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Biomedical subjects

G Downey

Publications and source records attributed to G Downey.

At least 19 recordsLinked to original sources
PubMed2002

A unique renal lesion in common variable immunodeficiency.

This article reports the case of a 33-year-old woman with common variable immunodeficiency (CVI) who developed renal failure 17 years after diagnosis and initiation of treatment with monthly IVIG. A renal biopsy revealed mesangial and paramesangial immune complex deposition and interstitial granulomatous infiltration. Renal function improved with oral corticosteroids, but did not return to normal. Decreasing the dose of IVIG had no effect on renal function. Immune dysfunction can be associated with both granulomatous disease and immune complex glomerulonephritis, or the latter may be related to chronic infection or immunoglobulin use. This is the first report of concomitant glomerular-tubulointerstitial lesions in this immunodeficiency syndrome. Renal function should be closely followed in patients with CVI.

Adult↗
PubMed2001

Targeting transgene expression for cystic fibrosis gene therapy.

We have developed an expression cassette for cystic fibrosis (CF) gene therapy using control elements from the human cytokeratin 18 gene (KRT18, also known as K18). KRT18 is naturally expressed in a spatial pattern similar to that of CFTR, the gene mutated in CF. We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression in various tissues. We found expression in nasal and bronchial epithelium, airway submucosal glands, gall bladder, and kidneys. Expression was low in pancreas and gut, and absent from liver and alveolar lung. This is consistent with the expression pattern reported for a K18lacZ transgenic mouse. Following delivery of a cytomegalovirus (CMV) major immediate-early promoter/enhancer-driven lacZ plasmid, we found expression in bronchi, submucosal glands, alveolar cells, liver, and kidney. We did not detect expression in nose, pancreas, gall bladder, or gut. Using fluorescently labeled plasmid delivered by means of liposomes, we identified the liver, alveolar lung, and kidneys as the major plasmid deposition sites. Our data demonstrate that a KRT18-driven expression vector delivered systemically can target gene expression to CF-affected tissues, despite an uneven distribution of plasmid DNA. A KRT18-based vector may be a useful alternative to viral promoter-based vectors in clinical gene therapy trials to treat CF.

Animals↗
PubMed2001

Immune function in patients with Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an inherited multisystem disorder characterized by exocrine pancreatic dysfunction and varying degrees of cytopenia. In addition, various immunological abnormalities have been noted. To clarify the issue of immunological competence or incompetence in SDS, we prospectively studied immune function in 11 patients with SDS. Seven suffered from recurrent bacterial infections and six from recurrent viral infections. Varying degrees of impairment were readily identified. All patients had neutropenia; total lymphocyte counts, however, were normal in all except one patient. Nine patients had B-cell defects comprising one or more of the following abnormalities: low IgG or IgG subclasses, low percentage of circulating B lymphocytes, decreased in vitro B-lymphocyte proliferation and a lack of specific antibody production. Seven out of nine patients studied had at least one T-cell abnormality comprising a low percentage of total circulating T lymphocytes or CD3+/CD4+ cell subpopulations or decreased in vitro T-lymphocyte proliferation. Five out of six patients studied had decreased percentages of circulating natural killer cells. Moreover, neutrophil chemotaxis was significantly low in all the patients studied. These data point to a major immunodeficiency component in SDS that places patients at heightened risk of infections, even if neutrophil numbers are protective. This finding broadens the definition of the syndrome substantially: it suggests that the SDS marrow defect occurs at the level of an early haematological-lymphocytic stem cell or that a combined marrow and thymic stromal defect accounts for the aberrant function of haematopoietic and lymphopoietic lineages.

Adolescent↗
PubMed2001

Involvement of actin filaments and integrins in the binding step in collagen phagocytosis by human fibroblasts.

In physiological conditions, collagen degradation by fibroblasts occurs primarily via phagocytosis, an intracellular pathway that is thought to require collagen receptors and actin assembly for fibril internalization and degradation. Currently it is unclear which specific steps of collagen phagocytosis in fibroblasts involve actin filament assembly. As studies of phagocytosis in fibroblasts are complicated by the relatively slow rate of particle internalization compared to professional phagocytes, we have examined the role of collagen receptors and actin only in the initial collagen binding step. Prior to the binding of collagen-coated fluorescent beads by human gingival fibroblasts, a cell type that is avidly phagocytic in vitro, cells were treated with cytochalasin D (actin filament barbed-end capping) or swinholide A (actin dimer sequestering and severing) or latrunculin B (actin monomer sequestering). Bead binding and immunostaining of (alpha)(2)(beta)(1) and (alpha)(3)(beta)(1) integrin collagen receptors were measured by flow cytometry. After 1-3 hours of coincubation with beads, cytochalasin D or swinholide A eliminated actin filaments stained by rhodamine-phalloidin and inhibited collagen bead binding (reductions of 25% and 50%, respectively), possibly because of cell rounding and restricted interactions with beads. In contrast, latrunculin enhanced binding dose-dependently over controls (twofold at 1 microM) and induced the formation of brightly staining aggregates of actin and the retention of long cytoplasmic extensions. Latrunculin also reduced surface (beta)(1), (alpha)(2) and (alpha)(3) integrin staining up to 40% in bead-free and bead-loaded cells, indicating that latrunculin enhanced collagen receptor internalization. As determined by fluorescence recovery after photobleaching, latrunculin increased the mobility of surface-bound (beta)(1) integrin. The stimulatory effect of latrunculin on collagen bead binding was reduced to control levels by treatment with a (beta)(1) integrin inactivating antibody while a (beta)(1) integrin blocking antibody abrogated both bead binding and the latrunculin-induced stimulation. Immunoblotting of bead-associated proteins showed that latrunculin completely eliminated binding of (beta)-actin to collagen beads but did not affect (beta)(1) integrin binding. These data indicate that latrunculin-induced sequestration of actin monomers facilitates the disengagement of actin from (beta)(1) integrin receptors, increases collagen bead binding and enhances collagen receptor mobility. We suggest that these alterations increase the probability of adhesive bead-to-cell interactions.

Actins↗
PubMed2000

Involvement of cytosolic phospholipase A2 and secretory phospholipase A2 in arachidonic acid release from human neutrophils.

The purpose of this study was to define the role of secretory phospholipase A2 (sPLA2), calcium-independent PLA2, and cytosolic PLA2 (cPLA2) in arachidonic acid (AA) release from fMLP-stimulated human neutrophils. While fMLP induced the release of extracellular sPLA2 activity and AA, 70% of sPLA2 activity remained associated with the cell. Treatment with the cell-impermeable sPLA2 inhibitors DTT or LY311-727, or the anti-sPLA2 Ab 3F10 all inactivated extracellular sPLA2 activity, but had minimal effect on neutrophil AA mass release. In contrast, coincubation of streptolysin-O toxin-permeabilized neutrophils with DTT, LY311-727, or 3F10 all decreased [3H8]AA release from [3H8]AA-labeled, fMLP-stimulated cells. Exposure to fMLP resulted in a decrease in the electrophoretic mobility of cPLA2, a finding consistent with cPLA2 phosphorylation, and stimulated the translocation of cPLA2 from cytosolic to microsomal and nuclear compartments. The role of cPLA2 was further evaluated with the cPLA2 inhibitor methyl arachidonyl fluorophosphonate, which attenuated cPLA2 activity in vitro and decreased fMLP-stimulated AA mass release by intact neutrophils, but had no effect on neutrophil sPLA2 activity. Inhibition of calcium-independent PLA2 with haloenol lactone suicide substrate had no effect on neutrophil cPLA2 activity or AA mass release. These results indicate a role for cPLA2 and an intracellular or cell-associated sPLA2 in the release of AA from fMLP-stimulated human neutrophils.

Arachidonic Acid↗
PubMed2000

Regulating the interpersonal self: strategic self-regulation for coping with rejection sensitivity.

People high in rejection sensitivity (RS) anxiously expect rejection and are at risk for interpersonal and personal distress. Two studies examined the role of self-regulation through strategic attention deployment in moderating the link between RS and maladaptive outcomes. Self-regulation was assessed by the delay of gratification (DG) paradigm in childhood. In Study 1, preschoolers from the Stanford University community who participated in the DG paradigm were assessed 20 years later. Study 2 assessed low-income, minority middle school children on comparable measures. DG ability buffered high-RS people from interpersonal difficulties (aggression, peer rejection) and diminished well-being (e.g., low self-worth, higher drug use). The protective effect of DG ability on high-RS children's self-worth is explained by reduced interpersonal problems. Attentional mechanisms underlying the interaction between RS and strategic self-regulation are discussed.

Adaptation, Psychological↗
PubMed2000

Rejection sensitivity and adolescent girls' vulnerability to relationship-centered difficulties.

Rejection sensitivity (RS)--the disposition to defensively expect, readily perceive, and intensely react to rejection--is a potential source of vulnerability for adolescent girls' relationship difficulties. RS is thought to develop from rejection experiences, including maltreatment. When adolescent girls enter romantic relationships, RS may prompt vigilance for rejection cues and reactions to perceived rejection that are maladaptive, including hostility. To preserve their romantic relationships, high RS girls may behave in ways that increase their risk of victimization or other negative outcomes. These claims were tested with longitudinal data from 154 minority, economically disadvantaged, middle school girls. RS prospectively predicted insecurity about a boyfriend's commitment and also a willingness to do things known to be wrong to maintain the relationship. RS predicted more physical aggression and nonphysical hostility during romantic conflicts. Implications for a relationship-centered approach to adolescent girls' characteristic vulnerabilities are discussed.

Adolescent↗
PubMed1999

Pain, negative mood, and perceived support in chronic pain patients: a daily diary study of people with reflex sympathetic dystrophy syndrome.

Chronic pain patients show substantial psychological distress, including depressed mood, anxiety, and anger. Nevertheless, the causal role of negative mood in the course of chronic pain conditions remains unclear. This study prospectively investigated the relationship between daily pain, negative mood, and social support in 109 people with reflex sympathetic dystrophy syndrome. Participants completed 28 daily diaries that included questions about pain, mood, and perceived support. Time-lagged within-subject analyses indicated that pain led to increases in depressed, anxious, and angry mood. Depressed mood, but not anxiety or anger, contributed to increases in pain. Perceived support had both main and buffering (interaction) effects on negative mood and a main effect on pain.

Adult↗
PubMed1999

Randomized trial of informed consent and recruitment for clinical trials in the immediate preoperative period.

BACKGROUND: The standard process of obtaining informed consent sometimes prevents physicians or patients from participating in clinical trials, partly because they are concerned about eventual treatment allocation or the physician is concerned the patient might harbor some uncertainty about the best treatment. Alternative randomization methods have been advocated that may address these and other concerns. METHODS: After institutional ethics committee gave its approval, the authors interviewed 770 patients before operation and asked them to consider enrolling in a mock anesthesia trial. Patients were allocated randomly to one of five methods of randomization and consent: one-sided informed consent (the most common approach), prerandomized consent to experimental treatment, prerandomized consent to standard treatment, one-sided physician-modified informed consent, or one-sided patient-modified informed consent. Recruitment rates were compared and sociodemographic and perioperative predictors of recruitment were identified. RESULTS: The randomization method did not result in any significant difference in recruitment rates: one-sided informed consent, 55.6%; prerandomized consent to experimental treatment, 53.3%; prerandomized consent to standard treatment, 53%; one-sided physician-modified informed consent, 60.7%; and one-sided patient-modified informed consent, 56.7% (P = 0.66). Multivariate predictors of recruitment were patient age >45 yr (odds ratio, 1.44; 95% confidence interval [CI], 1.08 to 1.93), English-speaking at home (1.49; 1.0 to 2.21), and male researcher-male patient interaction (1.37; 1.20 to 1.57). CONCLUSIONS: No evidence emerged that alternative randomization and consent designs resulted in increased recruitment rates compared with simple one-sided informed consent for a sham anesthesia trial in patients awaiting elective surgery. Older, male patients were more likely to provide consent.

Adolescent↗
PubMed1998

The self-fulfilling prophecy in close relationships: rejection sensitivity and rejection by romantic partners.

The authors hypothesized a self-fulfilling prophecy wherein rejection expectancies lead people to behave in ways that elicit rejection from their dating partners. The hypothesis was tested in 2 studies of conflict in couples: (a) a longitudinal field study where couples provided daily-diary reports and (b) a lab study involving behavioral observations. Results from the field study showed that high rejection-sensitive (HRS) people's relationships were more likely to break up than those of low rejection-sensitive (LRS) people. Conflict processes that contribute to relationship erosion were revealed for HRS women but not for HRS men. Following naturally occurring relationship conflicts, HRS women's partners were more rejecting than were LRS women's partners. The lab study showed that HRS women's negative behavior during conflictual discussions helped explain their partners' more rejecting postconflict responses.

Adult↗
PubMed1998

Rejection sensitivity and children's interpersonal difficulties.

Some children respond to social rejection in ways that undermine their relationships, whereas others respond with more equanimity. This article reports 3 studies that test the proposition that rejection sensitivity--the disposition to defensively (i.e., anxiously or angrily) expect, readily perceive, and overreact to social rejection--helps explain individual differences in response to social rejection. Data were from urban, minority (primarily Hispanic and African American) fifth to seventh graders. Study 1 describes the development of a measure of rejection sensitivity for children. Study 2 provides experimental evidence that children who angrily expected rejection showed heightened distress following an ambiguously intentioned rejection by a peer. Study 3 shows that rejection sensitive children behaved more aggressively and experienced increased interpersonal difficulties and declines in academic functioning over time.

Adolescent↗
PubMed1997

An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix.

UNLABELLED: Thirty-two evaluable patients with squamous cell cancer of the cervix were treated with i.v. paclitaxel 250 mg/m2 over 3 h every 21 days. They received standard premedications and granulocyte colony stimulating factor (G-CSF) support (5 micrograms/kg/day). Median (range) age was 49 (29-81) years and performance status Zubrod was 1 (0-2). One patient had a complete response and seven patients had a partial response (25%, 95% CI 8-38%). The median survival was 7.3 months. Granulocytopenia was brief and non-cumulative. G-CSF was used for a median (range) of 8 (1-15) days per cycle. IN CONCLUSION: paclitaxel is active in patients with squamous cell cancer of the cervix and is well tolerated in this dose schedule with G-CSF support.

Adult↗
PubMed1997

Involvement of the actin network in insulin signalling.

The purpose of the studies included in this chapter was to examine the role of the actin network in the propagation of insulin action leading to stimulation of glucose transport and activation of the mitogen-activated protein kinase cascade. The active insulin receptor phosphorylates tyrosine residues of intracellular proteins such as the insulin receptor substrate-1 (IRS-1) which acts as docking sites for molecules containing Src homology 2 (SH2) domains. One such molecule is phosphatidylinositol 3-kinase (PI 3-kinase) which becomes activated by binding to IRS-1. PI 3-kinase activity is required for the insulin-stimulation of glucose transport and glycogen synthesis. Grb2, a small adaptor molecule, can bind IRS-1 and, through the guanine nucleotide exchange factor Sos, leads to the activation of the small GTP binding protein Ras. Through a cascade of protein kinases, activation of Ras results in activation of the Erk 1 and 2 mitogen-activated protein kinases (MAPKs) which appear to control important nuclear and metabolic events. To investigate the role of the actin network in the propagation of insulin action leading to stimulation of glucose transport and the activation of the Erk MAPKs, we used the fungal metabolite cytochalasin D which disassembles the actin network. Actin disassembly abolished almost completely the ability of insulin to increase the rate of glucose transport into L6 muscle cells (myotubes) through prevention of the insulin-induced recruitment of glucose transporters to the plasma membrane which is the event that mediates the increase in the rate of transport. Actin disassembly did not affect either the insulin-mediated phosphorylation of IRS-1, the association of PI 3-kinase with this molecule, or the activation of IRS-1-associated PI 3-kinase. These results were also verified in another insulin responsive cell line, the 3T3-L1 adipocytes. In these cells, actin disassembly inhibited the insulin-induced recruitment of PI 3-kinase to intracellular membranes containing glucose transporters. Moreover, actin disassembly abolished the insulin-mediated phosphorylation of the Erk MAPKs. We conclude that the cellular actin network of insulin responsive cells is not required for the activation of PI 3-kinase but prevents its cellular redistribution. In contrast, intact actin filaments are essential for the propagation of insulin signals leading to the the activation of the MAPKs.

3T3 Cells↗
PubMed1996

Implications of rejection sensitivity for intimate relationships.

People who are sensitive to social rejection tend to anxiously expect, readily perceive, and overreact to it. This article shows that this cognitive-affective processing disposition undermines intimate relationships. Study 1 describes a measure that operationalizes the anxious-expectations component of rejection sensitivity. Study 2 provides experimental evidence that people who anxiously expect rejection readily perceive intentional rejection in the ambiguous behavior of others. Study 3 shows that people who enter romantic relationships with anxious expectations of rejection readily perceive intentional rejection in the insensitive behavior of their new partners. Study 4 demonstrates that rejection-sensitive people and their romantic partners are dissatisfied with their relationships. Rejection-sensitive men's jealousy and rejection-sensitive women's hostility and diminished supportiveness help explain their partners' dissatisfaction.

Adolescent↗
PubMed1996

Increased Po2 alters the bioelectric properties of fetal distal lung epithelium.

At birth the lung must efficiently clear the liquid from its air spaces and permanently convert from a fluid-secreting to a fluid-absorbing organ. When primary cultures of rat fetal distal lung epithelium (FDLE) grown on permeable supports were switched from a fetal (3%) to a postnatal (21%) oxygen environment, there was an increase in epithelial permeability as reflected by a dose-dependent decline in transepithelial resistance (Rt) 4 h later (3% = 239 +/- 19 omega.cm2; 21% = 170 +/- 28 omega.cm2; 50% = 98 +/- 20 omega.cm2; P < 0.05). The effect was transient, since monolayers initially maintained at 3% and switched to these higher oxygen concentrations subsequently had Rt values comparable to the 3% group at 48 h (3% = 153 +/- 17 omega.cm2; 21% = 181 +/- 19 omega.cm2; 50% = 192 +/- 21 omega.cm2; P = NS). Changes in Rt were associated with expected changes in the histological appearance of the interepithelial tight junctions, but intracellular actin content and distribution remained constant. Amiloride-sensitive equivalent short-circuit current increased within 18 h, with further increases after 48 h of exposure to postnatal oxygen concentrations. Ion substitution experiments suggested diminished FDLE Cl transport and increased Na transport. The amount of FDLE-alpha, -beta, and -gamma rat epithelial Na channel mRNA increased within 48 h of increasing the ambient oxygen concentration. These results suggest that the physiological increase in alveolar Po2 at birth is, at least in part, responsible for distal lung's permanent switch from Cl secretion to Na absorption at birth.

Animals↗
PubMed1996

Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix.

Twenty-six patients with squamous cell cancer of the cervix were treated with i.v. paclitaxel, 250 mg/m2 over 3 h every 21 days. They received steroid, H1 and H2 blocker premedications, and granulocyte-colony-stimulating factor (G-CSF) support (5 microgram/kg/day). No prior chemotherapy, except as a radiation sensitizer, was allowed. The median age was 50 (range, 36-81) years, and performance status Zubrod was 1 (range, 0-2). Eight (33%) patients had prior surgery, and 22 (92%) had prior radiation therapy. Twenty-four patients were evaluable for response; 2 were later found to be ineligible. Five patients had partial responses (21%; 95% confidence interval, 6-40%), and 14 (58%; 95% confidence interval, 35-78%) had stable disease. The median duration of response was 10 (range, 3-27+) weeks. The responses were within the radiation port (four responses) and outside of it (one response). The median interval from the start of irradiation to the start of paclitaxel in responding patients was 94 weeks, whereas in patients with stable disease it was 68 weeks, and in patients whose disease progressed it was 46 weeks. Eighty-eight percent of the 105 cycles of paclitaxel were administered at a dose of 250 mg/m2 or higher. Granulocytopenia was brief and noncumulative, with grades 3 and 4 experienced by 5 and 3 patients, respectively. G-CSF was used for a median of 7 (range, 2-14) days/cycle. Anemia was mild, with G3 noted in 3 patients, and thrombocytopenia was not significant. Infections and musculoskeletal pain were mild and infrequent. Sensory (14 patients G1 or G2 and 2 patients G3) and motor (4 patients G1 or G2 and 1 patient G3) neurotoxicity was noted. There was no significant cardiovascular toxicity. Paclitaxel is active in patients with squamous cell cancer of the cervix and is well tolerated at this dose schedule with G-CSF support.

Adult↗