched by the suggestion that simply rotating the patient during hysterosalpingography will resolve most cases of the condition. The fertility gain by single-tube recanalization in women with unilateral proximal tubal blockage is given further support. The use of oil-based media for selective salpingography and tubal catheterization is discussed. A hypothesis on the pathophysiology of proximal tubal blockage is presented. SUMMARY: The evidence clearly supports the use of selective salpingography and tubal catheterization for infertile women with proximal tubal blockage. The potential of the technique to play a wider role in the management of infertility is demonstrated by recent research.

Catheterization↗
PubMed2004

Notch signaling in vascular morphogenesis.

PURPOSE OF REVIEW: This review highlights recent developments in the role of the Notch signaling pathway during vascular morphogenesis, angiogenesis, and vessel homeostasis. RECENT FINDINGS: Studies conducted over the past 4 years have significantly advanced the understanding of the effect of Notch signaling on vascular development. Major breakthroughs have elucidated the role of Notch in arterial versus venular specification and have placed this pathway downstream of vascular endothelial growth factor. SUMMARY: An emerging hallmark of the Notch signaling pathway is its nearly ubiquitous participation in cell fate decisions that affect several tissues, including epithelial, neuronal, hematopoietic, and muscle. The vascular compartment has been the latest addition to the list of tissues known to be regulated by Notch. Unraveling the contribution of Notch signaling to blood vessel formation has resulted principally from gain-of-function and loss-of-function experiments in mouse and zebrafish. During the past 4 years, these mechanistic studies have revealed that Notch is required for the successful completion of several steps during vascular morphogenesis and differentiation. In addition, the findings that Notch mutations are linked to some late-onset hereditary vascular pathologic conditions suggest the added contribution of this signaling pathway to vascular homeostasis.

Animals↗
PubMed2006

Cellular fatty acid uptake: the contribution of metabolism.

PURPOSE OF REVIEW: The aim of this review is to highlight the importance of fatty acid metabolism as a major determinant in fatty acid uptake. In particular, we emphasize how the activation, intracellular transport and downstream metabolism of fatty acids influence their uptake into cells. RECENT FINDINGS: Studies examining fatty acid entry into cells have focused primarily on the roles of plasma membrane proteins or the question of passive diffusion. Recent studies, however, strongly suggest that a driving force governing fatty acid uptake is the metabolic demand for fatty acids. Both gain and loss-of-function experiments indicate that fatty acid uptake can be modulated by activation at both the plasma membrane and internal sites, by intracellular fatty acid binding proteins, and by enzymes in synthetic or degradative metabolic pathways. Although the mechanism is not known, it appears that converting fatty acids to acyl-CoAs and downstream metabolic intermediates increases cellular fatty acid uptake, probably by limiting efflux. SUMMARY: Altered fatty acid metabolism and the accumulation of triacylglycerol and lipid metabolites has been strongly associated with insulin resistance and diabetes, but we do not fully understand how the entry of fatty acids into cells is regulated. Future studies of cellular fatty acid uptake should consider the influence of fatty acid metabolism and the possible interactions between fatty acid metabolism or metabolites and fatty acid transport proteins.

Animals↗
PubMed2026

DPM2 promotes melanoma progression and serves as a prognostic factor.

Recently, dolichol phosphate mannose synthase (DPMS) has emerged as a promising new target for treatment in various cancers. Nonetheless, DPM2, a crucial element of the DPMS family, remains unexplored in melanoma research. This study aims to explore the predictive significance and biological role of DPM2, utilizing extensive databases and functional tests conducted in vitro. We conducted an in-depth examination of the DPM2 expression feature within The Cancer Genome Atlas database. Group differences were evaluated using Student's t-test, one-way analysis of variance, and long-rank test, while survival distributions were estimated using the Kaplan-Meier method. Functional experiments were conducted in multiple melanoma cell lines to evaluate the effects of altered DPM2 expression. Our research indicated a direct correlation between the expression levels of DPM2 and the severity of melanoma. In addition, an elevated level of DPM2 expression was significantly linked to unfavorable prognoses. Suppression of DPM2 inhibits the proliferation, migration, and invasion of melanoma cells and induces their apoptosis. These findings suggest that DPM2 plays a pivotal role in melanoma progression and may serve as an independent prognostic biomarker for the disease.

DPM2↗
PubMed2003

Tpit determines alternate fates during pituitary cell differentiation.

The T-box transcription factor Tpit was identified as a cell-specific factor for expression of the pituitary proopiomelanocortin (POMC) gene. Expression of this factor is exclusively restricted to the pituitary POMC-expressing lineages, the corticotrophs and melanotrophs. We have now determined the role of this factor in pituitary cell differentiation. Tpit is a positive regulator for late POMC cell differentiation and POMC expression, but it is not essential for lineage commitment. The pituitary intermediate lobe normally contains only Tpit-expressing melanotrophs. Inactivation of the Tpit gene results in almost complete loss of POMC-expressing cells in this tissue, which now has a large number of gonadotrophs and a few clusters of Pit-1-independent thyrotrophs. The role of Tpit as a negative regulator of gonadotroph differentiation was confirmed in transgenic gain-of-function experiments. One mechanism to account for the negative role of Tpit in differentiation may be trans-repression between Tpit and the gonadotroph-restricted factor SF1. These data suggest that antagonism between Tpit and SF1 may play a role in establishment of POMC and gonadotroph lineages and that these lineages may arise from common precursors.

Animals↗
PubMed2003

Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos.

Left-sided expression of Nodal in the lateral plate mesoderm is a conserved feature necessary for the establishment of normal left-right asymmetry during vertebrate embryogenesis. By using gain- and loss-of-function experiments in zebrafish and mouse, we show that the activity of the Notch pathway is necessary and sufficient for Nodal expression around the node, and for proper left-right determination. We identify Notch-responsive elements in the Nodal promoter, and unveil a direct relationship between Notch activity and Nodal expression around the node. Our findings provide evidence for a mechanism involving Notch activity that translates an initial symmetry-breaking event into asymmetric gene expression.

Animals↗
PubMed1999

Gata5 is required for the development of the heart and endoderm in zebrafish.

The mechanisms regulating vertebrate heart and endoderm development have recently become the focus of intense study. Here we present evidence from both loss- and gain-of-function experiments that the zinc finger transcription factor Gata5 is an essential regulator of multiple aspects of heart and endoderm development. We demonstrate that zebrafish Gata5 is encoded by the faust locus. Analysis of faust mutants indicates that early in embryogenesis Gata5 is required for the production of normal numbers of developing myocardial precursors and the expression of normal levels of several myocardial genes including nkx2.5. Later, Gata5 is necessary for the elaboration of ventricular tissue. We further demonstrate that Gata5 is required for the migration of the cardiac primordia to the embryonic midline and for endodermal morphogenesis. Significantly, overexpression of gata5 induces the ectopic expression of several myocardial genes including nkx2.5 and can produce ectopic foci of beating myocardial tissue. Together, these results implicate zebrafish Gata5 in controlling the growth, morphogenesis, and differentiation of the heart and endoderm and indicate that Gata5 regulates the expression of the early myocardial gene nkx2.5.

Amino Acid Sequence↗
PubMed2005

Geminin regulates neuronal differentiation by antagonizing Brg1 activity.

Precise control of cell proliferation and differentiation is critical for organogenesis. Geminin (Gem) has been proposed to link cell cycle exit and differentiation as a prodifferentiation factor and plays a role in neural cell fate acquisition. Here, we identified the SWI/SNF chromatin-remodeling protein Brg1 as an interacting partner of Gem. Brg1 has been implicated in cell cycle withdrawal and cellular differentiation. Surprisingly, we discovered that Gem antagonizes Brg1 activity during neurogenesis to maintain the undifferentiated cell state. Down-regulation of Gem expression normally precedes neuronal differentiation, and gain- and loss-of-function experiments in Xenopus embryos and mouse P19 cells demonstrated that Gem was essential to prevent premature neurogenesis. Misexpression of Gem also suppressed ectopic neurogenesis driven by Ngn and NeuroD. Gem's activity to block differentiation depended upon its ability to bind Brg1 and could be mediated by Gem's inhibition of proneural basic helix-loop-helix (bHLH)-Brg1 interactions required for bHLH target gene activation. Our data demonstrate a novel mechanism of Gem activity, through regulation of SWI/SNF chromatin-remodeling proteins, and indicate that Gem is an essential regulator of neurogenesis that can control the timing of neural progenitor differentiation and maintain the undifferentiated cell state.

Animals↗
PubMed2006

Wnt/beta-catenin signaling regulates vertebrate limb regeneration.

The cellular and molecular bases allowing tissue regeneration are not well understood. By performing gain- and loss-of-function experiments of specific members of the Wnt pathway during appendage regeneration, we demonstrate that this pathway is not only necessary for regeneration to occur, but it is also able to promote regeneration in axolotl, Xenopus, and zebrafish. Furthermore, we show that changes in the spatiotemporal distribution of beta-catenin in the developing chick embryo elicit apical ectodermal ridge and limb regeneration in an organism previously thought not to regenerate. Our studies may provide valuable insights toward a better understanding of adult tissue regeneration.

Ambystoma↗