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Biomedical subjects

S A Mitchell

Publications and source records attributed to S A Mitchell.

At least 37 records · Page 2Linked to original sources
PubMed2001

A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is used for the treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) for which it has a positive effect on laboratory values, may delay the development of liver failure and prolong the transplant-free disease period. Standard doses of UDCA (8-15 mg/kg daily) have been shown to be ineffective in the treatment of primary sclerosing cholangitis (PSC). We report on the findings (clinical, biochemical, histological, and cholangiographic) and side effects of a 2-year double-blind placebo-controlled preliminary study of high-dose UDCA in PSC patients. METHODS: Twenty-six patients with PSC were randomized to high-dose (20 mg/kg daily) UDCA or placebo. Cholangiography and liver biopsy were performed at entry and after 2 years. Symptoms, clinical signs, and liver biochemical tests were recorded at 3 monthly intervals. RESULTS: High-dose UDCA did not influence symptoms, but there was a significant improvement in liver biochemistry (serum alkaline phosphatase, P = 0.03; gamma-glutamyl transferase, P = 0.01) and a significant reduction in progression in cholangiographic appearances (P = 0.015) and liver fibrosis as assessed by disease staging (P = 0.05). In the treatment group, a significant increase in total bile acids and saturation with UDCA >70% confirmed patient compliance. No significant side effects were reported. CONCLUSIONS: High-dose UDCA may be of clinical benefit in PSC, but trials with a larger number of participants and of longer duration are required to establish whether the effect of high-dose UDCA on liver biochemistry, histology, and cholangiography in patients with PSC is translated into improved long-term survival.

Adult↗
PubMed2001

Protein factor requirements of the Apaf-1 internal ribosome entry segment: roles of polypyrimidine tract binding protein and upstream of N-ras.

It has been reported previously that the 5' untranslated region of the mRNA encoding Apaf-1 (apoptotic protease-activating factor 1) has an internal ribosome entry site (IRES), whose activity varies widely among different cell types. Here it is shown that the Apaf-1 IRES is active in rabbit reticulocyte lysates, provided that the system is supplemented with polypyrimidine tract binding protein (PTB) and upstream of N-ras (unr), two cellular RNA binding proteins previously identified to be required for rhinovirus IRES activity. In UV cross-linking assays and electrophoretic mobility shift assays with individual recombinant proteins, the Apaf-1 IRES binds unr but not PTB; however, PTB binding occurs if unr is present. Over a range of different cell types there is a broad correlation between the activity of the Apaf-1 IRES and their content of PTB and unr. In cell lines deficient in these proteins, overexpression of PTB and unr stimulated Apaf-1 IRES function. This is the first example where an IRES in a cellular mRNA has been shown to be functionally dependent, both in vitro and in vivo, on specific cellular RNA binding proteins. Given the critical role of Apaf-1 in apoptosis, these results have important implications for the control of the apoptotic cascade.

Animals↗
PubMed2001

Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the -308 and -627 positions in the TNF-alpha and IL-10 promoter genes, respectively, and susceptibility to PSC. METHODS: TNF-alpha -308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 -627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls. RESULTS: A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (OR(combined data)=3.2 (95% confidence intervals (CI) 1.8--4.5); p(corr)=10(-5)). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (OR(combined data)=3.2 (95% CI 1.2--9.0); p(corr)=0.006 ). There was no difference in the -627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (OR(combined data)=3.8, p(corr)=10(-6) v OR(combined data)=3.2, p(corr)=10(-5) v OR(combined data )=3.41, p(corr)=10(-4), respectively). CONCLUSIONS: This study identified a significant association between possession of the TNF2 allele, a G-->A substitution at position -308 in the TNF-alpha promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 -627 promoter polymorphism and PSC.

Adult↗
PubMed2001

Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation.

Neuropeptide pharmaceuticals have potential for the treatment of neurological disorders, but the blood-brain barrier (BBB) limits entry of peptides to the brain. Several strategies to improve brain delivery are currently under investigation, including glycosylation. In this study we investigated the effect of O-linked glycosylation on Ser(6) of a linear opioid peptide amide Tyr-D-Thr-Gly-Phe-Leu-Ser-NH(2) on metabolic stability, BBB transport, and analgesia. Peptide stability was studied in brain and serum from both rat and mouse by high-performance liquid chromatography. BBB transport properties were investigated by rat in situ perfusion. Tail-flick analgesia studies were performed on male ICR mice, injected i.v. with 100 microg of peptide ligand. Glycosylation of Ser(6) of the peptide led to a significant increase in enzymatic stability in both serum and brain. Glycosylation significantly increased the BBB permeability of the peptide from a value of 1.0 +/- 0.2 microl x min(-1) x g(-1) to 2.2 +/- 0.2 microl x min(-1) x g(-1) (p < 0.05), without significantly altering the initial volume of distribution. Analgesia studies showed that the glycosylated peptide gave a significantly improved analgesia after i.v. administration compared with nonglycosylated peptide. The improved analgesia profile shown by the glycosylated peptide is due in part to an improvement in bioavailability to the central nervous system. The bioavailability is increased by improving stability and transport into the brain.

Analgesics, Opioid↗
PubMed2000

Improved bioavailability to the brain of glycosylated Met-enkephalin analogs.

The blood-brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cyclic opioid peptide [D-Cys(2,5),Ser(6),Gly(7)] enkephalin. The peptide was glycosylated on the Ser(6) via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague-Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the delta-opioid receptor, and mixed effect on binding to the mu-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C.

Animals↗
PubMed2000

Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability.

Endogenous peptides (e.g. enkephalins) control many aspects of brain function, cognition, and perception. The use of these neuroactive peptides in diverse studies has led to an increased understanding of brain function. Unfortunately, the use of brain-derived peptides as pharmaceutical agents to alter brain chemistry in vivo has lagged because peptides do not readily penetrate the blood-brain barrier. Attachment of simple sugars to enkephalins increases their penetration of the blood-brain barrier and allows the resulting glycopeptide analogues to function effectively as drugs. The delta-selective glycosylated Leu-enkephalin amide 2, H(2)N-Tyr-D-Thr-Gly-Phe-Leu-Ser(beta-D-Glc)-CONH(2), produces analgesic effects similar to morphine, even when administered peripherally, yet possesses reduced dependence liability as indicated by naloxone-precipitated withdrawal studies. Similar glycopeptide-based pharmaceuticals hold forth the promise of pain relief with improved side-effect profiles over currently available opioid analgesics.

Analgesics, Opioid↗
PubMed2000

Initiation of Apaf-1 translation by internal ribosome entry.

The apoptotic protease activating factor (Apaf-1) plays a central role in apoptosis: interaction of this protein with procaspase-9 leads to cleavage and activation of this initiator caspase. In common with other mRNAs whose protein products have a major regulatory function, the 5' untranslated region (UTR) of Apaf-1 is long, G-C rich and has the potential to form secondary structure. We have shown that the 5' UTR of Apaf-1 contains an internal ribosome entry segment, located in a 233 nucleotide region towards the 3' end of the leader, and that the translation initiation of this mRNA occurs only by internal ribosome entry. The Apaf-1 IRES is active in almost all human cell types tested, including Human cervical carcinoma (HeLa), Human liver carcinoma (HepG2), Human breast carcinoma (MCF7), Human embryonic kidney (HK293), African Green Monkey kidney (COS7) and Human lung (MRC5). The Apaf-1 IRES initiates translation as efficiently as the HRV IRES, but is less active than the c-myc IRES. We propose that the Apaf-1 IRES ensures that a constant cellular level of Apaf-1 protein is maintained even under conditions where cap-dependent translation is compromised. Oncogene (2000) 19, 899 - 905.

5' Untranslated Regions↗
PubMed2000

Cell-cell contact increases radioresistance in head and neck carcinoma cell lines.

PURPOSE: To investigate the in vitro radiosensitivity of microcolonies from head and neck cancers of varying degrees of differentiation. MATERIALS AND METHODS: The location of individual squamous-cell carcinoma (SCC) cells in tissue culture flasks was recorded using computerized microscopy. This allowed the positions of the cells to be continually revisited, which enabled manual sizing of individual microcolonies, both at the time of irradiation (0-5 Gy) and following a post-irradiation incubation period during which the microcolonies were assessed for clonogenic survival. RESULTS: When irradiated as microcolonies with 0-3 Gy, malignant cells had plating efficiencies (PE; applying multiplicity corrections) that were lower than expected when compared with the PE of cells irradiated individually. However, at between 2 Gy and 3 Gy the PE values became similar and at higher doses the 'corrected PE' of microcolonies became higher than that of individually irradiated cells. CONCLUSION: These data show that cell cell interactions can occur in malignant cells in a manner similar to that demonstrated previously in non-malignant cells. Cells within microcolonies demonstrate increased radioresistance compared with cells irradiated singly.

Carcinoma, Squamous Cell↗
PubMed2000

Reversible tacrolimus-induced neurotoxicity isolated to the brain stem.

Diplopia, nystagmus, visual hallucinations, and internuclear ophthalmoplegia developed in a 30-year-old woman 84 days after she received a matched, unrelated bone marrow transplant for chronic myeloid leukemia. A regimen of tacrolimus had been administered since the transplantation was performed. MR imaging revealed bilaterally symmetric regions of signal abnormality with abnormal contrast enhancement in the brain stem. No supratentorial abnormality was present. Tacrolimus therapy was discontinued, and the symptoms resolved. MR imaging that was performed 10 days after tacrolimus was discontinued showed resolution of the abnormalities.

Adult↗
PubMed1999

The response of human glioma cell lines to low-dose radiation exposure.

PURPOSE: To examine the low-dose radiation response of a series of radioresistant human glioma cell lines and determine if low-dose hypersensitivity is a characteristic of these cells. MATERIALS AND METHODS: The clonogenic survival of six radioresistant human glioma cell lines was measured following exposure to graded, single, very low doses of X-rays in vitro. High resolution was achieved using either a Dynamic Microscopic Image Processing Scanner (DMIPS) or a cell sorter (CS). RESULTS: In five of the six cell lines tested, low-dose hypersensitivity (HRS) was demonstrated although in the sixth, a grade III astrocytoma line, it was not. These results are consistent with previous data indicating that low-dose hypersensitivity is more marked in more radioresistant cell lines although the difference between the glioblastoma cell lines with differing SF2 is not marked. CONCLUSION: Low-dose hypersensitivity is common in radioresistant glioma cell lines. This may have implications for the treatment of these tumours if further studies confirm that HRS translates to increased effectiveness per gray in vivo when very low doses per fraction are used.

Astrocytoma↗
PubMed1999

Psychological and perceived situational predictors of physical activity: a cross-sectional analysis.

The purpose of this study was to identify psychological and self-reported situational factors that are associated with degree of involvement in moderate-intensity physical activity at various stages of adult life. The study is grounded in Personal Investment Theory which proposes that personal incentives, sense of self and perceived options determine behavior. Participants aged 18 and above, selected by random-digit dialling, were invited to participate in a study on physical activity habits. Of 251 who agreed to participate, 41.4% were male (N = 104) and 58.6% were female (N = 147). These participants were asked the number of days per week that they engaged in physical activity which accumulated a total of 30 min or more. The 140 participants who indicated one or more days of activity answered questions concerning personal incentives for physical activity, sense of self and perceived barriers. Stepwise multiple regression analyses and discriminant function analysis indicated that Personal Investment Theory is able to predict up to 29% of the variance associated with voluntary participation in moderate-intensity physical activity. Discussion focuses on implications for physical activity programs for citizens at different stages of their adult life.

Adolescent↗
PubMed1999

Credentialing and privileging of advanced practice nurses.

Credentialing and privileging are increasingly common administrative processes that advanced practice nurses must complete. With the intention of assuring the public of safe health care provided by qualified personnel, several federal and state organizations have developed criteria that licensed practitioners must meet. Managed care organizations are also creating credentialing and privileging guidelines for practitioners who are applying to their provider panels. Understanding the requirements of these processes is essential to advanced practice nurses establishing themselves in practice. This article explains the guidelines from federal, state, and institutional agencies and offers recommendations to practitioners as they prepare for the credentialing process. Also included are sample forms for establishing a practice agreement and a privilege-delineation request.

Contract Services↗
PubMed1998

The management of primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by a progressive, obliterating fibrosis of the intrahepatic and extrahepatic bile ducts. The pathogenesis of PSC is unknown, but it is thought to be an immune-mediated disease. Although the role of cupruretics, immunosuppressants (corticosteroids, azathioprine, tacrolimus, methotrexate), antifibrogenic agents, and ursodeoxycholic acid in the treatment of primary sclerosing cholangitis is reviewed, none of these agents has been shown to retard or reverse the rate of disease progression. Of these therapies, ursodeoxycholic acid at high doses looks the most promising, but large trials are needed to establish whether treatment with high-dose ursodeoxycholic acid influences the morbidity and mortality associated with primary sclerosing cholangitis.

Adrenal Cortex Hormones↗
PubMed1998

The analyst's knowledge and authority.

Current controversies about the nature of the knowledge analysts offer their patients and the kinds of authority they can legitimately claim are of central importance in the evolution of psychoanalytic ideas. These controversies reflect deep differences regarding basic assumptions about both epistemology and the nature of mind. An approach to these issues is offered which, it is argued, is closer to broad cultural shifts in thinking about knowledge in general than is the traditional psychoanalytic stance. Implications for theory and clinical practice are explored.

Humans↗
PubMed1997

Review article: the management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by a progressive obliterating fibrosis of the intrahepatic and extrahepatic bile ducts. The pathogenesis of PSC is poorly understood but it is thought to be an immune-mediated disease. The optimal therapy which successfully improves symptoms, delays progression towards liver failure and transplantation and prevents the onset of cholangiocarcinoma remains elusive. Although current treatments are used to manage cholestasis and its consequences and some of the more general complications of the disease, none of the current therapeutic agents have been shown to retard and reverse the rate of disease progression. The role of cupruretics, corticosteroids, methotrexate, antifibrogenic agents and ursodeoxycholic acid in the treatment of PSC is reviewed. Orthotopic liver transplantation remains the only therapeutic option for advanced PSC but the timing of transplantation remains controversial and the possibility of recurrence of the disease in the graft is increasingly recognised. It is likely that greater insight into the pathogenetic mechanisms involved in PSC will allow therapy to be targetted more specifically at the biliary epithelium.

Chelating Agents↗