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Biomedical subjects

John M Fitzpatrick

Publications and source records attributed to John M Fitzpatrick.

At least 19 recordsLinked to original sources
PubMed2006

Urinary markers for prostate cancer.

Prostate cancer is the commonest solid-organ malignancy to affect men in Europe and the USA; it is estimated that one in six men will develop this cancer in their lifetime. Current screening relies on a digital rectal examination with a serum prostate-specific antigen test. Novel urinary diagnostic tests are potentially interesting screening tools for this disease. We examined published reports assessing the use of urinary markers for the diagnosis of prostate cancer. Using a PubMed-based search we identified studies of urinary markers for prostate cancer published from 1985 to February 2006 using the search terms 'urine', 'marker' and 'prostate cancer'. Studies to date have used small cohorts and relied on prostatic biopsies to provide histology. The sensitivity and specificity of markers are wide ranging but with only a few studies published on each putative marker it is difficult to assess their potential impact. Using urinary biomarkers for prostate cancer is a relatively novel diagnostic approach; they are appealing as a screening test because they are not invasive. Further work is needed to identify and validate 'signature markers' indicative of prostatic malignancy. The newer proteomic platforms are promising biomarker discovery tools that might uncover the next generation of urinary biomarkers.

Biomarkers, Tumor↗
PubMed2006

The pathology of bladder cancer: An update on selected issues.

OBJECTIVE: To achieve a closer relationship between urologists and pathologists and to use a common language and identical objectives in the pathology of bladder cancer. METHODS AND RESULTS: Special emphasis was given to an analysis of the new World Health Organization (WHO) grading system, to the interpretation of the last Tumour-Nodes-Metastasis staging rules, and to identifying new markers of prognostic significance in clinical practice. A consensus was achieved on the main points. CONCLUSIONS: The 2004 WHO grading system must become acceptable to clinicians, perhaps by a minimal modification of the present terminology. Simple transurethral resection-biopsy should be expressed in terms of clinical rather than pathological staging. Although there are substantial improvements, no new markers can be recommended for routine use in histopathology at present.

Biomarkers, Tumor↗
PubMed2006

HSP90 expression: a new predictive factor for BCG response in stage Ta-T1 grade 3 bladder tumours.

OBJECTIVES: Although Bacillus Calmette-Guérin (BCG) instillations are considered as the adjuvant treatment of choice for stage Ta-T1 grade G3 bladder tumours, there is no consensus for a predictive factor to assess BCG success. This study attempted to evaluate if heat shock proteins (HSPs) could be useful predictive markers in BCG responses. METHODS: Thirty-three primary resected G3 superficial bladder tumours were included in the study. All patients received adjuvant BCG instillations. The mean follow-up was 56 mo (range: 24-132 mo). HSP expression was evaluated by immunochemistry. RESULTS: In the 33 patients, 18 had no recurrence (group 1), 9 had recurrence with no muscular invasion (group 2), and 6 had an invasive recurrence (group 3). A significant correlation was found between lack of expression of HSP90 and BCG response: the mean HSP expression was 92.7%, 84.4%, and 26.7% for groups 1, 2 and 3 tumours, respectively (p<0.0001). For the 6 patients who did not positively respond to BCG, HSP expression was <40%. All the tumours with a HSP90 expression >40% positively responded to BCG, corresponding to group 1 or 2 patients. In contrast, HSP60 expression was not correlated to the BCG response. CONCLUSIONS: HSP90 could be considered as a very promising marker to assess BCG treatment response. Low HSP90 expression (<40%) could be useful to predict BCG failure and early stage cystectomy could be proposed for these selected patients with primary high-risk grade 3 superficial bladder tumours.

Adjuvants, Immunologic↗
PubMed2006

Effects of the dual 5 alpha-reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines.

BACKGROUND: The profound reduction in serum dihydrotestosterone (DHT) observed with the dual 5 alpha-reductase inhibitor (5ARI) dutasteride makes it an attractive agent for prostate cancer therapy. The objective of the current study was to determine whether dutasteride would induce apoptosis in a range of prostate epithelial cell lines and primary cultures. METHODS: Both human prostate androgen-sensitive cell lines (PwR-1E, PNT-2, LNCaP, and PC3[AR2]) and an androgen-independent cell line (PC-3) were grown to confluence. Primary epithelial cells extracted from fresh prostate cancer radical prostatectomy specimens also were grown to confluence under optimal conditions. Total cellular protein was extracted to confirm cytokeratin 18 and antihuman alpha-methylacyl-CoA racemase (AMACR) expression of the primary cells. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry after 24 hours of culture in from 0 microM to 10 microM of dutasteride. RESULTS: Dutasteride induced a dose-dependent increase in apoptosis in the androgen-sensitive prostate cell lines PwR-1E, PNT-2, and LNCaP and in the androgen receptor-expressing PC3(AR2) cell line. However, there was no significant apoptosis noted in the parental PC-3 cells. Of 16 primary epithelial cultures that were treated, 7 cultures were induced to undergo apoptosis, and 9 cultures were unresponsive. All primary cultures were positive for cytokeratin 18 expression, confirming their epithelial phenotype. Responder epithelial cells were positive for AMACR expression. CONCLUSIONS: The results of the current study confirmed that dutasteride differentially induced apoptosis in a subset of prostate cell lines and primary prostate epithelial cells. Understanding the cellular phenotype may indicate susceptible cells.

Apoptosis↗
PubMed2006

Effects of heat shock and hypoxia on neonatal neutrophil lipopolysaccharide responses: altered apoptosis, Toll-like receptor-4 and CD11b expression compared with adults.

BACKGROUND: Dysfunctional inflammatory responses have been implicated in several neonatal inflammatory disorders following infection and hypoxia. OBJECTIVES: We aimed to study the effects of in vitro hypoxia and heat shock (HS) on normal adult and newborn neutrophil migration (CD11b) and persistence (apoptosis) following lipopolysaccharide (LPS) stimulation. METHODS: The mechanism for altered LPS responses was assessed at the level of the LPS signalling receptors, Toll-like receptor-4 (TLR-4), TLR-2 and CD14 expression in normal neonates and adults. RESULTS: In adults, although hypoxia delayed neutrophil apoptosis, LPS enhanced this response. In contrast, HS (42 degrees C) increased adult apoptotic rates and abrogated the LPS responses. Both hypoxia and HS prevented the LPS-induced increase in adult CD11b although it was unaltered in neonates. Adult TLR-4 neutrophil expression was increased by LPS and hypoxia, and decreased in HS, possibly explaining their variable LPS responsiveness. In contrast, neonatal neutrophils were LPS hyporesponsive which may be mediated by failure of TLR-4 upregulation with LPS. CONCLUSIONS: Neonates do not have increased LPS responsiveness in hypoxia or heat shock in vitro, which may prevent hyperinflammation and thereby minimise tissue damage in inflammation or infection.

Adult↗
PubMed2006

Heat shock-induced protection of renal proximal tubular epithelial cells from cold storage and rewarming injury.

Cold storage and reperfusion injury to transplanted kidneys contributes to increased incidence of delayed graft function and may have a negative impact on graft survival. This study examined the mechanisms by which previous heat shock protects against cell death in an in vitro model of kidney storage. Cold storage is mimicked by incubating human renal proximal tubular epithelial (HK-2) cells in University of Wisconsin solution at 4 degrees C with and without subsequent rewarming. Heat shock was induced by incubation of cells at 42 degrees C for 1 h. Altered protein expression was measured by Western blot, and cell viability and apoptosis were measured by propidium iodide DNA staining using flow cytometry. The specific role of heat-shock protein 70 (HSP-70) was determined both by siRNA knockdown and by stable overexpression approaches. Cold storage and rewarming-induced cell death was associated with decreased expression of HSP-70, HSP-90, HSP-27, and Bcl-2. Previous heat shock significantly reduced HK-2 cell death after cold storage and rewarming and was associated with the maintenance of HSP-70, HSP-27, and Bcl-2 protein levels. Blocking heat stress-induced HSP-70 with siRNA did not significantly block the protective effect of heat stress against cold storage and rewarming cell death; however, overexpression of HSP-70 protected HK-2 cells from this stress. It is concluded that previous heat shock protects HK-2 cells from cold storage and rewarming injury. siRNA inhibition of HSP-70 induction did not block the protective effect of heat shock, indicating that HSP-70 is not essential to the heat stress-induced protective effect reported in this study.

Blotting, Western↗
PubMed2006

The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations.

PURPOSE: We reviewed the effects of 5alpha-reductase inhibitors on prostate specific antigen and clarified the adjustments that should be made to compensate for these effects to ensure that the usefulness of prostate specific antigen for detecting prostate cancer is maintained. MATERIALS AND METHODS: We reviewed articles published in the scientific literature with relevance to the effects of 5alpha-reductase inhibitors on the usefulness of prostate specific antigen for detecting prostate cancer. RESULTS: A total serum prostate specific antigen of 4.0 ng/ml has traditionally been used as the threshold for triggering prostate biopsy. However, clinical trials of finasteride and dutasteride have shown that 5alpha-reductase inhibitors decrease serum prostate specific antigen in patients with and without prostate cancer. To compensate, the doubling rule has been applied in clinical trials and clinical practice. However, doubling serum prostate specific antigen may overestimate actual prostate specific antigen in some patients receiving 5alpha-reductase inhibitors for up to 6 to 9 months, accurately estimate prostate specific antigen from 1 to 3 years and underestimate it thereafter. An increase in prostate specific antigen of 0.3 ng/ml from nadir as a trigger for biopsy maintains 71% sensitivity for prostate cancer in men receiving dutasteride with 60% specificity, similar to the 4.0 ng/ml prostate specific antigen cutoff using placebo. CONCLUSIONS: We propose that a prostate specific antigen increase from nadir of 0.3 ng/ml or greater could represent an alternative to the doubling rule for monitoring prostate specific antigen in patients on 5alpha-reductase inhibitors. The prostate specific antigen increase from nadir appears to be a more accurate cancer indicator than a doubled value in some patients.

Cholestenone 5 alpha-Reductase↗
PubMed2006

Induction of nitric oxide synthase is a key determinant of progression to pulmonary injury in experimental pancreatitis.

BACKGROUND: The immunomodulatory potential of nitric oxide provides prospective strategies to attenuate inappropriate inflammatory reactions. This study tested the hypothesis that inhibition of nitric oxide synthase (NOS) reduces end-organ injury in pancreatitis. METHODS: Pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injection of 20% L-arginine (500 mg/100 g of body weight). Animals were randomized into four groups of 45: Pancreatitis without intervention; pre-treatment with i.p. aminoguanidine (AMG) (50 mg/kg), an isoform-specific inhibitor of inducible NOS; post-treatment with AMG (50 mg/kg); and controls. Pancreatic and pulmonary pathology, neutrophil infiltration (myeloperoxidase activity), endothelial permeability (bronchoalveolar lavage, wet:dry weight ratio), NOS expression, and concentrations of pro-inflammatory cytokines (tumor necrosis factor-alpha; interleukin-6) were assessed. RESULTS: Inhibition of iNOS significantly reduced end-organ injury. Pancreatic and pulmonary injury scores were markedly attenuated in the AMG treatment groups compared with no intervention (p < 0.05). Increased endothelial permeability (2,411.1 +/- 47.9) and neutrophil sequestration (1.99 +/- 0.01) were manifest in the untreated animals compared with AMG pretreatment (1,286.8 +/- 35.1 and 1,548.0 +/- 0.1; p < 0.05). In addition, a significant reduction in inflammatory cytokine concentrations was observed (p < 0.05). CONCLUSIONS: Inhibition of inducible NOS encourages a more benign immunologic profile, minimizing the deleterious effects of unrestrained neutrophil sequestration subsequent to pancreatitis.

Animals↗
PubMed2006

The natural history of benign prostatic hyperplasia.

The progression of benign prostatic hyperplasia (BPH) can be defined as a deterioration of clinical variables such as lower urinary tract symptoms (LUTS), health-related quality of life and peak flow rate, increased prostate size, or unfavourable outcomes such as acute urinary retention (AUR) and BPH-related surgery. The natural history of BPH is best analysed from longitudinal studies of community-dwelling men. In the Olmsted county study, which followed for 12 years a randomly selected cohort of 2115 men aged 40-79 years, there was an average increase in the International Prostate Symptom Score (IPSS) of 0.18 points per year, ranging from 0.05 for men in their fifties to 0.44 for those in their seventies. There was also a decrease in peak flow rate of 2% per year and a median prostate growth of 1.9% per year. The cumulative incidence of AUR was low (2.7% over 4 years). Information can also be collected from the placebo arms of controlled studies of men with symptomatic BPH, although the strict trial inclusion criteria and indeed the taking of a placebo itself introduce biases which limit the analysis of the natural history of the disease in this way, and its applicability to the general population. Hence, in the Medical Therapy of Prostatic Symptoms study, there is clear evidence that symptom deterioration, defined by a worsening of the IPSS of > or = 4 points, was by far the most prevalent progression event (79.5%), with a cumulative incidence of 14% over a mean follow-up of 4.5 years. As in the longitudinal community-based studies, AUR was rather uncommon (14.8% of overall progression events) with a cumulative incidence of 2%. BPH-related surgery, which was a secondary criterion in the study, was required in 5% of men. Similar conclusions can be drawn from a 2-year placebo-controlled study (ALTESS) assessing the impact of alfuzosin 10 mg once daily on LUTS/BPH progression in 1522 men with symptomatic BPH at high risk of developing AUR. Symptom deterioration was clearly the main progression event, with a cumulative incidence of 16.8%, compared to BPH-related surgery (6.5%) and AUR (2.2%). Thus, there is evidence from longitudinal studies, and to a lesser extent from the placebo arms of large controlled studies, that BPH is a progressive disease. Symptom worsening is by far the most frequently occurring progression event. Identifying those patients at risk of BPH progression is crucial to optimize their management.

Adrenergic alpha-Antagonists↗
PubMed2006

Management of acute urinary retention.

Acute urinary retention (AUR) is a common urological emergency, characterized by a sudden and painful inability to pass urine. There is high variability within and among countries in its management, which can be explained not only by differences in access to care but also by a lack of harmonization and consensus on the best way to proceed. Immediate treatment consists of bladder decompression, usually by a urethral catheter, although a suprapubic catheter offers several advantages not often exploited by urologists. Until recently, secondary management consisted almost exclusively of prostatic surgery within a few days (emergency surgery) or a few weeks (elective surgery) after a first AUR episode. The greater morbidity and mortality associated with emergency surgery, and the potential morbidity associated with prolonged catheterization, has led to the increasing use of a trial without catheter; this involves catheter removal after 1-3 days, allowing the patient to void in 23-40% of cases, and surgery, if needed, at a later stage. Alpha1-adrenergic blockers given before catheter removal improve the chances of success. A high prostate-specific antigen level and postvoid residual urine volume, and response to alfuzosin treatment after a first AUR episode managed conservatively, may help to identify patients at risk of an unfavourable outcome.

Adrenergic alpha-Antagonists↗