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Biomedical subjects

S Thornton

Publications and source records attributed to S Thornton.

At least 19 recordsLinked to original sources
PubMed2000

Heterogeneous effects of IL-2 on collagen-induced arthritis.

IL-2 is generally considered a pro-inflammatory cytokine that exacerbates Th1-mediated disease states, such as autoimmune arthritis. Consistent with this role for IL-2, recent studies from our laboratory demonstrate that IL-2 mRNA is markedly increased during the acute stage of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. To further define the role of IL-2 in CIA, the levels of IL-2 protein and its receptor and the effects of IL-2 administration were analyzed during CIA. IL-2 protein and IL-2R were preferentially expressed at disease onset, compared with later stages of disease. Administration of recombinant human IL-2 (rhIL-2) at, or just before, disease onset exacerbated disease; surprisingly, rhIL-2 given before disease onset inhibited CIA, associated with reduced cellular and humoral responses to type II collagen. Determination of in vivo serum levels of Th1 and Th2 cytokines in response to rhIL-2 treatment demonstrated that IFN-gamma, but not IL-4, was markedly up-regulated in response to IL-2. In mice treated with anti-IFN-gamma Ab, both early and late IL-2 administration exacerbated CIA. Thus, IL-2 can have two opposite effects on autoimmune arthritis, a direct stimulatory effect and an indirect suppressive effect that is mediated by IFN-gamma.

Acute Disease↗
PubMed2000

On the mechanism of protection of distal joints after local gene transfer in collagen-induced arthritis.

Considerable interest has been generated by the observation that adenovirus-mediated gene delivery to a single arthritic joint results in suppression of arthritis in distal joints associated with the presence of small numbers of transduced cells in distal joints. It has been proposed that this is mediated by trafficking of transduced cells from the injected to distal joints. There are, however, alternative explanations that have not been explored, including the possibility that transgene protein or infectious virions circulate to distal sites. To investigate these possibilities, a replication-incompetent adenovirus encoding viral IL-10 (vIL-10) was administered to naive mice and to mice with collagen-induced arthritis by intraarticular, periarticular, or intravenous injection. In all cases, the ability to protect distal joints correlated with serum levels of vIL-10 protein. After intraarticular or intravenous injection, vIL-10 cDNA could be detected not only in distal joints, but also in the liver, which is the major target of circulating adenovirus, demonstrating that adenovirus circulating through the bloodstream is taken up by the joint tissue. Periarticular administration of adenovirus, which resulted in lower serum levels of vIL-10, protected only the injected paws and failed to induce trafficking immunoregulatory cells capable of suppressing distal disease. These observations suggest that circulating vIL-10 protein is the major mediator of distal protection. The presence of small numbers of transduced cells at distal sites can be accounted for by transduction of distal synovium after entry of adenovirus virions into the circulation.

Adenoviridae↗
PubMed2000

Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer.

Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are anti-inflammatory proteins that can suppress collagen-induced arthritis (CIA). These and related proteins have shown efficacy in the treatment of human rheumatoid arthritis; however, neither alone is able to completely suppress disease. Furthermore, they have short half-lives, necessitating frequent administration. To determine the ability of these proteins to act synergistically following gene transfer, arthritis was induced in DBA/1 male mice by immunization with type II collagen on days 0 and 21. Mice were injected i.v. either before disease onset (day 20) or after disease onset (day 28) with 1010 particles of adenovirus encoding vIL-10, a soluble TNF receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both vectors, or a control vector lacking a transgene. Significant synergism was observed with the combination of vIL-10 and sTNFR-Ig, with a substantial reduction in both the incidence and severity of disease as well as inhibition of progression of established disease. sTNFR-Ig alone had no effect on CIA. vIL-10 alone inhibited disease when given before disease onset, but had minimal effect on established disease. Both proteins inhibited spleen cell proliferation and IFN-gamma secretion in response to stimulation with type II collagen, but only vIL-10 reduced the synovial mRNA levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6. These findings demonstrate that vIL-10 and sTNFR-Ig act synergistically in suppressing CIA and suggest that gene transfer offers a potential therapeutic modality for the treatment of arthritis.

Adenoviridae↗
PubMed2000

The effects of placental extracts from normotensive and preeclamptic women on vasoconstriction and oxidative metabolism.

OBJECTIVE: A circulating factor derived from the placenta has been implicated in the pathogenesis of preeclampsia. The aim of this study was to determine whether placental extracts from normotensive women and women with preeclampsia increase oxidative metabolism and histamine-induced vasoconstriction in porcine carotid artery. STUDY DESIGN: Placental extracts from normotensive women and women with preeclampsia were applied to porcine carotid artery, and oxidative metabolism was measured. Histamine-induced isometric force responses were also determined in the absence and presence of placental extracts. RESULTS: Application of placental extracts to porcine carotid artery caused a fall in oxygen tension, which reflects increased consumption. Extracts from placentas taken from women with preeclampsia caused a greater fall than those from normotensive women (0.117 +/- 0.026 vs 0.018 +/- 0.0024 micromol oxygen per milligram; P < or =.01). Histamine-induced contractions were potentiated by extracts from preeclampsia but not from those of women without hypertension. The maximal steady-state force values were 13,137 +/- 3647, 12,921 +/- 3684, and 21,673 +/- 7189 N/m(-2) for control, normotensive, and preeclamptic samples at 10-micromol/L histamine (P < or =.05, compared with control placental extracts). CONCLUSIONS: Placental extracts from women with preeclampsia cause a greater stimulation of porcine artery oxygen consumption and exacerbation of histamine-induced vasoconstriction than extracts from normotensive women.

Animals↗
PubMed2000

Increase in community-acquired methicillin-resistant Staphylococcus aureus at a Naval Medical Center.

A retrospective review of methicillin-resistant Staphylococcus aureus isolates from the Naval Medical Center, San Diego, for the years 1994 through 1997, found that the annual number of community-acquired MRSA isolates increased during the period. These outpatient isolates were more likely than inpatient isolates to be sensitive to a greater number of antibiotics.

Hospital Bed Capacity, 300 to 499↗
PubMed2000

Fertility preservation of boys undergoing anti-cancer therapy: a review of the existing situation and prospects for the future.

With the advancement of medical science, most cancers in children are now treatable, the cure rate being almost 85%. In boys, one side effect of treatment (chemotherapy and radiotherapy) is destruction of the sperm precursor cells in the testis, resulting in the failure of sperm formation after puberty, and consequent infertility. At the time of anti-cancer treatment, future fertility of the boy patient is at the very bottom of the relative quality of life (RQL) parameters list; however, in adults infertility is an important issue following cure from cancer. In this article we have first reviewed the existing situation with regard to the state of the art of fertility preservation in young boys with cancer, and have then raised clinical and ethical issues and suggested a way forward. The review concludes with the emphasis that certain important issues still need to be resolved and, until these are, then the different techniques available should be confined to approved, ethical clinical trials where efficacy and safety can be fully evaluated.

Adolescent↗
PubMed1999

Changes in the expression of myometrial ryanodine receptor mRNAs during human pregnancy.

Uterine contraction is triggered by a rise in intracellular free Ca(2+) concentration ([Ca2+]i), and although ryanodine-sensitive Ca(2+) release channels (RyRs) play a key role in the regulation of [Ca(2+)](i) in skeletal and cardiac muscle, much less is known about their role in smooth muscle. In this study, we investigated the expression of RyR mRNAs (ryr1-3) during human pregnancy by examining myometrial samples (n=18) taken, with informed consent and ethical approval, from non-pregnant patients undergoing hysterectomy, and patients undergoing elective caesarean section (at term, prior to or following the onset of labour). Ca(2+) release channel expression was determined both qualitatively and quantitatively, using reverse transcription-polymerase chain reaction (RT-PCR) analysis, RNase protection assays, and in situ mRNA hybridisation. RT-PCR analysis demonstrated that all three ryr genes, as well as the gene encoding the type I inositol 1,4,5-trisphosphate receptor (InsP(3)RI), are expressed in human myometrium. Quantitation by RNase protection assays showed that ryr3 and InsP(3)RI mRNAs are the most abundant, while ryr2 mRNA is barely detectable. In situ mRNA hybridisation confirmed that ryr3 and InsP(3)RI mRNAs are both localised to myometrial smooth muscle cells. The expression of ryr2 and ryr3 mRNA is down-regulated at the end of pregnancy compared to non-pregnant myometrium, indicating that ryanodine-sensitive Ca(2+) release channels are differentially expressed. The relative conservation of ryr1 expression is consistent with a role for Ca(2+) release from ryanodine-sensitive stores in the mechanism of uterine contractility during labour.

Adolescent↗
PubMed1999

Association of the course of collagen-induced arthritis with distinct patterns of cytokine and chemokine messenger RNA expression.

OBJECTIVE: To quantitate changes in cytokine and chemokine messenger RNA (mRNA) levels during the development and progression of collagen-induced arthritis (CIA) in mice. METHODS: Mice with CIA were scored for arthritis and killed at weekly intervals. Cytokine and chemokine mRNA levels were determined by RNase protection assays of total paw RNA. RESULTS: Arthritic paws exhibited mRNA levels of interleukin-1beta (IL-1beta), IL-2, macrophage inflammatory protein 2 (MIP-2), IL-6, IL-1 receptor antagonist, RANTES, tumor necrosis factor alpha (TNFalpha), TNFbeta, MIP-1alpha, IL-11, transforming growth factor beta1 (TGFbeta1), TGFbeta2, and TGFbeta3 that were increased above mRNA levels in paws of normal, unimmunized mice and that exhibited distinct temporal patterns of mRNA expression. Clinically uninvolved paws also exhibited an increase in mRNA levels of IL-11, RANTES, TNFalpha, TNFbeta, and MIP-1alpha. CONCLUSION: The observed differential temporal cytokine and chemokine mRNA expression patterns suggest that specific cytokines and chemokines have defined roles at various times during the course of autoimmune arthritis. Since most of these cytokines and chemokines are found in human rheumatoid arthritis (RA) synovium and synovial fluids, these findings may have relevance to RA.

Animals↗
PubMed1999

Manual-assisted cognitive-behaviour therapy (MACT): a randomized controlled trial of a brief intervention with bibliotherapy in the treatment of recurrent deliberate self-harm.

BACKGROUND: The treatment of deliberate self-harm (parasuicide) remains limited in efficacy. Despite a range of psychosocial, educational and pharmacological interventions only one approach, dialectical behaviour therapy, a form of cognitive-behaviour therapy (CBT), has been shown to reduce repeat episodes, but this is lengthy and intensive and difficult to extrapolate to busy clinical practice. We investigated the effectiveness of a new manual-based treatment varying from bibliotherapy (six self-help booklets) alone to six sessions of cognitive therapy linked to the booklets, which contained elements of dialectical behaviour therapy. METHODS: Thirty-four patients, aged between 16 and 50, seen after an episode of deliberate self-harm, with personality disturbance within the flamboyant cluster and a previous parasuicide episode within the past 12 months, were randomly assigned to treatment with manual-assisted cognitive-behaviour therapy (MACT N = 18) or treatment as usual (TAU N = 16). Assessment of clinical symptoms and social function were made at baseline and repeated by an independent assessor masked to treatment allocation at 6 months. The number and rate of all parasuicide attempts, time to next episode and costs of care were also determined. RESULTS: Thirty-two patients (18 MACT; 14 TAU) were seen at follow-up and 10 patients in each group (56% MACT and 71% TAU) had a suicidal act during the 6 months. The rate of suicidal acts per month was lower with MACT (median 0.17/month MACT; 0.37/month TAU; P = 0.11) and self-rated depressive symptoms also improved (P = 0.03). The treatment involved a mean of 2.7 sessions and the observed average cost of care was 46% less with MACT (P = 0.22). CONCLUSIONS: Although limited by the small sample, the results of this pilot study suggest that this new form of cognitive-behaviour therapy is promising in its efficacy and feasible in clinical practice.

Adolescent↗
PubMed1999

Factors determining end-expiratory alveolar pressure after cardiac surgery.

Intrinsic positive end-expiratory pressure can occur when the sternum is closed following cardiac surgery, causing anaesthetic and surgical problems. We measured intrinsic positive end-expiratory pressure after sternal closure in two studies of patients undergoing coronary artery bypass grafting with the same anaesthetic regime. In one, patients were ventilated at 10 breaths min-1, in the other they were randomized to be ventilated at 10 or 20 breaths min-1. After sternal closure, intrinsic positive end-expiratory pressure increased significantly, especially in patients in whom it had been present before sternotomy. Multiple linear regressions with the pooled data from the studies showed that intrinsic positive end-expiratory pressure was positively correlated with ventilatory rate (P < 0.005), age (P < 0.005) and Body Mass Index (P < 0.0005), and negatively with FEV1, as percentage of predicted (P < 0.01). There was no correlation between intrinsic positive end-expiratory pressure and a history of smoking. As there was no difference in expiratory resistance between patients ventilated at the two different rates, any effect on intrinsic positive end-expiratory pressure of the higher ventilatory rates could have been due only to the shorter expiratory time.

Age Factors↗
PubMed1999

The effect of labour and maternal oxytocin infusion on fetal plasma oxytocin concentration.

It is not known whether human labour is associated with increased fetal oxytocin production or transfer of oxytocin across the placenta. Previous reports are contradictory, due in part, to the influence of maternal analgesia on fetal production. We determined plasma oxytocin concentration in the umbilical artery and vein of women after vaginal delivery and after caesarean section with general anaesthesia before or after the onset of labour. The results demonstrate that fetal production of oxytocin is not influenced by general anaesthesia, thus enabling comparison of labour and nonlabour samples at caesarean section. Labour was not associated with an increase in fetal oxytocin production. Oxytocin was also measured in the umbilical artery and vein during maternal oxytocin infusion to assess placental transfer. The results do not support transfer of oxytocin across the placenta in women.

Adjuvants, Anesthesia↗
PubMed1999

Oxytocin increases the [Ca2+]i sensitivity of human myometrium during the falling phase of phasic contractions.

Oxytocin is commonly used to induce or augment labor, but its mode of action is uncertain. To address the issue, isometric tension and the intracellular free Ca2+ concentration ([Ca2+]i) were simultaneously recorded from isolated strips of pregnant human myometrium loaded with fura 2. The changes in [Ca2+]i and tension during phasic contractions were indistinguishable in myometrium taken before or after the onset of labor, enabling samples to be pooled. Oxytocin (10 nM) had no effect on basal [Ca2+]i or tension, but it increased both the [Ca2+]i and the tension recorded during phasic contractions. Analysis of the [Ca2+]i-tension relationship revealed that during the falling (relaxation) phase of the contractile response, oxytocin increased the tension recorded at each [Ca2+]i. By manipulating extracellular Ca2+ during phasic contractions, it was possible to ensure that the [Ca2+]i signals were similar in the presence and absence of oxytocin, yet oxytocin still improved the [Ca2+]i-tension relationship. We conclude that 10 nM oxytocin increases the [Ca2+]i sensitivity of the contractile proteins only after a contraction has begun, possibly by causing inhibition of myosin light chain phosphatase.

Calcium↗
PubMed1999

Oxytocin receptor expression in human term and preterm gestational tissues prior to and following the onset of labour.

Oxytocin receptor (OTR) mRNA expression has previously been demonstrated in human myometrium, decidua, chorion and amnion but the effect of gestational age and the onset of labour has not been determined in these individual tissues. Spatial OTR mRNA expression was examined by in situ hybridization and ligand binding was confirmed using autoradiography with the iodinated oxytocin antagonist d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH29]-vasotocin (125I-OTA). Tissue was collected at term (>37 weeks of gestation) or preterm (24-36 weeks of gestation) caesarean section and classified as labour (contractions every 5 min associated with cervical dilatation) or non-labour. OTR mRNA expression was measured as optical density units from autoradiographs. There was a highly significant (P<0.001) effect of tissue type on expression of OTR mRNA with expression greatest in myometrium, low in decidua and chorion and not detected in placenta. Similar results were obtained with the 125I-OTA-binding studies, indicating that the message was translated. Amnion had an apparently high level of both hybridization and 125I-OTA binding in some samples, but a lack of specificity prevented quantification of the signal in this tissue type. Term myometrium (labour and non-labour) had significantly higher (P<0.01) OTR mRNA expression than preterm myometrium, but there was no further increase in mRNA concentration associated with labour onset. In contrast, 125I-OTA binding in myometrium was already high at 33 weeks and did not increase further either later in pregnancy or with labour. In decidua there was no effect of gestational age or labour onset on OTR mRNA expression or 125I-OTA binding. In summary, OTR mRNA expression in the myometrium increased in late pregnancy whereas decidual expression was much lower and did not rise at term.

Amnion↗
PubMed1998

Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer.

Autoimmune arthritides are characterized by an imbalance between pro- and anti-inflammatory cytokines. Viral IL-10 (vIL-10) shares many of the anti-inflammatory properties of mouse and human IL-10, but lacks their immunostimulatory properties and may therefore offer superior immunosuppression. Viral IL-10 has a short half-life; however, genetic modification of cells in vivo offers a potential means of achieving prolonged therapeutic titers. To determine the effects on collagen-induced arthritis of vIL-10 gene transfer, DBA/1 mice were administered i.v. or intra-articular injections of Av(vIL-10), a replication-deficient adenovirus encoding vIL-10. The i.v. injection of Av(vIL-10) before disease onset delayed the onset and reduced the severity of collagen-induced arthritis, but treatment of established disease was ineffective. The preventative effects were not due to decreased anti-type II collagen Ab production. Rather, T cells from mice treated with Av(vIL-10) demonstrated a decreased in vitro proliferative response to type II collagen, and a delay was observed in up-regulation of synovial mRNA for the proinflammatory cytokines IL-2 and IL-1beta. Intra-articular injection of Av(vIL-10) into knee joints did not reduce arthritis in the knees, but inhibited the development of arthritis in the paws. Humoral and cellular immune responses against Av(vIL-10) were observed. These results demonstrate that vIL-10 can significantly alter the course of autoimmune arthritis and emphasize the complexities of using gene transfer as a method of drug delivery for arthritis.

Adenoviridae↗