Genetic basis for idiopathic scoliosis brought a step nearer.
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Adolescent↗
Biomedical subjects
S Clark
Publications and source records attributed to S Clark.
Differential capacities of CD4+, CD8+, and CD4-CD8- T cell subsets to express IL-18 receptor and produce IFN-gamma in response to IL-18.
IL-12 and IL-18 have the capacity to stimulate IFN-gamma production by T cells. Using a T cell clone, we reported that IL-18 responsiveness is generated only after exposure to IL-12. Here, we investigated the induction of IL-18 responsiveness in resting CD8+, CD4+, and CD4-CD8- T cells. Resting T cells respond to neither IL-12 nor IL-18. After stimulation with anti-CD3 plus anti-CD28 mAbs, CD8+, CD4+, and CD4-CD8- T cells expressed IL-12R, but not IL-18R, and produced IFN-gamma in response to IL-12. Cultures of T cells with anti-CD3/anti-CD28 in the presence of rIL-12 induced IL-18R expression and IL-18-stimulated IFN-gamma production, which reached higher levels than that induced by IL-12 stimulation. However, there was a substantial difference in the expression of IL-18R and IL-18-stimulated IFN-gamma production among T cell subsets. CD4+ cells expressed marginal levels of IL-18R and produced small amounts of IFN-gamma, whereas CD8+ cells expressed higher levels of IL-18R and produced more IFN-gamma than CD4+ cells. Moreover, CD4-CD8- cells expressed levels of IL-18R comparable to those for CD8+ cells but produced IFN-gamma one order higher than did CD8+ cells. These results indicate that the induction of IL-18R and IL-18 responsiveness by IL-12 represents a mechanism underlying enhanced IFN-gamma production by resting T cells, but the operation of this mechanism differs depending on the T cell subset stimulated.
Animals↗
Psychobiological heterogeneity of familial and sporadic schizophrenia.
BACKGROUND: Although schizophrenia is presumed to be heterogeneous, there has been limited success distinguishing familial from sporadic cases. We used psychobiological measures to examine heterogeneity, as they may be closer to neurobiology than symptoms. Smooth pursuit eye movement quality (SPEM) and dichotic listening (DL) tests to tones and words were used to assess hemispheric laterality asymmetry. METHODS: Forty-six research unit patients participated in assessments of family history (FH) and physiological measures. FH was categorized by three exclusive groups: FH-1 patients had a chronic schizophrenia-related psychosis in a first-degree relative, FH-2 had it in second-degree relative, and FH-3 had no family member with a reoccurrence. RESULTS: Analysis of variance showed a significant group difference for SPEM and DL tones. SPEM was significantly worse in all three schizophrenia groups than for the normal comparison subjects. Among the schizophrenia groups, the nonfamilial group (FH-3) had the worst SPEM quality, FH-2 had intermediate quality, and FH-1 had the best quality. Conversely, only the nonfamilials (FH-3) had normal right hemispheric lateralization for tones, whereas familials did not, and FH-2 again had intermediate values. The lateralization quotient for DL words did not significantly differ among the groups. CONCLUSIONS: SPEM was affected most in sporadic, not familial schizophrenia, whereas dichotic listening was most affected in familial schizophrenia. This double dissociation supports the utility of the familial/sporadic distinction and suggests that etiological factors in different forms of schizophrenia may impact principally on distinct neurobiological substrates, despite similar patient phenomenology.
Adult↗
Possible role for gp160 in constitutive but not insulin-stimulated GLUT4 trafficking: dissociation of gp160 and GLUT4 localization.
GLUT4-containing vesicles are constantly cycling in both basal and insulin-stimulated states. Our previous studies have shown that basal cycling of GLUT4 is impaired under conditions of high glucose or glucosamine and, as a consequence, GLUT4 is retained intracellularly in low-density microsomes [Filippis A., Clark, S., and Proietto, J. (1997) Biochem. J. 324, 981-985]. In addition to GLUT4 itself, a major protein component of GLUT4-containing vesicles is a glycoprotein of Mr 160000 (gp160). In all studies so far published gp160 has been co-localized with GLUT4 under all conditions. In this study, we show that retention of GLUT4 in low-density microsomes (enriched in Golgi apparatus) is associated with a decrease in gp160 levels in this compartment. A concomitant increase of gp160 in high-density microsomes (enriched in endoplasmic reticulum), demonstrates for the first time a dissociation in the localization of gp160 and GLUT4. Despite the marked decrease in gp160 levels in the GLUT4-containing compartment, insulin-stimulated translocation was normal, while little gp160 appeared in the plasma membrane in response to insulin. The retention of gp160 in the high-density microsomes is apparently not due to a change in the glycosylation state of gp160 as measured by [3H]mannose incorporation. It is concluded that, in rat adipocytes, gp160 is not required for insulin-stimulated translocation, but may be necessary for constitutive trafficking of the GLUT4-containing vesicle.
5'-Nucleotidase↗
Characterization of the hyperpolarization-activated chloride current in dissociated rat sympathetic neurons.
1. Dissociated rat superior cervical ganglion (SCG) neurons have been shown to possess a hyperpolarization-activated inwardly rectifying chloride current. The current was not altered by changes in external potassium concentration, replacing external cations with NMDG (N-methyl-D-glucamine) or by addition of 10 mM caesium or barium ions. 2. The reversal potential of the current was altered by changing external anions. The anion selectivity of the current was Cl- > Br- > I- > cyclamate. All substituted permeant anions also blocked the current. 3. The current was blocked by DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid), 9AC (anthracene-9-carboxylic acid) and NPPB (5-nitro-2-(3-phenylpropylamino)benzoic acid) but was unaffected by SITS (4-acetamido-4'-isothiocyanatostilbene- 2,2'-disulphonic acid) and niflumic acid. The effective blockers were voltage dependent; DIDS and NPPB were more effective at depolarized potentials while 9AC was more effective at hyperpolarized potentials. 4. The current was enhanced by extracellular acidification and reduced by extracellular alkalinization. Reducing external osmolarity was without effect in conventional whole-cell recording but enhanced current amplitude in those perforated-patch recordings where little current was evident in control external solution. 5. The current in SCG neurons was blocked by external cadmium and zinc. ClC-2 chloride currents expressed in Xenopus oocytes were also sensitive to block by these divalent ions and by DIDS but the sensitivity of ClC-2 to block by cadmium ions was lower than that of the current in SCG neurons. 6. Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments showed the presence of mRNA for ClC-2 in SCG neurons but not in rat cerebellar granule cells which do not possess a hyperpolarization-activated Cl- current. 7. The data suggest that ClC-2 may be functionally expressed in rat SCG neurons. This current may play a role in regulating the internal chloride concentration in these neurons and hence their response to activation of GABAA receptors.
Animals↗
Comprehensive nutrition plan improves cardiovascular risk factors in essential hypertension.
Increased arterial pressure is known to be influenced by a variety of nutrients. Compliance with dietary recommendations for risk reduction is often limited by the complexity of their implementation. In addition, how improvements in total diet, rather than single nutrients, influence concomitant cardiovascular risk factors has not been thoroughly explored. We assessed the effects of a nutritionally complete prepared meal program, the Campbell's Center for Nutrition and Wellness plan (CCNW), compared with dietary therapy in which participants received a structured nutritional assessment and prescription and selected their own foods, in 101 women and men with mild-to-moderate hypertension. Outcome measures included blood pressure (BP), lipids and lipoproteins, glucose, glycosylated hemoglobin (HbA1c), insulin, homocysteine, nutrient intake, compliance, and quality of life. Both dietary interventions significantly lowered BP (P < .0001), while simultaneously improving the overall cardiovascular risk profile. Significantly greater benefits were observed with the CCNW plan as compared with the participant selected diet in cholesterol and LDL levels (both P < .0001), LDL:HDL (P < .001), HbA1c (P < .05), homocysteine (P < .001), total nutrient intake (P < .0001), compliance (P < .0001), and quality of life (P < .001). This study demonstrates that improving the total diet to include the full array of recommended dietary guidelines, rather than focusing on single nutrients, has significant benefits for the cardiovascular risk profile of hypertensive persons beyond BP control. Compared with typical dietary therapy, the comprehensive CCNW meal plan has significantly greater effects on multiple cardiovascular risk factors while yielding greater compliance and improved quality of life.
Adult↗
Prospective family predictors of aggression toward female partners for at-risk young men.
Social learning models of the intergenerational transmission of aggression were tested for an at-risk sample of young adult men who entered a longitudinal study (Oregon Youth Study) in Grade 4 and were assessed with a female partner in young adulthood (17-20 years old). The associations of 2 family process variables--parental dyadic aggression and unskilled parenting, assessed both in late childhood and early adolescence with the son's later aggression toward a partner--were examined. Parental antisocial behavior was hypothesized to be associated with both family process variables. Unskilled parenting was hypothesized to play a key role in the son's later aggression toward an intimate partner, mediated by his development of antisocial behavior by adolescence. Fully prospective structural equation models were tested with multimethod, multiagent data, including both observed and reported aggression toward the partner. Findings indicate that the major hypothesized pathways through unskilled parenting practices and the boys' antisocial behavior were implicated in the intergenerational transmission of aggression.
Adolescent↗
High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.
Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes. Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies. Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments. We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.
Animals↗
Quantifying digital vascular disease in patients with primary Raynaud's phenomenon and systemic sclerosis.
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Angioscopy↗
Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.
PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.
Adult↗
Interleukin-1 represses COLIA1 promoter activity in calvarial bones of transgenic ColCAT mice in vitro and in vivo.
Interleukin-1 (IL-1) inhibits collagen synthesis in osteoblastic cell lines and primary osteoblast-like cells. However, promoter elements regulating type I collagen A1 (COLIA1) expression in vivo and in organ culture may differ from those regulating expression in cell culture. We have examined the effects of IL-1 on reporter gene activity in neonatal transgenic mouse calvariae bearing COLIA1 promoter-chloramphenicol acetyltransferase (ColCAT) fusion genes. The parent construct, ColCAT 3.6, contains 3.5 kb of 5' flanking sequence and 115 bp of 5' untranslated region fused to the CAT reporter. In 48-h calvarial organ cultures, IL-1 repressed ColCAT 3.6 promoter activity and collagen synthesis in a dose-related manner, with a maximal inhibition of 40-65%. This repression was retained in 5' deletion constructs truncated to-1719 bp. The inhibition of transgene mRNA was blocked by cycloheximide, indicating a requirement for new protein synthesis. Pretreatment with indomethacin diminished the inhibitory effect of IL-1 on CAT activity and collagen synthesis, suggesting partial mediation by prostaglandins. Local in vivo injection of IL-1 (500 ng) decreased calvarial transgene mRNA after 8 h, an effect that was partially blocked by indomethacin. ColCAT transgenic mice represent a useful model for in vitro and in vivo assessment of COLIA promoter regulation by cytokines and other factors.
Animals↗
Bridging the gaps: an assessment of culture in an integrated system.
After healthcare organizations merge, how do employees of different work cultures integrate? A study of four Colorado facilities in one delivery system reveals where employees reported similarities, differences, and problems--and the author tells how these issues were addressed.
Awareness↗
To sign or not to sign verbal orders.
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Authorship↗
APRN licensure bill introduced in the Senate and House.
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Humans↗
Ultrastructure of the oocysts, sporocysts, and sporozoites of Toxoplasma gondii.
Transmission and scanning electron microscopy were used to study the ultrastructure of the oocysts, sporocysts, and sporozoites of the VEG strain of Toxoplasma gondii and to compare the ultrastructure of sporozoites with tachyzoites (from the peritoneum of mice) and bradyzoites (from brain tissue cysts in mice). Oocysts were surrounded by a thin veil of finely reticulate material. The oocyst wall consisted of 3 layers and contained a previously unknown disc-shaped micropyle that appeared as a depression in the oocyst wall. The sporocyst contained 4 sporozoites and a residuum of lipid and amylopectin granules. The sporocyst wall was 3-layered with the innermost layer consisting of 4 curved plates held together at sutures by an interposed strip. Exposure to excysting fluid caused the interposed strip to separate from the curved plates, which curled inward releasing the sporozoites. Sporozoites had a posteriorly located nucleus and all the organelles typical for coccidian zoites. Sporozoites, tachyzoites, and bradyzoites had similar numbers of rhoptries but differed in the numbers and sizes of micronemes, dense granules, amylopectin granules, and lipid bodies.
Animals↗
Are race and ethnicity in STD analyses still of relevance?
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Data Collection↗
A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma.
IL-12 and IFN-gamma-inducing factor (IGIF) have the capacity to stimulate IFN-gamma production by T cells. Using an IL-12-responsive T cell clone, 2D6, we investigated how these two cytokines collaborate for IFN-gamma production. 2D6 obtained from cultures containing rIL-12 produced IFN-gamma in response to rIGIF. 2D6 from cultures deprived of IL-12 for 24 h produced only marginal levels of IFN-gamma production following stimulation with either rIL-12 or rIGIF alone. However, simultaneous stimulation of these 2D6 cells with both cytokines resulted in strikingly enhanced levels of IFN-gamma production. 2D6 could also be maintained in the presence of rIL-2 instead of rIL-12. 2D6 lines maintained with rIL-12 (2D6(IL-12)) or rIL-2 (2D6(IL-2)) exhibited differential IGIF responsiveness: both lines responded similarly to rIL-2 or rIL-12, whereas the 2D6(IL-12) or 2D6(IL-2) exhibited high or marginal IGIF responsiveness, respectively. The 2D6(IL-12) line expressed IGIF receptor (IGIFR), whereas the 2D6(IL-2) did not. Overnight exposure of the 2D6(IL-12) to rIL-2 reduced IGIFR expression and conversely, exposure of the 2D6(IL-2) to rIL-12 restored IGIFR expression. IGIFR expression by these 2D6 lines correlated with the capacity to produce IFN-gamma in response to rIGIF. Purified naive T cells stimulated with anti-CD3 plus anti-CD28 mAb and subsequently cultured with rIL-12 were also found to express IGIFR and induce enhanced IFN-gamma production following IGIF stimulation. These results indicate that the induction of IGIFR by IL-12 represents one of the mechanisms underlying the synergy between IL-12 and IGIF in IFN-gamma production.
Animals↗
Increased flux through the hexosamine biosynthesis pathway inhibits glucose transport acutely by activation of protein kinase C.
The hexosamine biosynthesis pathway and protein kinase C (PKC) activation mediate hyperglycaemia-induced impaired glucose transport, but the relative role of each pathway is unknown. Following a 2 h preincubation of rat adipocytes in the presence of either high glucose (30 mM) plus insulin (0.7 nM) or glucosamine (3 mM), both high glucose and glucosamine inhibited subsequent basal and insulin-stimulated glucose transport, measured at 5.0 mM glucose. Azaserine, an inhibitor of the enzyme glutamine:fructose-6-phosphate aminotransferase, abolished the effect of high glucose, but not that of glucosamine. Ro-31-8220, an inhibitor of PKC, reversed the effects of both high glucose and glucosamine, suggesting that flux through the hexosamine biosynthesis pathway impaired glucose transport acutely by activating PKC. Both high glucose and glucosamine caused a 3-fold increase in PKC activity; this effect of high glucose, but not that of glucosamine, was partially decreased by azaserine. Neither high glucose nor glucosamine altered basal or insulin-stimulated plasma membrane GLUT1 levels, whereas both treatments decreased basal, but not insulin-stimulated, GLUT4 levels. Azaserine abolished the effect of high glucose, but not that of glucosamine, on basal plasma membrane GLUT4 levels. Ro-31-8220, which returned glucose transport to control values, caused a further decrease in plasma membrane GLUT4 levels. It is concluded that, in rat adipocytes, an acute increase in flux through the hexosamine biosynthesis pathway inhibits glucose transport by activation of PKC.
Adipocytes↗