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Biomedical subjects

David Stone

Publications and source records attributed to David Stone.

At least 19 recordsLinked to original sources
PubMed2006

CD16+ monocyte-derived macrophages activate resting T cells for HIV infection by producing CCR3 and CCR4 ligands.

The CD16(+) monocyte (Mo) subset produces proinflammatory cytokines and is expanded in peripheral blood during progression to AIDS, but its contribution to HIV pathogenesis is unclear. In this study, we investigate the capacity of human CD16(+) and CD16(-) Mo subsets to render resting CD4(+) T cells permissive for HIV replication. We demonstrate that CD16(+) Mo preferentially differentiate into macrophages (Mphi) that activate resting T cells for productive HIV infection by producing the CCR3 and CCR4 ligands CCL24, CCL2, CCL22, and CCL17. CD16(+), but not CD16(-), Mo-derived Mphi from HIV-infected and -uninfected individuals constitutively produce CCL24 and CCL2. Furthermore, these chemokines stimulate HIV replication in CD16(-) Mo:T cell cocultures. Engagement of CCR3 and CCR4 by CCL24 and CCL2, respectively, along with stimulation via CD3/CD28, renders T cells highly permissive for productive HIV infection. Moreover, HIV replicates preferentially in CCR3(+) and CCR4(+) T cells. These findings reveal a new pathway of T cell costimulation for increased susceptibility to HIV infection via engagement of CCR3 and CCR4 by chemokines constitutively produced by CD16(+) Mo/Mphi. Thus, expansion of CD16(+) Mo in peripheral blood of HIV-infected patients and their subsequent recruitment into tissues may contribute to chronic immune activation and establishment of viral reservoirs in resting T cells.

Antigens, CD↗
PubMed2006

Eating disorder symptomatology among ballet dancers.

OBJECTIVE: The current study sought to compare eating disorder symptomatology among ballet dancers and individuals with restricting anorexia nervosa (RAN), bulimia nervosa (BN), and no eating pathology. METHOD: Twenty-nine female ballet dancers completed assessments and were compared with an archival dataset of 26 women with RAN, 47 women with BN, and 44 women with no eating pathology. Eating disorder diagnoses and behaviors were assessed with a semi-structured clinical interview, the Eating Disorder Inventory (EDI), and a weight history interview. RESULTS: Eighty-three percent of dancers met lifetime criteria for AN (6.9%), BN (10.3%), AN+BN (10.3%), or EDNOS (55.0%). Moreover, dancers looked more similar to eating-disordered individuals than to control individuals on measures of eating pathology. CONCLUSION: Despite previous emphasis on the pathology AN, the current findings suggest that dancers frequently engage in binge eating and purging behaviors. Moreover, it appears that their pathology is as severe as that of non-dancing women with eating disorders.

Adult↗
PubMed2006

Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells.

Intestinal mucosa is constantly exposed to normal environmental antigens. A significant number of intestinal mucosal T cells are being deleted through apoptosis. In contrast, T cells from inflamed mucosa of ulcerative colitis patients did not undergo apoptosis. In this study, we determined whether the apoptosis of normal mucosal T cells was induced by antigen receptor stimulation and further determined pathways that mediated the apoptosis. Freshly isolated lamina propria T cells were stimulated with CD3 mAb and apoptosis was determined by Annexin V staining. Normal mucosal T cells underwent apoptosis upon CD3 mAb stimulation whereas the T cells from inflamed mucosa did not. The apoptosis in normal T cells was blocked by TRAIL-R1:Fc and an inhibiting CD95 antibody. Interestingly, decoy receptor (DcR)1, DcR2, and DcR3 that compete with death receptor (DR)4/5 and CD95 were highly expressed by the T cells from inflamed mucosa, but much lower by T cells from normal mucosa. Our data suggest that normal mucosal T cells are constantly deleted in response to environmental antigens mediated through DR4/5 and CD95 pathways and mucosal T cells from ulcerative colitis resist to undergoing apoptosis due to highly expression of DcR1, DcR2, and DcR3.

Adult↗
PubMed2006

Association of parental pretransplant psychosocial assessment with post-transplant morbidity in pediatric heart transplant recipients.

Because parents assume the primary responsibility for providing ambulatory post-transplant care to pediatric patients, pretransplant psychosocial evaluation in these recipients is usually focused on parents rather than on patients themselves. We sought to determine whether pretransplant parental psychosocial evaluation predicts post-transplant medical outcome at current levels of psychosocial support. We compared relative risk (RR) of rejection and hospitalizations (days of all-cause hospitalization) following initial discharge in patients in 'risk' and 'control' groups defined by their pretransplant parental psychosocial evaluation. We also compared the two groups of patients for the proportion of all outpatient trough cyclosporine A (CSA) or tacrolimus (FK) levels that were < 50% of the target level (defined as the mid-therapeutic range level). There were seven patients in the 'risk' group with a median age 0.25 yr (range 0.19-14.7 yr) and total follow up 20.5 patient-yr. There were 21 patients in the 'control' groups with a median age of 2.1 yr (range 0.05-16.2 yr) and total follow up of 71.3 patient-yr. There was no significant difference between the groups in rejection-risk or days of all-cause hospitalization early after transplant (first six months). During the late period (after the first six months), there were 11 rejection episodes in the 'risk' group over 17.4 patient-yr and four rejection episodes in control group over 61.8 patient-yr of follow up. After adjustment for age and race, patients in the 'risk' category had a RR of 3.4 for developing a rejection episode (p = 0.06) and 3.1 for being inpatient (p < 0.001) during the late period. Patients in the risk group were 2.9 times more likely to have subtherapeutic trough levels (< 50% target level) of calcineurin inhibitor (CSA or FK) during both early and late periods (p < 0.01 for both periods) after adjustment for patient age and race. We conclude that pretransplant parental psychosocial risk assessment is associated with post-transplant morbidity in children after cardiac transplantation. These patients may benefit from closer outpatient monitoring and a higher level of psychosocial support.

Adolescent↗
PubMed2005

The shavenoid gene of Drosophila encodes a novel actin cytoskeleton interacting protein that promotes wing hair morphogenesis.

The simple cellular composition and array of distally pointing hairs has made the Drosophila wing a favored system for studying planar polarity and the coordination of cellular- and tissue-level morphogenesis. The developing hairs are filled with F-actin and microtubules and the activity of these cytoskeletons is important for hair morphogenesis. On the basis of mutant phenotypes several genes have been identified as playing a key role in stimulating hair formation. Mutations in shavenoid (sha) (also known as kojak) result in a delay in hair morphogenesis and in some cells forming no hair and others several small hairs. We report here the molecular identification and characterization of the sha gene and protein. sha encodes a large novel protein that has homologs in other insects, but not in more distantly related organisms. The Sha protein accumulated in growing hairs and bristles in a pattern that suggested that it could directly interact with the actin cytoskeleton. Consistent with this mechanism of action we found that Sha and actin co-immunoprecipitated from wing disc cells. The morphogenesis of the hair involves temporal control by sha and spatial control by the genes of the frizzled planar polarity pathway. We found a strong genetic interaction between mutations in these genes consistent with their having a close but parallel functional relationship.

Actins↗
PubMed2005

CD16+ monocytes exposed to HIV promote highly efficient viral replication upon differentiation into macrophages and interaction with T cells.

The CD16+ subset of monocytes is dramatically expanded in peripheral blood during progression to AIDS, but its contribution to HIV pathogenesis is unknown. Here, we demonstrate that CD16+ but not CD16- monocytes promote high levels of HIV replication upon differentiation into macrophages and interaction with T cells. Conjugates formed between CD16+ monocyte-derived macrophages and T cells are major sites of viral replication. Furthermore, similar monocyte-T cell conjugates detected in peripheral blood of HIV-infected patients harbor HIV DNA. Thus, expansion of CD16+ monocytes during HIV infection and their subsequent recruitment into tissues such as lymph nodes, brain, and intestine may contribute to HIV dissemination and establishment of productive infection in T cells.

CD4 Antigens↗
PubMed2005

Acceptance of HIV antibody testing among inpatients and outpatients at a public health hospital: a study of rapid versus standard testing.

Patients of unknown HIV status who were admitted to the inpatient unit or who were undergoing evaluation in the outpatient clinic of a public health hospital were randomized to receive either the standard HIV test or a rapid HIV test. Patients ranged from 21-71 years of age, and 71% were male. Eleven percent were Hispanic, 36% black, and 48% Caucasian. 35% were injection drug users (IVDU) and 3% men who have sex with men (MSM). The waiting period for the standard test was 2 weeks, and that for rapid testing was approximately 20 minutes. Patients were provided with a telephone number and told to call and schedule a follow-up appointment to receive their standard test results. We found no statistical difference in the acceptance rates of either testing modality overall or with respect to age or gender. We did find a significantly greater percentage of Hispanic patients accepting rapid testing over standard testing (p = 0.04). The overall acceptance rates of rapid and standard testing were 60% and 41%, respectively. This was far lower than expected, and was due in part to the 40% of patients who refused testing because of their having a previous HIV test. All patients who had received previous testing had tested HIV negative, and we did not discover any new cases of HIV in the 103 patients tested during the study. Of those we tested, 95% of those receiving the rapid test and 43% of those receiving the standard test were informed of their status (p < 0.001). Failure of patients to return for follow-up visits accounts for the low percentage of individuals successfully informed of their standard test results. The study suggests that rapid HIV testing is at least as palatable as standard testing in our population. In addition, a far greater percentage of patients are informed of their status using the rapid HIV test. HIV testing programs at our hospital may not be cost effective as our population appears to have been heavily tested previously. Prior to initiating an HIV testing program within a hospital setting, it is imperative to determine the percentage of patients previously tested for HIV.

AIDS Serodiagnosis↗
PubMed2004

Differences in the cellular distribution of D1 receptor mRNA in the hippocampus of bipolars and schizophrenics.

Several lines of evidence have pointed to a role of the dopamine system in the pathophysiology of schizophrenia. A recent postmortem study demonstrated a selective decrease of tyrosine hydroxylase fibers on pyramidal neurons in sector CA2 in the hippocampus of schizophrenics. Although both brain imaging and postmortem studies have examined the distribution of the D1 receptor in the prefrontal and cingulate cortex, no study to date has examined its expression of mRNA using a high-resolution autoradiographic approach. In order to further assess whether the regulation of the dopamine D1 receptor is altered in hippocampal neurons in this disorder, we used in situ hybridization (ISH) to measure the expression of messenger RNA for this receptor in the dentate gyrus and sectors CA1-4. Both the number of cells expressing D1 mRNA and the amount of expression per cell were measured in 15 schizophrenic, 15 bipolar disorder, and 15 normal control subjects. The results show a significant (21%) and selective decrease in D1 mRNA expression in sector CA3 of schizophrenic subjects. First-degree relatives of schizophrenics did not show any differences in either the expression of D1 mRNA per cell or the number of cells expressing this mRNA when compared to a separate group of normal controls matched for age and PMI. Subjects with bipolar disorder also showed a significant (25%) and selective increase of D1 mRNA expression in sector CA2. Other hippocampal sectors did not show significant changes. These findings in schizophrenics and bipolars were also associated with inverse changes in the overall number of neurons expressing D1 mRNA in sectors CA3 and CA2, respectively. This study shows diagnosis-specific changes in D1 mRNA expression in the hippocampus of schizophrenic versus bipolar subjects and suggests that this neuromodulatory system may show distinct changes in the pathophysiology of the two disorders.

Adult↗
PubMed2004

Inturned localizes to the proximal side of wing cells under the instruction of upstream planar polarity proteins.

Planar polarity development in the Drosophila wing is under the control of the frizzled (fz) pathway. Recent work has established that the planar polarity (PP) proteins become localized to either the distal, proximal, or both sides of wing cells. Fz and Dsh distal accumulation is thought to locally activate the cytoskeleton to form a hair . Planar polarity effector (PPE) genes such as inturned (in) are not required for the asymmetric accumulation of PP proteins, but they are required for this to influence hair polarity. in mutations result in abnormal hair polarity and are epistatic to mutations in the PP genes. We report that In localizes to the proximal side of wing cells in a PP-dependent and PP-instructive manner. We further show that the function of two other PPE genes (fuzzy and fritz) is essential for In protein localization, a finding consistent with previous genetic data that suggested these three genes function in a common process. These data indicate that accumulation of proteins at the proximal side of wing cells is a key event for the distal activation of the cytoskeleton to form a hair.

Animals↗
PubMed2004

Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells.

Virus-specific CD8(+) T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon gamma assays presently used. Here, we demonstrate that HIV-1-specific CD8(+) T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4(+) T cells or addition of interleukin 2-neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4(+) T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1-specific CD4(+) T helper cell responses. These data demonstrate a loss of HIV-1-specific CD8(+) T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1-specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.

AIDS Vaccines↗
PubMed2004

Pheromone-induced polarization is dependent on the Fus3p MAPK acting through the formin Bni1p.

During mating, budding yeast cells reorient growth toward the highest concentration of pheromone. Bni1p, a formin homologue, is required for this polarized growth by facilitating cortical actin cable assembly. Fus3p, a pheromone-activated MAP kinase, is required for pheromone signaling and cell fusion. We show that Fus3p phosphorylates Bni1p in vitro, and phosphorylation of Bni1p in vivo during the pheromone response is dependent on Fus3p. fus3 mutants exhibited multiple phenotypes similar to bni1 mutants, including defects in actin and cell polarization, as well as Kar9p and cytoplasmic microtubule localization. Disruption of the interaction between Fus3p and the receptor-associated Galpha subunit caused similar mutant phenotypes. After pheromone treatment, Bni1p-GFP and Spa2p failed to localize to the cortex of fus3 mutants, and cell wall growth became completely unpolarized. Bni1p overexpression suppressed the actin assembly, cell polarization, and cell fusion defects. These data suggest a model wherein activated Fus3p is recruited back to the cortex, where it activates Bni1p to promote polarization and cell fusion.

Actin Cytoskeleton↗
PubMed2004

Prenatal diagnostic procedures used in pregnancies with congenital malformations in 14 regions of Europe.

OBJECTIVE: To investigate outcomes of ultrasound investigations (US) and invasive diagnostic procedures in cases of congenital malformations (CM), and to compare the use of invasive prenatal test techniques (amniocentesis (AC) versus chorionic villus sampling (CVS)) among European populations. DESIGN: Analysis of data from population-based registries of CM. SUBJECTS: 25 400 cases of CM recorded by 14 EUROCAT registries covering a total population of 1,013,352 births 1995-99. RESULTS: US were performed in 91% of cases, and positively detected CM in 35% of cases. AC was performed in 24% of the cases and CVS in 3% of cases. Thirty-eight percent of invasive tests gave positive results. Fifty-two percent of cases with maternal age > or = 35 years had an invasive test performed compared to 20% of cases with younger mothers. Considerable variation was found between registries in the uptake rate of invasive tests in cases with older maternal age and on the use of invasive tests with only four regions employing CVS techniques in at least a third of the cases having invasive tests. For chromosomal anomalies US gave positive results in 46% of cases with maternal age < 35 years with US performed and in 36% of cases with maternal age > or = 35 years with US performed. CONCLUSION: Prenatal US was performed in 91% of all pregnancies with CM but the test was only positive in a third of the cases. There was large regional variation in the uptake rate of invasive tests with maternal age of 35 years or more. For every CVS carried out there were nine AC tests. US is an important tool in the prenatal diagnosis of chromosomal anomalies in Europe.

Abnormalities, Multiple↗
PubMed2004

Development and validation of a radioimmunoassay for fish insulin-like growth factor I (IGF-I) and the effect of aquaculture related stressors on circulating IGF-I levels.

This paper describes the development and validation of a commercially available radioimmunoassay (RIA) for the detection of fish insulin-like growth factor-I (IGF-I). The assay was developed using recombinant barramundi IGF-I as antigen and recombinant tuna IGF-I as radiolabelled tracer and standard. Assay sensitivity was 0.15 ng/ml, inter-assay variation was 16% (n = 9) and intra-assay variation was 3% (n = 10). Cross reactivity of less than 0.01% was found with salmon insulin, salmon IGF-II and barramundi IGF-II, less than 0.5% with human IGF-I and less than 1% with human IGF-II. Parallel dose-response inhibition curves were shown for barramundi (Lates calcarifer), coho salmon (Oncorhynchus kisutch), Southern Bluefin tuna (Thunnus maccoyii), tilapia (Oreochromis mossambicus), and seabream (Pagrus auratus) IGF-I. The assay was then used to measure stress related changes in different aquacultured fish species. Salt water acclimated Atlantic salmon smolts (Salmo salar) bathed for 2 h in fresh water showed significantly lower IGF-I concentrations than control smolts two days after the bath (53.1 compared to 32.1 ng/ml), with levels of IGF-I also lower in smolts exhibiting stunted growth (stunts). Capture and confinement of wild tuna in sea-cages resulted in a significant decrease in IGF-I levels (28 ng/ml) when compared to tuna captured and sampled immediately (48 ng/ml), but had recovered to starting levels after 3 weeks (43 ng/ml). Handling and isolation in silver perch (Bidyanus bidyanus) led to a gradual decline in IGF-I over a 12 h period (36-19 ng/ml) but showed signs of recovery by 24 h (24 ng/ml) and had recovered fully 72 h after treatment (40 ng/ml). A similar trial in black bream (Acanthopagrus butcherii) showed comparable results with IGF-I levels gradually decreasing (40-26 ng/ml) over 24 h, results that were mirrored by cortisol concentrations which increased during this time (1-26 ng/ml). In the studies presented here changes in IGF-I levels were not observed for at least 3 h after exposure to the stressor. We suggest this is due to the endocrine nature of IGF-I regulation and the clearance rate of IGF-I in vivo.

Animals↗
PubMed2004

Colocolonic intussusception of a giant pseudopolyp in a patient with ulcerative colitis: a case report and review of the literature.

Adult intussusception in the setting of inflammatory bowel disease (IBD) is a rare phenomenon. Giant pseudopolyps, while generally considered benign, may function as lead points for intussusception. Diagnosis and management of intussusception in the setting of IBD can be fraught with hazards. We report the case of a 27-year-old male, recently diagnosed with ulcerative colitis and giant pseudopolyps, who presented with colocolonic intussusception and obstruction. Diagnosis was confirmed using CT imaging and the patient underwent resection of the colocolonic intussusception without reduction. The following case underscores the challenges in managing adult intussusception in the setting of IBD and allows for a review of the literature to date. Resection of non-reduced intussusception, rather than endoscopic or enema reduction, should continue to be definitive treatment of patients presenting with this unusual problem.

Adult↗
PubMed2004

Inflammatory response of human tendon fibroblasts to cyclic mechanical stretching.

BACKGROUND: The cellular and molecular mechanisms for the development of tendinopathy are not clear, but inflammatory mediators produced by tendon fibroblasts in response to repetitive mechanical loading may be an important factor. HYPOTHESES: (1) Cyclic stretching of tendon fibroblasts affects the production of leukotriene B(4) and the expression of 5-lipoxygenase; and (2) the production level of leukotriene B(4) is inversely related to that of prostaglandin E(2). STUDY DESIGN: Controlled laboratory study. METHODS: Human patellar tendon fibroblasts were uniaxially stretched in the presence of indomethacin (25 micro M) or MK-886 (10 micro M). After stretching for 4 hours, followed by 4 hours rest, levels of prostaglandin E(2), leukotriene B(4), and expression of 5-lipoxygenase were measured. RESULTS: Stretched tendon fibroblasts increased the levels of leukotriene B(4) but did not appreciably change the expression of 5-lipoxygenase. Indomethacin decreased the cellular production of prostaglandin E(2) but caused increased leukotriene B(4) levels. MK-886 caused decreased production of leukotriene B(4) but increased production of prostaglandin E(2). CONCLUSIONS: Cyclic stretching of human tendon fibroblasts increases the production of prostaglandin E(2) and leukotriene B(4). Blocking prostaglandin E(2) production leads to increased leukotriene B(4) levels and vice versa. CLINICAL RELEVANCE: The use of nonsteroidal anti-inflammatory drugs for the treatment of tendon inflammation might increase the levels of leukotriene B(4) within the tendon, potentially contributing to the development of tendinopathy.

Adult↗