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Biomedical subjects

J Smyth

Publications and source records attributed to J Smyth.

At least 19 recordsLinked to original sources
PubMed2003

Phase I and pharmacokinetic study of Yondelis (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours.

Yondelis (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 microg/m(2), initially as a 1-h infusion, and later at doses between 1000 and 1800 microg/m(2) as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 microg/m(2) for the 1-h infusion schedule and 1800 microg/m(2) when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3-4 increase in transaminases (not considered DLT) and grades 3-4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 microg/m(2) given as a 3-h infusion.

Adult↗
PubMed2003

Current research and treatment for epithelial ovarian cancer. A Position Paper from the Helene Harris Memorial Trust.

In March 2003, an international mulltidisciplinary group of scientists and clinicians with a specific interest in ovarian cancer met for 4 days to discuss research into and treatment of this challenging disease. Under the headings of molecular genetics, molecular biology, the biology of ovarian cancer, old therapies, new targets and the early detection of the disease, this Position Paper summarises the presentations and discussion from the 9th Biennial Helene Harris Memorial Trust Forum on Ovarian Cancer. In particular, we highlight the potential of international collaborations in translating laboratory science into useful clinical interventions.

Antineoplastic Agents↗
PubMed2003

Parenteral nutrition solution retrieved by lumbar puncture following left saphenous vein catheterization.

Two extremely preterm infants had silastic lines inserted via the left great saphenous vein for intravenous feeding. Clinical deterioration approximately 10 days later led to lumbar puncture as part of a sepsis screen. Parenteral nutrition solution was recovered in the cerebrospinal fluid and heralded potentially life-threatening catheter malposition. The cases illustrate another percutaneous central line-associated morbidity, which is avoidable by careful verification of line position. All previously reported cases of this unusual complication are reviewed and we describe its likely mechanism. We postulate that the phenomenon is a complication peculiar to percutaneous catheterization of the left lower limb.

Australia↗
PubMed2002

New markers and therapies for coronary artery disease in renal patients.

Coronary artery disease is very frequent in dialysis patients, and influences their survival while on dialysis and even after renal transplantation. There are problems with screening tools in that they have reduced sensitivity and specificity in the uraemic individual. There is a real need for additional and complementary markers of coronary disease in these patients. We discuss some novel ideas for screening and for intervention in this most challenging clinical setting.

Biomarkers↗
PubMed2001

Semliki Forest virus-based vaccines: persistence, distribution and pathological analysis in two animal systems.

This study has examined the persistence, distribution and pathological changes following intramuscular administration of Semliki Forest virus (SFV) vaccine vectors in mice and chickens. Administration of recombinant SFV RNA particles showed persistence at the injection site of mice up to 7 days, transient detection in secondary lymphoid organs and no dissemination to distal sites. In contrast, administration of a layered SFV DNA/RNA vector and a conventional standard naked DNA vector resulted in long-term persistence at the injection site, plasmid DNA being detected at 8 months post-inoculation in mice. Plasmid DNA was found distributed throughout the body, and tissues distal from the site of injection were positive up to 3 months. A similar pattern was observed in chickens. Mild pathological changes were observed at the injection site only, and plasmid DNA or recombinant RNA was not detected in mouse foetuses. These findings indicate that SFV-based vectors have the potential to be developed as safe vaccines.

Animals↗
PubMed2001

Pathways mediating sexual abuse and eating disturbance in children.

OBJECTIVE: To examine the relationship between childhood maltreatment and eating disorders in a sample of children. METHOD: Twenty 10-15-year-old female children who were receiving treatment following reported childhood sexual abuse and 20 age-matched controls were compared on a series of measures assessing eating disorder behaviors, body image concerns, substance use, mood, impulsive behavior, and self-concept. RESULTS: Sexually abused children reported higher levels of eating disorder behaviors, impulsive behaviors, and drug abuse than controls. Furthermore, behavioral impulsivity provided the strongest mediational effect between a history of childhood sexual abuse and purging and restrictive dieting behavior. Drug use proved to be a significant secondary mediator of the childhood sexual abuse eating disorder behavior association. DISCUSSION: These data support the hypothesis that childhood sexual abuse is related to disordered eating in children, and extend similar findings that have been previously reported with adults. Behavioral impulsivity and drug use appear to be significant mechanisms that influence eating disorder behavior following childhood sexual abuse.

Adolescent↗
PubMed2001

The use of ecological momentary assessment approaches in eating disorder research.

OBJECTIVE: Eating disorder (ED) research is increasingly focusing on the proximal antecedents to disordered eating behavior. Such antecedents may include cognitions, environmental stimuli, social interactions, and affective states. Current ED theories suggest that the relationships between antecedents and eating behavior may be complex, including interaction associations, time-lagged effects, and associations that persist only for brief periods of time. Similarly, these theories often include the consequences of behavior-influencing variables of interest (e.g., short-term reductions in negative affect). Careful examination of such theories, however, has been limited by a reliance on data collection methods not appropriate for testing these effects. METHOD: This study examines alternative methods for data collection and analysis that overcome previously noted limitations, using data collected in several studies with eating-disordered participants. RESULTS: The development of a technique called ecological momentary assessment (EMA) allows the ongoing study of behavior in its natural context and reduces biases associated with retrospective recall. The development of technology that allows the sophisticated collection and storage of such data (e.g., palm-top computers), along with statistical procedures for analyzing hierarchically nested, repeated measures data, allow precise testing of complex theoretical models. DISCUSSION: We demonstrate several important features of this research: (1) patients are willing and able to engage in EMA studies, (2) data not possible to collect using other designs are obtainable, (3) complex theoretical models can be evaluated using these data and appropriate statistical methods, and (4) the collection and analysis of EMA data present unique difficulties to ED researchers. Finally, we endorse and provide recommendations for the use of EMA in future ED research and practice.

Data Collection↗
PubMed2001

Eating disturbance and sexual trauma in childhood and adulthood.

OBJECTIVE: This study examined the relationship between sexual trauma and eating disorder behavior, taking into account the effects of developmental stage of the victim and the effects of multiple sexual assaults. METHOD: Four groups of adult women took part in this study. Subjects were either victims of childhood sexual abuse, victims of rape in adulthood, victims of both childhood sexual abuse and rape, and controls who were not traumatized sexually. All subjects were assessed with semistructured interviews and self-report inventories that assessed eating disorder behavior, general psychopathology, and impulsivity. RESULTS: Victims of childhood sexual abuse differed from controls on measures of eating disorder behavior and individuals who had experienced both childhood sexual abuse and rape in adulthood were most likely to display eating disorder-related psychopathology. Victims of childhood sexual abuse also distinguished themselves with high levels of eating disorder behavior plus multiple forms of impulsive self-destructive behavior. DISCUSSION: This study provides additional support for the association between childhood sexual abuse and eating disorder behavior. Childhood sexual abuse may be particularly linked to the presence of binge eating behavior and several other forms of impulsive self-destructive behavior.

Adult↗
PubMed2001

Individual differences in the diurnal cycle of salivary free cortisol: a replication of flattened cycles for some individuals.

Free cortisol measured in saliva has been shown to have the same diurnal rhythm as serum cortisol, one that typically declines rapidly throughout the waking day. A recent study showed that over 15% of a sample of community individuals who were monitored over two days did not show the typical diurnal rhythm. The present study specifically tested the hypothesis that there is significant between-subject variation (individual differences) in diurnal rhythms using multi-level, random regression models. Analyses of participants from four studies were conducted; studies varied in terms of the number of saliva samples taken per day, the number of days studied, and participants' demographic and health status. Significant individual differences of diurnal cycle in each of the four samples were found. In at least 10% of each sample no significant diurnal cycles was detected; however, the overall mean level of cortisol of those with flat cycles differed among the samples. These results suggest that some people do not have the expected diurnal rhythm of cortisol secretion. It is not clear what the determinants of this finding are or if there are any health consequences of having a flat cycle.

Adolescent↗
PubMed2001

Activity of the dolastatin analogue, LU103793, in malignant melanoma.

LU103793, a synthetic analogue of dolastatin 15, showed interesting pre-clinical activity in melanoma xenografts. In this phase II multicentre trial, 80 chemotherapy-naïve patients with metastatic melanoma received a total of 218 cycles of treatment. The response rate showed one complete and three partial responses of median duration six months (range 3-9.1). Toxicity was moderate, mostly haematological (neutropenia grade 4 in 16%, grade 3 in 3%). There were no significant problems with hypertension or other non-haematological toxicities.

Adult↗
PubMed2001

Sperm factor induces intracellular free calcium oscillations by stimulating the phosphoinositide pathway.

Injection of a porcine cytosolic sperm factor (SF) or of a porcine testicular extract into mammalian eggs triggers oscillations of intracellular free calcium ([Ca(2+)](i)) similar to those initiated by fertilization. To elucidate whether SF activates the phosphoinositide (PI) pathway, mouse eggs or SF were incubated with U73122, an inhibitor of events leading to phospholipase C (PLC) activation and/or of PLC itself. In both cases, U73122 blocked the ability of SF to induce [Ca(2+)](i) oscillations, although it did not inhibit Ca(2+) release caused by injection of inositol 1,4,5-triphosphate (IP(3)). The inactive analogue, U73343, had no effect on SF-induced Ca(2+) responses. To determine at the single cell level whether SF triggers IP(3) production concomitantly with a [Ca(2+)](i) rise, SF was injected into Xenopus oocytes and IP(3) concentration was determined using a biological detector cell combined with capillary electrophoresis. Injection of SF induced a significant increase in [Ca(2+)](i) and IP(3) production in these oocytes. Using ammonium sulfate precipitation, chromatographic fractionation, and Western blotting, we determined whether PLCgamma1, PLCgamma2, or PLCdelta4 and/or its splice variants, which are present in sperm and testis, are responsible for the Ca(2+) activity in the extracts. Our results revealed that active fractions do not contain PLCgamma1, PLCgamma2, or PLCdelta4 and/or its splice variants, which were present in inactive fractions. We also tested whether IP(3) could be the sensitizing stimulus of the Ca(2+)-induced Ca(2+) release mechanism, which is an important feature of fertilized and SF-injected eggs. Eggs injected with adenophostin A, an IP(3) receptor agonist, showed enhanced Ca(2+) responses to CaCl(2) injections. Thus, SF, and probably sperm, induces [Ca(2+)](i) rises by persistently stimulating IP(3) production, which in turn results in long-lasting sensitization of Ca(2+)-induced Ca(2+) release. Whether SF is itself a PLC or whether it acts upstream of the egg's PLCs remains to be elucidated.

Adenosine↗
PubMed2001

Informed consent and randomised controlled trials.

Truly informed consent is a difficult thing to achieve! Patients are not healthy volunteers and their vulnerability challenges their ability to assess the risk/benefit of health choices. In this paper we consider some or the issues surrounding this important aspect of modern practice, and offer some suggestions on how to improve the process, with the goal of increasing participation in clinical research, and enhancing patients' confidence in their medical advisors.

Ethics, Medical↗
PubMed2000

Medicine and story: a novel clinical panorama arising from a unitary mind/body approach to physical illness.

Since 1987, all patients referred by family physicians for internal medicine consultation at the Institute for Integrative Health Studies (Christchurch, New Zealand) have been assessed by the author from both physical (normative internal medicine) and psychological (psychodynamic, interpersonal, object relations, and self psychological) perspectives. Depending upon the material emerging in each case, the treatment options available for the particular disorder, and patient preferences, many patients have gone on to mind/body oriented discussions or psychotherapy with the author (detailed in Broom 1997), or with one of a team of therapists supervised by the author. This clinical experience, mixing internal medicine and psychotherapy approaches to physical illnesses (with or without organic findings), points to the following: (1) Profound connections between the patients' perceptions of their life-events and experience and the development of illness in both organic and nonorganic illnesses; (2) a rich fund of information in the patients' verbal language about the meaning of the illnesses; (3) the crucial importance of clinical attunement to macro- and micro-life events surrounding symptom emergence; and (4) the decisive role a clinician's implicit paradigm of "personhood" plays in patient care. This paper broadly outlines the presuppositions for this integrative clinical approach, and illustrates the approach with case material. Additionally, it summarizes the kinds of listening, and other skills, that have proved clinically useful. In all, the material illustrates that a combination of orthodox biomedical approaches and a "story approach" (which focuses on meaning leading to illness) offers considerable potential benefits to patients with physical symptomatologies including those with organic findings.

Adult↗
PubMed1999

The differential impact of training stress and final examination stress on herpesvirus latency at the United States Military Academy at West Point.

In this study, we searched for evidence for reactivation of three latent herpesviruses, Epstein-Barr virus (EBV), herpes simplex virus type-1 (HSV-1), and human herpesvirus 6 (HHV-6), in West Point cadets experiencing two different stressors. Blood samples were obtained from cadets before and after a 6-week training period known as "Cadet Basic Training" (CBT), at a baseline prior to final examinations, and then once again during the week of final examinations. Antibody titers to latent HSV-1, EBV, and HHV-6 were determined as a measure of the steady-state expression of latent virus. EBV virus capsid antigen (VCA) IgG antibody titers were unchanged in blood samples obtained prior to and immediately after CBT. However, EBV antibody titers were significantly higher in the blood sample obtained during examination week than in the baseline period before examination; they were also higher than antibody titers before/after CBT. None of the serum samples were positive for EBV VCA IgM antibodies, indicating that the changes in antibody titers to EBV were not associated with recent EBV infections in the class. No significant changes in antibody titers to HSV-1 or HSV-6 were found over the identical time periods, including examination week. Academic stress but not CBT modulated the steady-state expression of latent EBV, resulting in the reactivation of latent virus. The same stressors, however, did not affect the steady-state expression of latent HSV-1 or HSV-6, at least as measured by changes in antibody titers. The data provide additional evidence of the impact of different psychological stressors on the steady-state expression of latent herpesviruses.

Adult↗
PubMed1999

Inhibition of transforming growth factor alpha (TGF-alpha)-mediated growth effects in ovarian cancer cell lines by a tyrosine kinase inhibitor ZM 252868.

The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01CDDP. Transforming growth factor alpha (TGF-alpha)-stimulated growth was completely inhibited by concentrations > or =0.3 microM in the PE01 and PE04 cell lines and by > or =0.1 microM in SKOV-3 cells. TGF-alpha inhibition of PE01CDDP growth was reversed by concentrations > or =0.1 microM ZM 252868. TGF-alpha-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations > or =0.3 microM, completely inhibited TGF-alpha-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 microM ZM 252868 in PE01, SKOV-3 and PE01CDDP cells. These data indicate that the EGF receptor-targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor.

Cell Division↗