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Biomedical subjects

R P Marshall

Publications and source records attributed to R P Marshall.

At least 19 recordsLinked to original sources
PubMed2002

The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats.

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg x kg(-1) x day(-1)) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182+/-11% (mean+/-SEM) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75+/-12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56+/-6% (p<0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.

Animals↗
PubMed2001

Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis.

Dramatic activation of the coagulation cascade has been extensively documented for pulmonary fibrosis associated with acute and chronic lung injury. In addition to its role in hemostasis, thrombin exerts profibrotic effects via activation of the major thrombin receptor, protease-activated receptor-1. In this study, we examined the effect of the direct thrombin inhibitor, UK-156406 on fibroblast responses in vitro and on bleomycin-induced pulmonary fibrosis in rats. UK-156406 significantly inhibited thrombin-induced fibroblast proliferation, procollagen production, and connective tissue growth factor (CTGF) mRNA levels when used at equimolar concentration to the protease. Thrombin levels in bronchoalveolar lavage fluid and expression of thrombin and protease-activated receptor-1 in lung tissue were increased after intratracheal instillation of bleomycin. The characteristic doubling in lung collagen in bleomycin-treated animals (38.4 +/- 2.0 mg versus 17.1 +/- 1.4 mg, P < 0.01) was preceded by significant elevations in alpha1(I) procollagen and CTGF mRNA levels (3.0 +/- 0.4-fold and 6.3 +/- 0.4-fold respectively, (P < 0.01), and total inflammatory cell number. UK-156406, administered at an anticoagulant dose, attenuated lung collagen accumulation in response to bleomycin by 35 +/- 12% (P < 0.05), inhibited alpha1(I) procollagen and CTGF mRNA levels by 50% and 35%, respectively (P < 0.05), but had no effect on inflammatory cell recruitment. This is the first report showing that direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed2000

Distress experienced by participants during an epidemiological survey of posttraumatic stress disorder.

We examined the potential for epidemiological studies of mental disorders, specifically of posttraumatic stress disorder (PTSD), to cause further harm to participants involved. Of 1,000 randomly selected Australian Vietnam veterans, 641 agreed to participate in an epidemiological survey. Participants were asked about distress experienced during the interview when traumatic events were raised. Significant distress attributed to the interview was reported by 75.3% of those with current PTSD, 56.5% of those with past PTSD, and 20.6% of those with no PTSD diagnosis. Distress did not affect participants' use of medical services following the interview nor did it affect their willingness to continue participating in the study. We concluded that research interviews about PTSD may cause short-term distress, but found no evidence of long-term harm.

Adult↗
PubMed2000

Medical-care costs associated with posttraumatic stress disorder in Vietnam veterans.

OBJECTIVE: This study examined the relationship between medical-care costs of Vietnam veterans and predictor factors, including posttraumatic stress disorder (PTSD). METHOD: We merged medical-care cost data from the Department of Veterans' Affairs and the Health Insurance Commission with data from an epidemiological study of 641 Australian Vietnam veterans. Posttraumatic stress disorder and other factors were examined as predictors of medical-care cost using regression analysis. RESULTS: We found that a diagnosis of PTSD was associated with medical costs 60% higher than average. Those costs appeared to be partly associated with higher treatment costs for physical conditions in those with PTSD and also related mental health comorbidities. Major predictors of medical-care cost were age ($137 per year for each 5-year increase in age) and number of diagnoses reported ($81 to $112 per year for each diagnosis). Mental health factors such as depression ($14 per year for each symptom reported) and anxiety ($27 per year for each symptom reported) were also important predictors. CONCLUSIONS: The findings indicate that, however they are incurred, high healthcare and, presumably, also economic and personal costs are associated with PTSD. There is an important social obligation as well as substantial economic reasons to deal with these problems. From both perspectives, continued efforts to identify and implement effective prevention and treatment programs are warranted.

Adult↗
PubMed2000

Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.

BACKGROUND: Familial cases of cryptogenic fibrosing alveolitis (CFA) have previously been reported; however, the prevalence and genetic background of this disorder are not known. The clinical and epidemiological findings of 25 families identified within the UK are reported. METHODS: Adult pulmonary physicians in the UK were asked to identify all families under their care in which two or more individuals had been diagnosed with fibrosing alveolitis of unknown cause. A detailed structured questionnaire was sent to each proband to delineate possible environmental/occupational exposures and to obtain complete pedigree data. Physicians were also asked to provide clinical and diagnostic information. RESULTS: Twenty five families were identified comprising 67 cases. Suitable data for analysis were available for 21 families (57 cases). The male:female ratio was 1. 75:1 (p<0.05). A high resolution computed tomographic (HRCT) scan was performed in 93% and a diagnosis of CFA confirmed on biopsy specimens in 32%. The mean age at diagnosis was 55.5 (2.5) years. Fifty percent of cases were ever smokers and 18% had been diagnosed as asthmatic. Exposure to known fibrogenic agents was recorded by 36% of patients. Clinical signs/symptoms and histological findings were indistinguishable from non-familial cases. CONCLUSIONS: This study represents the largest cohort of familial CFA cases reported to date and confirms a prevalence of 1.34 cases per 10(6) in the UK population. Although rare, such cases represent an important subgroup in which a genetic susceptibility to pulmonary fibrosis is particularly evident. Familial patients are younger at diagnosis but otherwise indistinguishable from non-familial cases. The mode of inheritance is as yet unclear but a number of genetic loci are likely to be involved and are the subject of ongoing studies.

Adult↗
PubMed2000

Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor.

The expression of renin-angiotensin system components and the elevation of angiotensin-converting enzyme (ACE) in a number of fibrotic lung diseases suggests angiotensin II (AII) could play a role in the pathogenesis of pulmonary fibrosis. However, the effect of AII on lung fibroblasts has not previously been assessed and the mechanisms by which AII induces cell proliferation in mesenchymal cells are not fully understood. We have examined the ability of AII to stimulate fetal and adult human lung fibroblast proliferation in vitro. In particular, we have assessed the receptor subtypes involved and the possible autocrine role of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF), two recognized fibroblast mitogens. Angiotensin type 1 (AT1), but not type 2, receptors were identified on fetal and adult human lung fibroblasts by immunocytochemistry. AII (1 microM) increased DNA synthesis (determined by [(3)H]thymidine incorporation) in fetal and adult cells by 211 +/- 18% and 150 +/- 14%, respectively (p < 0.01), and was inhibited by a specific AT1 receptor antagonist, Losartan (74 +/- 14%). A proliferative response to AII was confirmed by direct cell counts. Subsequently, fibroblasts were incubated with neutralizing antibodies to TGF-beta and PDGF. Anti-TGF-beta antibodies inhibited AII-induced DNA synthesis by 73 +/- 13%. However, no effect was seen with anti-PDGF antibodies. In conclusion, we have shown that angiotensin II induces human lung fibroblast proliferation in vitro via activation of the AT1 receptor and involves the autocrine action of TGF-beta.

Adult↗
PubMed2000

Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome.

The fibroproliferative phase of acute respiratory distress syndrome (ARDS) has traditionally been regarded as a late event but recent studies that suggest increased lung collagen turnover within 24 h of diagnosis challenge this view. We hypothesized that fibroproliferation is initiated early in ARDS, characterized by the presence of fibroblast growth factor activity in the lung and would relate to clinical outcome. Patients fulfilling American/European Consensus Committee criteria for ARDS and control patients ventilated for non-ARDS respiratory failure underwent bronchoalveolar lavage (BAL) and serum sampling within 24 h of diagnosis and again at 7 d. The ability of BAL fluid (BALF) to stimulate human lung fibroblast proliferation in vitro was examined in relation to concentrations of N-terminal peptide for type III procollagen (N-PCP-III) in BALF/serum and clinical indices. At 24 h, ARDS lavage fluid demonstrated potent mitogenic activity with a median value equivalent to 70% (range 31-164) of the response to serum, and was significantly higher than control lavage (32% of serum response, range 11-42; p < 0.05). At 24 h, serum N-PCP-III concentrations were elevated in the ARDS group compared with control patients (2.8 U/ml; range 0.6-14.8 versus 1.1 U/ml; range 0.4-3.7, p < 0.0001) as were BALF N-PCP-III concentrations (2.9 U/ml; range 0. 6-11.4 versus 0.46 U/ ml; range 0.00-1.63, p < 0.01). In addition, BALF N-PCP-III concentrations at 24 h were significantly elevated in nonsurvivors of ARDS compared with survivors (p < 0.05). At 7 d, the mitogenic activity remained elevated in the ARDS group compared with control (p < 0.05) and was also significantly higher in ARDS nonsurvivors compared with survivors (67%; range 45-120 versus 31%; range 16-64, p < 0.05). These data are consistent with the hypothesis that fibroproliferation is an early response to lung injury and an important therapeutic target.

Adolescent↗
PubMed1999

Combat, dissociation, and posttraumatic stress disorder in Australian Vietnam veterans.

The specificity of various wartime stressors for different posttraumatic stress disorder (PTSD) symptoms is inconsistently reported in the literature. Combat, wounding, and peritraumatic dissociation have not been assessed together in their effects on each of the various PTSD symptom clusters. This cohort study of a random sample of male Australian Army Vietnam veterans yielded psychiatric assessments of 641 subjects. PTSD measures comprised symptom criteria for reexperiencing, numbing and avoidance, hyperarousal, and PTSD diagnosis both lifetime and current within the past month. Logistic regression is used to examine the effects of combat, wounding, and peritraumatic dissociation together on PTSD. Combat experiences comprised four components derived from a principal components analysis of combat experiences: direct combat exposure, exposure to death and injury, exposure to civilian death and injury, and exposure to mutilation. Each was differentially related to reexperiencing, avoidance, hyperarousal, and PTSD diagnosis. Being wounded was not related to lifetime or current PTSD and peritraumatic dissociation was related to all diagnostic components of PTSD in the presence of other variables.

Australia↗
PubMed1998

DRG cost weights--getting it right.

Inadequate cost weights are a major problem in casemix funding systems. Clinicians should understand the basis for the cost weights underpinning the hospital payment system in their State and their own hospital. Clinician managers need valid patient costing data if they are to benchmark and improve cost-effectiveness while maintaining and enhancing quality. The cost model approach for determining cost weights has inherent limitations, and, the alternative, detailed patient costing, requires efficient hospital information technology systems. A simplified approach to patient costs, which uses existing hospital data systems, may be useful for smaller hospitals. A better classification system and funding formulas incorporating reliable cost weights derived from patient costing should overcome many of the deficiencies in the current casemix payments systems.

Australia↗
PubMed1998

Postwar experiences and treatment-seeking behavior in a community counselling setting.

Previous research investigating the impact of postwar experiences on Vietnam veterans has focused on veteran morbidity. This emphasis has meant that the impact of these factors on treatment-seeking behavior has received little empirical attention. This study examined the association between postwar factors and treatment-seeking behavior in a sample of 692 Australian Vietnam veterans. Logistic regression analyses were used to compute the odds ratios associated with postwar experiences and self-referral to a community-based counselling service. Results suggest that veterans who reported experiencing negative feelings toward others when they first arrived home were more likely to seek treatment. Other factors, such as a veteran's perception of societal attitudes and the reception they received, were not associated with treatment-seeking behavior.

Adaptation, Psychological↗
PubMed1998

Posttraumatic stress disorder and other predictors of health care consumption by Vietnam veterans.

A total of 641 randomly selected Australian veterans of the Vietnam War were interviewed about their use of health care in the previous two weeks to determine what factors contributed to health care consumption. Seventy-three variables were examined by univariate linear regression and then grouped into seven categories relating to age, physical and mental health, predisposition to posttraumatic stress disorder (PTSD), deployment and repatriation experiences, and membership in veterans groups. PTSD was associated with an additional cost of $79 in health care for the two-week period. Each physical diagnosis was associated with an additional $28. Alcohol consumption was not related to health care costs. Other important variables contributing to costs were depression, educational status, the quality of the repatriation experience, and social support.

Adult↗
PubMed1998

Risk factors for posttraumatic stress disorder in Australian Vietnam veterans.

OBJECTIVE: The aims of this paper are to determine the risk factors for combat-related posttraumatic stress disorder (PTSD) and to examine the relative contribution of pre-military factors, pre-trauma psychiatric diagnoses, military factors such as combat posting, and combat and casualty stress exposure. METHOD: An epidemiological cohort study using standardised psychiatric, social and health interviews was undertaken with a national random sample of male Australian Army Vietnam veterans. Multivariate logistic regression was used to examine the relative contribution of factors derived from interview and from military records in four categories: pre-enlistment circumstances including home life, education, major life stress; pre-Vietnam psychiatric diagnoses; military experiences before and during Vietnam; and combat and stress experiences. RESULTS: Of the 128 data items examined, significant associations were found for 39, in addition to combat stress. Pre-enlistment items accounted for about 3% of the deviance towards PTSD diagnosis, pre-enlistment psychiatric diagnosis about 13%, military variables about 7% and combat stress about 18%; all factors together accounted for 42%. CONCLUSIONS: The results confirm that pre-military and military variables make only a small but significant contribution to PTSD either alone or after controlling for combat stress; that psychiatric diagnoses of depression, dysthymia and agoraphobia make strong contributions to PTSD; but that combat stress makes the largest contribution even after controlling for the effects of other variables. Psychiatric diagnoses and combat stress appear to be independent in their effects on PTSD.

Adult↗
PubMed1998

Posttraumatic stress disorder and comorbidity in Australian Vietnam veterans: risk factors, chronicity and combat.

OBJECTIVE: The objective of this study was to examine the relationship between combat-related posttraumatic stress disorder (PTSD) and comorbid DSM-III-R psychiatric diagnoses to determine commonalities in risk factors, relative onsets and the role of combat exposure. METHOD: An epidemiological cohort study using standardised psychiatric, social and health interviews was undertaken with a national random sample of male Australian Army Vietnam veterans. Interviews and searches of military records yielded risk factors for PTSD, which were examined for association with each psychiatric diagnosis. Relative onsets of PTSD and each Diagnostic Interview Schedule diagnosis were compared. Comorbidity odds ratios were adjusted for combat exposure effects using logistic regression, and the relation between each diagnosis and combat was assessed after controlling for PTSD. RESULTS: Commonality of risk factor profile was evident for several diagnoses, and for many their onset preceded PTSD onset. Combat was independently related to only a few diagnoses after controlling for PTSD, and PTSD remained strongly associated with several conditions after controlling for combat exposure. CONCLUSIONS: The analysis suggests that the disorders that may constitute risk factors or vulnerabilities for PTSD comprise depression and dysthymia, antisocial personality disorder, agoraphobia and simple phobia, while those that may be consequent on PTSD are panic and generalised anxiety disorder, drug use disorders and somatoform pain disorder. Alcohol and drug use disorders and social phobia may have a mixed aetiology, while obsessive-compulsive disorder may be serendipitously related to PTSD through an association with risk of combat. Gambling disorder is unrelated.

Adult↗
PubMed1997

The pathogenesis of pulmonary fibrosis: is there a fibrosis gene?

Interstitial fibrosis is seen in the lung in response to a variety of insults, and often appears stereotypical in terms of its clinical and pathological features. However, exposure to a known aetiological factor does not always lead to fibrosis. For example in bleomycin-induced pulmonary fibrosis, a wide variation in response is seen both in humans and in animal models, which is not completely accounted for by known risk factors. These observations and the existence of a number of familial forms of lung fibrosis suggest a genetic predisposition. Current hypotheses concerning the pathogenesis of pulmonary fibrosis propose an initial stage involving the influx of inflammatory cells into the interstitium. These cells, together with activated resident cells are then thought to release polypeptide mediators that stimulate the fibroblast proliferation and matrix protein synthesis typical of these disorders. Genetic influences could have an important role in regulating a number of these events, altering the immunological response to injury or modulating collagen metabolism in the lung. However, despite recent advances in molecular genetic techniques, there have been few human studies to date. Most have concentrated on genetic loci with a high degree of polymorphism such as the human leucocyte antigen (HLA) system and yield conflicting results. Others offer tantalising but as yet, incomplete insights into the mechanisms involved. Defining the genetic abnormalities underlying both the familial forms of pulmonary fibrosis and the variations seen in response to lung injury should enhance our understanding of the pathogenic processes and help to focus research in this area.

Animals↗
PubMed1997

Help-seeking in Vietnam veterans: post-traumatic stress disorder and other predictors.

This study investigated factors predicting help-seeking from the Department of Veterans' Affairs (DVA) by Vietnam veterans. Data used were from a national Australian survey of Vietnam veterans' health (n = 641) conducted between July 1990 and April 1993. The survey involved current clinical assessments and retrospective questionnaires, supplemented with health and service records retrieved from the DVA and Army personnel files. Measures included the 1989-90 Australian Bureau of Statistics Health Survey questionnaire, and mental health, sociodemographic and operational deployment history questionnaires. For both current and lifetime diagnoses of post-traumatic stress disorder, a third of the veterans with the disorder had never obtained any health care entitlement from the DVA. Other than physical and mental problems, which accounted for the greatest proportion of the help-seeking odds, significant factors predicting help-seeking included factors such as: predeployment personality, combat exposure, the veterans' own attitudes towards their deployment, experiences during deployment, experiences during repatriation and membership of ex-service organisations. These findings on how post-traumatic stress disorder and other health problems relate to help-seeking patterns could help in developing prevention and care programs for stress disorder.

Australia↗
PubMed1997

Surviving the war zone experience: preventing psychiatric casualties.

This paper describes a conceptual framework for the development and evaluation of stress-prevention programs for military personnel. In recognition of the diversity of stressors present within a war zone, we propose that an effective prevention program must operate on two levels if it is to deal with the effects of war zone exposure. Prevention programs must target (1) the occupational and/or traumatic stressor(s) within the war zone and (2) the ensuing post-exposure behaviors. A case study is presented to illustrate some of the key prevention issues for military personnel.

Humans↗
PubMed1997

Variations in living donor graft rates by dialysis clinic: effect on outcome and cost of chronic renal failure therapy.

OBJECT: Examination of nephrology practice variations in living donor renal grafts to determine their influence on organ supply, quality, and cost of chronic renal failure therapy. MATERIALS: Saskatchewan chronic dialysis, cadaveric, and living donor renal grafts in 1983-1994 inclusive. RESULTS: Saskatchewan has three dialysis (I, II, III) and one transplant clinic. In the period the renal graft incidences/million population by these dialysis clinics by organ source were; Cadaveric: 23.1, 23.2, 21.1 (p = ns). Living: 5.4, 21.7, 8.3 (I or III vs II p < 0.000, I vs III p < 0.061). Total: 28.7, 44.7, 29.4. Living donor series A is 79 grafts in patients under age 60 with primary renal disease. Series B is 20 grafts in patients with secondary renal disease or over age 59. Series A ten-year actuarial patient survival is 92% and B 44%. Series A ten-year actuarial graft survival (including regrafts) is 77% and B 39%. Rehabilitation rate in patients with functioning grafts is 88.5%. Province-wide extension of the Clinic II living-donor graft rate in 1983-1994 would have produced 160 more renal grafts or 59% of those receiving chronic dialysis in 1994. The annual maintenance for a graft with the initial grafting cost taken over five years was $10,825 and the dialysis cost $40,100. CONCLUSIONS: (1) nephrology practice variations caused a 2.5-4.0-fold difference in living donor renal graft rates, indicating patient education by the attending nephrologist influences the living donor transplantation rate, (2) with such education the combined living donor and the cadaveric organ supply virtually meets graft demand, (3) living donor renal grafts yield a better quantity and quality of life and better cost control than dialysis with their annual cost being one-quarter that for dialysis.

Actuarial Analysis↗