Biomedical subjects

G Fisher

Publications and source records attributed to G Fisher.

At least 19 recordsLinked to original sources

PubMed2006

Long-term outcome among men with conservatively treated localised prostate cancer.

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10-30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients.

Aged↗

PubMed2006

Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome--a European perspective.

AIM: To use an evidence-based approach to evaluate the safety and tolerability of the treatments available for irritable bowel syndrome (IBS), or in clinical development, in Europe. A separate review appraises the evidence for the efficacy of these therapies. METHODS: A literature search (for 1980 to 2005) was completed for all relevant clinical trial data and other articles which included safety information on the use of pharmacological IBS therapies. Clinical trials were scored according to the level of safety information, and adverse event incidence reported when possible. RESULTS: The tolerability of many of the agents used to treat IBS in Europe is poorly understood. However, serotonergic agents, such as tegaserod and alosetron, which are currently unavailable in Europe, have undergone rigorous assessment in IBS and their benefits have been established. Following initial marketing of alosetron for use in patients with IBS with diarrhoea, concerns about severe constipation and ischaemic colitis resulted in restriction of its use to women with severe IBS symptoms. This highlights the importance of post-marketing surveillance and post-marketing studies in refining the therapeutic indication of new IBS therapies, which will help to identify appropriate recipients for the drug and establish the impact of adverse reactions in clinical practice. CONCLUSIONS: There is a significant lack of data on the safety and tolerability of the therapies currently used routinely to treat IBS in Europe. The newer agents have undergone rigorous assessment, such that their benefits and risks in treating IBS are established. Defining their place among the spectrum of available therapies remains challenging when the benefits and risks of the older treatments are so poorly characterized.

Adverse Drug Reaction Reporting Systems↗

PubMed2006

Systematic review: the efficacy of treatments for irritable bowel syndrome--a European perspective.

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder, characterized by abdominal pain/discomfort, bloating and altered bowel habit. AIM: To conduct a systematic evidence-based review of pharmacological therapies currently used, or in clinical development, for the treatment of IBS in Europe. The safety and tolerability of these therapies are the subject of an accompanying review. METHODS: A literature search was completed for randomized controlled studies which included adult patients with IBS and an active or placebo control, assessed IBS symptoms, and were published in English between January 1980 and June 2005. The level of evidence for efficacy was graded according to the quality of the trial design and the study outcome. RESULTS: There is some evidence for improvement of individual IBS symptoms with antidiarrhoeals (diarrhoea), antispasmodics (abdominal pain/discomfort), bulking agents (constipation), tricyclic antidepressants (abdominal pain/discomfort) and behavioural therapy. In contrast, there is strong evidence for the improvement of global IBS symptoms with two new serotonergic agents: the 5-HT4 selective agonist tegaserod (IBS with constipation) and the 5-HT3 antagonist alosetron (IBS with diarrhoea). Further data are required for the 5-HT3 antagonist, cilansetron, and the mixed 5-HT3 antagonist/5-HT4 agonist renzapride before their utility in IBS can be appraised. CONCLUSIONS: There is limited evidence for the efficacy, safety and tolerability of therapies currently available in Europe for the treatment of IBS. Overall, there is an absence of pharmacological agents licensed specifically for the treatment of IBS subtypes, and new agents are awaited in Europe that will allow changes in clinical practice to focus on and improve global IBS symptoms.

Adult↗

PubMed2004

Pharmacokinetics of remifentanil and its major metabolite, remifentanil acid, in ICU patients with renal impairment.

BACKGROUND: The pharmacokinetics of remifentanil, an opioid analgesic metabolized by non-specific esterases, and its principal metabolite, remifentanil acid (RA), which is excreted via the kidneys, were assessed as part of an open-label safety study in intensive care unit (ICU) patients with varying degrees of renal impairment. METHODS: Forty adult ICU patients with normal/mildly impaired renal function (creatinine clearance [CL(cr)] 62.9 (sd) 14.5 ml min(-1); n=10) or moderate/severe renal impairment (CL(cr) 14.7 (15.7) ml min(-1); n=30) were included. Remifentanil was infused for up to 72 h, at a starting rate of 6-9 microg kg(-1) h(-1) titrated to achieve a target sedation level, with additional propofol (0.5 mg kg(-1) h(-1)) if required. Intensive arterial sampling was performed for up to 72 h after infusion. Pharmacokinetic parameters obtained by simultaneous modelling of remifentanil and RA data were statistically compared between the two groups. RESULTS: Remifentanil pharmacokinetics were not significantly affected by renal status. RA clearance in the moderate/severe group was reduced to about 25% that of the normal/mild group (41 (29) vs 176 (49) ml kg(-1) h(-1), P<0.0001). Metabolic ratio, a predictor of the ratio of RA to remifentanil concentrations at steady state, was approximately eight-fold higher in the moderate/severe group relative to the normal/mild group (116 (110) vs 15 (4), P<0.0001). Maximum RA levels approached 700 ng ml(-1) in the moderate/severe group. CONCLUSIONS: Although RA accumulates in patients with moderate/severe renal impairment, pharmacokinetic modelling predicts that RA concentrations during a 9 microg kg(-1) h(-1) remifentanil infusion for up to 15 days would not exceed those reported in the present study, for which no associated prolongation of mu-opioid effects was observed.

Adolescent↗

PubMed2002

Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.

AIMS: The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. METHODS: The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. RESULTS: Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. CONCLUSIONS: Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.

Acute Disease↗

PubMed2002

Anti-Mta associated with three cases of hemolytic disease of the newborn.

The Mta antigen is a low-frequency red blood cell (RBC) surface antigen and is an established antigen of the MNSs blood group system. There has been one report of anti-Mta-induced hemolytic disease of the newborn (HDN) in the literature to date. We describe a family in which three children were affected by neonatal anemia. The clinical and hematologic findings were consistent with HDN, despite repeatedly negative direct antiglobulin tests (DAT) on cord RBCs. Serologic investigations showed that the mother's serum contained anti-Mta. The father and all three children phenotyped as Mta+, while the mother was Mta-. Adsorption and elution experiments gave results which suggested that anti-Mta may be implicated in recurrent HDN in this family.

Journal Article↗

PubMed2001

Plasma L-arginine is markedly reduced in pregnant women affected by preeclampsia.

The objective of this study was to determine the concentration of free L-amino acids and in particular of L-arginine in the plasma of pregnant women affected by preeclampsia compared to healthy pregnant women in order to know if an alteration in the concentrations of these amino acids occurs in preeclamspia. Twelve pregnant women affected by preeclampsia and twelve pregnant control women, ages 28-35 years old and at the 35-36 weeks of pregnancy were studied. The blood analysis of free amino acids was carried out by using a high performance liquid chromatographic (HPLC) fluorometric method and OPA-NAC as derivatizing agent for the amino acid determination. In the blood of women affected by preeclampsia L-arginine is markedly reduced compared to controls (about five-fold lower, P<0.01). The other amino acids also are significantly reduced, but to lesser extents (about 1.5 times lower, P<0.05). Thus, the determination of L-arginine in the blood of pregnant women could potentially constitute an additional marker for the early diagnosis of preeclampsia.

Adult↗

PubMed2001

Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 or T4 rectal cancer.

BACKGROUND: A prospective study was undertaken to evaluate the response and toxicity of neoadjuvant chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. PATIENTS AND METHODS: Since 1995, 30 patients (18 males; median age, 56 (range, 25-83) years) have received preoperative chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. All patients underwent an endorectal ultrasound, CT scan, and review in our multidisciplinary Gastrointestinal Tumor Board before treatment. All patients had pathology-demonstrated invasive adenocarcinoma of the rectum. Eleven patients were Stage T3N0, 14 were T3N1, and five were T4N1. Patients received radiotherapy to the primary tumor and draining lymph nodes (45 Gy) followed by a tumor boost (50.4-54 Gy). Protracted-venous-infusion 5-fluorouracil (225 mg/m2 per day, seven days per week) was administered throughout treatment. Surgical resection was performed six to ten weeks after completing chemoradiotherapy. Using endorectal ultrasound measurements, the primary tumor was a median of 4 (range, 0-12) cm from the anal verge, encompassed 50 (range, 20-90) percent of the rectal circumference, and was 6 (range, 3-12) cm in diameter. RESULTS: No Grade 4 toxicity was observed during chemoradiotherapy. Three patients experienced Grade 3 toxicity (diarrhea), and four patients required a treatment interruption of greater than three days. All patients completed at least 90 percent of the prescribed radiotherapy dose. All patients underwent surgical resection. Ninety-four percent had clear surgical margins. All pathologic specimens had significant evidence of necrosis, hyalinization, and fibrosis. Thirty-three percent of the specimens had a complete pathologic response (defined as no evidence of viable tumor cells). Of the 19 patients with ultrasound-staged N1 disease, only five had pathologic evidence of nodal involvement after chemoradiotherapy. Of the 25 patients with ultrasound-staged T3 disease, pathologic staging revealed eight with T0, two with T1, five with T2, and ten with T3 disease. Of the five patients with ultrasound-staged T4 disease, pathologic staging revealed two with T0, one with T2, and two with T3 disease. No patient developed progressive disease while on treatment. Two patients have experienced local failure at 6 and 20 months, and one patient failed in the liver at seven months. Twenty-seven patients remain free of disease with a median follow-up of 20 (range, 3-53) months. CONCLUSION: Our experience suggests that preoperative chemoradiotherapy is well tolerated, down-stages tumors, and sterilizes regional lymph nodes.

Adenocarcinoma↗

PubMed2001

EGF receptor crosstalks with cytokine receptors leading to the activation of c-Jun kinase in response to UV irradiation in human keratinocytes.

Ultraviolet (UV) irradiation causes photoageing through induction of matrix-degrading metalloproteinases (MMP), which are upregulated by activator protein-1 (AP-1) (Jun/Fos). The c-Jun kinase activity proves to be critically important in the regulation of AP-1 activity. Our previous studies showed that UV irradiation activates epidermal growth factor receptor (EGFR) and cytokine receptors leading to the activation of c-Jun kinase in cultured human skin keratinocytes in vitro and in human skin in vivo. However, the mechanism of UV-induced cell surface receptor activation and the crosstalk among growth factor receptor and cytokine receptors were not fully investigated. This study showed that UV (30 mJ/cm(2))-induced EGFR tyrosine phosphorylation in a manner similar to EGF (100 ng/ml), or IL-1beta (10 ng/ml) in cultured human keratinocytes. In all cases, EGFR tyrosine phosphorylation was completely inhibited by pretreatment of PD153035 (100 nM, 1 h). Also observed was that UV induced autophosphorylation of interleukin 1 receptor associated kinase (IRAK) in a manner analogous to IL-1beta or EGF. In both UV and EGF cases, the phosphorylation of IRAK was inhibited by pretreatment of PD153035. However, IL-1beta-induced IRAK activation was not affected by PD153035. In vitro kinase assay using GST-c-Jun as a substrate revealed that pretreatment of PD153035 completely inhibited UV- and IL-1-induced c-Jun kinase activity in cultured keratinocytes. Taken together, the above data suggest that EGFR plays dominant role in the crosstalk among growth factor receptor and cytokine receptors leading to the activation of c-Jun kinase upon UV irradiation, and that EGFR could be one of the targets for clinical and cosmetical prevention of UV-induced skin aging.

Adult↗

PubMed2001

Immunocytochemical localization of a caveolin-1 isoform in human term extra-embryonic membranes using confocal laser scanning microscopy: implications for the complexity of the materno-fetal junction.

This immunochemical, immunocytochemical, histological and ultrastructural study demonstrates the presence of caveolin 1 in a number of locations in term human extra-embryonic membranes. Strong expression was observed in fetal blood vessel endothelial cells of chorionic villi (cv) and in cv, amniotic and chorionic plate mesenchymal cells, but weak expression was characteristic of trophoblast. Expression in the amniotic epithelium indicated a stronger association with apical as opposed to baso-lateral membranes. Strong immunoreactivity in the thin lining layer of the maternal blood space of the basal plate was a surprising finding. Previously defined as trophoblast, we argue that this is at least partly endothelium based on this new histological, ultrastructural and immunocytochemical data.

Amnion↗

PubMed2001

Black-white unions: West Indians and African Americans compared.

In this research we use 1990 PUMS data to compare the propensity for unions between African Americans and native whites with the propensity for unions between British West Indians and native whites. In addition, we distinguish women and men. Descriptive statistics indicate that West Indians, with the exception of men who arrived as adults, are more likely than African Americans to have white partners. After the introduction of controls for several correlates of intermarriage, however, West Indian men of any generation have lower exogamy rates than African American men, while exogamy rates are higher among West Indian women who arrived as children or who were born in the United States than among African American women. Thus we find no consistent evidence of greater exogamy for British West Indians than for African Americans.

Adolescent↗

PubMed2001

Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes.

Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.

Blotting, Western↗

PubMed2000

The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear.

We have demonstrated that the phenotype of the mouse mutant sex-linked fidget ( slf ) is caused by developmental malformations of the inner ear that result in hearing loss and vestibular dysfunction. Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome. These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene. In this paper, we have identified the nature of the slf mutation, and demonstrated that it is an X chromosomal inversion with one breakpoint close to Brn4. This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube. Finally, these results demonstrate that the slf mutation is a good mouse model for the most prevalent form of X-linked congenital deafness in man, which is associated with mutations in the human Brn4 ortholog, POU3F4.

Animals↗

PubMed2000

UV-induced expression of GADD45 is mediated by an oxidant sensitive pathway in cultured human keratinocytes and in human skin in vivo.

The expression of GADD45 was examined in cultured skin keratinocytes and in human skin in vivo following UV irradiation. Northern blot analysis revealed that UV-induced the expression of GADD45 (alpha, beta, gamma) in a time- and dose-dependent manner. Messenger RNA of GADD45 (alpha, beta, gamma) increased within 30 min, peaked at 4 h and remained elevated for at least 8 h following UV irradiation in vitro and in vivo. Maximal induction of GADD45alpha was approximately 5-fold compared to the level in sham-irradiated controls. Similarly H2O2 and IL-1 also induced GADD45alpha expression in cultured human keratinocytes. The kinetics of induction of GADD45alpha by H2O2, IL-1beta and UV were very similar. Interestingly, UV-induced GADD45alpha expression was inhibited by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase, and antioxidant, N-acetyl-L-cysteine (NAC), indicating the involvement of reactive oxygen species in UV signaling. Previously we have shown that EGF receptor activation by UV is prerequisite for subsequent activation of NADPH oxidase and generation of reactive oxygen species. We therefore examined the effect of EGF receptor inhibitor on UV-induced GADD45alpha expression. Our results showed that PD168393, a potent EGF receptor inhibitor, blocked UV-induced GADD45alpha expression. Collectively, our data suggest that UV-induced GADD45alpha expression occur via an EGF receptor-mediated oxidative pathway sensitive to antioxidant regulation.

Acetylcysteine↗

PubMed2000

Definitions of allied health services in urban community contexts: consumer perspectives.

This study, as part of a larger project designed to increase allied health services to underserved urban community agencies, focussed on understanding how consumers defined the services provided in community agencies. Consumers were asked to describe what they defined as service and what constituted good service provision. Qualitative methods were used to conduct key-informant interviews and focus groups with consumers and staff at six community agencies representing different underserved populations, including ethnic and racial minority groups, the homeless, and individuals with disabilities living in the community. Four major themes emerged across the data: 1) the struggle to maintain a stable life with a chronic illness or disability; 2) services need to help solve life challenges; 3) the challenge of accessing and maintaining services; and 4) the need for a peer community. Data analysis revealed that services are difficult to access within and outside community agencies, services need to address short-term as well as long-term issues, and services in the community are still driven by a professional or expert model despite the availability of peer models. Recommendations for health professionals working in community settings are provided.

Activities of Daily Living↗

PubMed1999

NMR probe for the simultaneous acquisition of multiple samples.

A dual channel probe for the simultaneous acquisition of NMR data from multiple samples has been developed. This multiplex probe consists of two noninteracting sample coils that are each capable of detecting NMR signals at the same resonant frequency with good sensitivity and resolution. 13C free induction decays for the two samples, methanol (13C, 99%) and carbon tetrachloride (13C, 99%), were acquired simultaneously at 75.44 MHz using a single transmitter pulse and separate NMR receivers. S/N measurements are comparable to those observed using single coils. No evidence of cross talk is evident in the spectra even after considerable signal averaging. The probe demonstrates the feasibility of significant parallelism in NMR, which will be of interest in situations where high throughput analysis is desired.

Carbon Tetrachloride↗

PubMed1999

Abdominal obesity reduction in indigenous men.

OBJECTIVES: To assess the effectiveness of a men's 'waist loss' program over one year in Indigenous men. DESIGN: Pre-and post-test measurements of 47 Indigenous men on four island groups in the Torres Strait region of Northern Australia involved in a version of the 'GutBuster' program, modified by and for Indigenous men. RESULTS: Weight, waist and hip size of 47 men, and body fat estimated from electrical impedence measures of 27 men, were compared at baseline, after approx 2 months, approx 6 months and approx one year. Average weight loss was 3.3 kg (3.5%), and waist loss 4.0 cm (3.5%). The average percentage decrease in fat mass (FM) was 10.8%. An environmental audit technique highlighted modifications needed to the environment to assist behaviour change. CONCLUSIONS: Education-behaviour change interventions of this kind may offer opportunities for health improvements in Indigenous men.

Abdomen↗

PubMed1998

Free D- and L-amino acids in ventricular cerebrospinal fluid from Alzheimer and normal subjects.

Free D-Ser, D-Asp and total D-amino acids were significantly higher (p < 0.05) in Alzheimer (AD) ventricular CSF than in normal CSF. There was no significant difference in the total L-amino acids between AD and normal CSF, but L-Gln and L-His were significantly higher (p < 0.05) in AD-CSF. The higher concentrations of these D- and L-amino acids in AD ventricular CSF could reflect the degenerative process that occurs in Alzheimer's brain since ventricular CSF is the repository of amino acids from the brain.

Alzheimer Disease↗