Biomedical subjects

K J Simpson

Publications and source records attributed to K J Simpson.

At least 19 recordsLinked to original sources

PubMed2006

Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma.

Understanding how RhoC expression and activation are regulated is essential for deciphering its contribution to tumorigenesis. Here, we report that RhoC expression and activation are induced by the epithelial to mesenchymal transition (EMT) of colon carcinoma. Using LIM 1863 colon cancer cells, RhoC protein expression and subsequent activation were detected coincident with the loss of E-cadherin and acquisition of mesenchymal characteristics. Several Ets-1 binding sites were identified in the RhoC promoter, and evidence was obtained using chromatin immunoprecipitation that Ets-1 can regulate RhoC expression during the EMT. Interestingly, a marked decrease in RhoA activation associated with the EMT was observed that corresponds to the increase in RhoC expression. Use of shRNA established that RhoA inhibits and RhoC promotes post-EMT cell migration, demonstrating functional significance for their coordinate regulation. To assess the importance of RhoC expression in colon cancer, immunohistochemistry was performed on 566 colorectal tumors with known clinical outcome. The level of RhoC ranged from no expression to high expression, and statistical analysis revealed that elevated RhoC expression correlates with poor outcome as well as aberrant expression and localization of E-cadherin. These data provide one mechanism for how RhoC expression is regulated in colon carcinoma and substantiate its utility as a prognostic marker.

Biomarkers, Tumor↗

PubMed2005

A biomechanical comparison between the single-axis and multi-axis total knee arthroplasty systems for the stand-to-sit movement.

BACKGROUND: Compared to the design of a traditional multi-axis total knee arthroplasty, the single-axis arthroplasty studied has a fixed flexion/extension center of rotation in the femoral component. The influence of this characteristic on functional daily activity, i.e., stand-to-sit, is not well understood. The purpose of this study was to investigate the effect of different arthroplasty designs on knee kinematic and lower limb muscular activation for the stand-to-sit movement. METHODS: Sixteen unilateral, posterior-stabilized knee arthroplasty participants (8 single-axis and 8 multi-axis) with excellent Knee Society scores performed 4 trials of the stand-to-sit test. Three-dimensional video analysis of whole body and joint kinematics and electromyography analysis of quadriceps and hamstrings were conducted. One-way ANOVAs were used for statistical analyses (alpha=0.05). FINDINGS: The multi-axis group showed some functional adaptations while sitting down. The single-axis group exhibited less arthroplasty limb quadriceps electromyography and hamstring co-activation electromyography than the multi-axis group. For the arthroplasty limb, single-axis demonstrated less abduction angular displacement and reached peak abduction earlier than the multi-axis arthroplasty limb. The estimated effect size for this study was 0.196. INTERPRETATION: The single-axis design requires less eccentric knee extensor muscle activation and exhibits greater medio-lateral stability than the multi-axis designs. Findings from this study could provide useful information to orthopedic knee surgeons and rehabilitative specialists.

Adaptation, Physiological↗

PubMed2003

Liver death and regeneration in paracetamol toxicity.

Paracetamol overdose (POD) is a major clinical problem as the commonest cause of fulminant hepatic failure (FHF) in the UK and the USA. While the main loss of liver mass occurs following hepatocyte necrosis, hepatocyte apoptosis has also been reported to occur during paracetamol toxicity in murine liver. Hepatocyte apoptosis has not previously been identified in human liver and the significance of apoptosis in paracetamol toxicity is not known. In this study of paracetamol toxicity in human liver after POD, hepatocyte apoptosis was identified at time of liver transplantation or death and was associated with striking regenerative activity. The biological significance of apoptosis is unclear but the rates of apoptosis found (0.6%) could account for a significant loss of hepatic parenchyma. The stimulus for apoptosis is not known but it is unlikely to be induced directly by paracetamol since it is absent from serum at this time. The possibility that apoptosis may be induced by Kupffer cell activation with cytokine production is raised. Patients who develop FHF after POD have a poor prognosis, with few therapeutic options apart from liver transplantation; an understanding of the dynamics of liver regeneration and ongoing cell loss by apoptosis may allow the development of new therapies in these patients.

Acetaminophen↗

PubMed2002

Anorexia nervosa and culture.

Anorexia nervosa is currently considered a disorder confined to Western culture. Its recent identification in non-Western societies and different subcultures within the Western world has provoked a theory that Western cultural ideals of slimness and beauty have infiltrated these societies. The biomedical definition of anorexia nervosa emphasizes fat-phobia in the presentation of anorexia nervosa. However, evidence exists that suggests anorexia nevosa can exist without the Western fear of fatness and that this culturally biased view of anorexia nervosa may obscure health care professionals' understanding of a patient's own cultural reasons for self-starvation, and even hinder their recovery.

Adolescent↗

PubMed2002

Paracetamol toxicity: epidemiology, prevention and costs to the health-care system.

Paracetamol has been used as an analgesic and antipyretic for many years, with toxicity first noted in the 1960s. Since then the incidence of poisoning has increased, and paracetamol is now the most common drug in self-poisoning, with a high rate of morbidity and mortality. The use, abuse and ways of reducing paracetamol toxicity are reviewed, but in view of the potential for harm, serious consideration should be given to changing the legal status of paracetamol, possibly to a prescription-only medicine.

Acetaminophen↗

PubMed2001

Differential expression of the whey acidic protein gene during lactation in the brushtail possum (Trichosurus vulpecula).

The whey acidic protein (WAP) is a whey protein found in the milk of a number of species. We have isolated and characterised a WAP cDNA clone from the brushtail possum (Trichosurus vulpecula) and examined its expression in the mammary gland. The amino acid sequences of WAP from the possum and another marsupial, the tammar wallaby, share 69% identity, however, less sequence identity exists between the marsupial and eutherian WAP sequences (30-37%). The possum and tammar WAP genes consist of three four-disulphide core (4-DSC) domains, with a WAP motif at the beginning of each domain. In contrast, the eutherian WAP sequences consist of two 4-DSC domains with the WAP motif only present in the second domain. This WAP motif is also present in a number of protease inhibitors found in a wide range of species. Phylogenetic analysis of marsupial and eutherian WAP sequences suggests that the ancestral WAP gene has three domains and that one of the domains has been deleted from the eutherian gene. The profile of WAP gene expression in the possum mammary gland changed throughout lactation, with WAP mRNA levels reaching a peak between days 106 and 177 of lactation. The level of WAP mRNA in the mammary gland appeared to be correlated with the level of circulating prolactin in the lactating female and was different to that observed for several other whey protein genes. Overlapping expression of the WAP and early lactation protein genes, both of which are putative protease inhibitors, may provide protection of milk immunoglobulins that are required for the prolonged period of passive immune transfer to the marsupial pouch young.

Amino Acid Sequence↗

PubMed2001

Referral patterns and social deprivation in paracetamol-induced liver injury in Scotland.

Paracetamol overdose is the commonest cause of acute liver failure in the UK, which has led to measures to restrict its sale. We aimed to establish whether changes in the referral of patients with paracetamol-induced acute liver failure have occurred since the introduction of legislation. We compared data from patients admitted to the Scottish Liver Transplantation Unit in 1992-98 with those admitted in 1998-2001. The incidence of paracetamol-induced liver failure, severity of patients' illness, and outcome did not differ between the groups. Patients with paracetamol-induced acute liver failure had higher Carstairs scores (1.99 [95% CI 1.33-2.65]; n=190) than patients with non-paracetamol acute liver failure (0.02 [-0.79 to 0.84]; n=68). We have shown an association between paracetamol-induced acute liver failure and social deprivation.

Acetaminophen↗

PubMed2000

The gene for a novel member of the whey acidic protein family encodes three four-disulfide core domains and is asynchronously expressed during lactation.

Secretion of whey acidic protein (WAP) in milk throughout lactation has previously been reported for a limited number of species, including the mouse, rat, rabbit, camel, and pig. We report here the isolation of WAP from the milk of a marsupial, the tammar wallaby (Macropus eugenii). Tammar WAP (tWAP) was isolated by reverse-phase HPLC and migrates in SDS-polyacrylamide gel electrophoresis at 29.9 kDa. tWAP is the major whey protein, but in contrast to eutherians, secretion is asynchronous and occurs only from approximately days 130 through 240 of lactation. The full-length cDNA codes for a mature protein of 191 amino acids, which is comprised of three four-disulfide core domains, contrasting with the two four-disulfide core domain arrangement in all other known WAPs. A three-dimensional model for tWAP has been constructed and suggests that the three domains have little interaction and could function independently. Analysis of the amino acid sequence suggests the protein belongs to a family of protease inhibitors; however, the predicted active site of these domains is dissimilar to the confirmed active site for known protease inhibitors. This suggests that any putative protease ligand may be unique to either the mammary gland, milk, or gut of the pouch young. Examination of the endocrine regulation of the tWAP gene showed consistently that the gene is prolactin-responsive but that the endocrine requirements for induction and maintenance of tWAP gene expression are different during lactation.

Amino Acid Sequence↗

PubMed2000

Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis.

Paracetamol-induced hepatic necrosis is the most common form of toxic liver injury experienced in clinical practice in the UK and USA. Recently, reports have described prevention of hepatic necrosis, induced by other hepato-toxins, by inhibiting tumour necrosis factor alpha (TNFalpha). The aim of the present study was to determine the role of TNFalpha in paracetamol-induced hepatic necrosis. Six-week-old CBA/J female mice were given 300 mg/kg paracetamol by intraperitoneal (IP) injection after an 8-h fast. Hepatic expression of TNFalpha was measured by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR). Serum TNFalpha was measured by ELISA. One hour prior to paracetamol injection, mice were also given blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, interleukin 10 (IL-10), and dexamethasone. Hepatic injury was measured by serum aspartate aminotransferase and histological assessment on haematoxylin and eosin (H&E)-stained liver sections. There was a significant increase in serum TNFalpha at 6 h (control 0.002+/-0.002 ng/ml, n=7; paracetamol-treated 0.022+/-0.007 ng/ml, n=5, p<0.05), but hepatic TNFalpha expression did not change up to 24 h following paracetamol injection. Histologically severe centrilobular hepatic necrosis was noted at 3 h and progressed for 24 h after paracetamol poisoning. Death rate, serum aspartate aminotransferase, and hepatic histology were not significantly different between the groups treated with blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, IL-10, and dexamethasone, compared with controls. In conclusion, there is no evidence to suggest that modulation of TNFalpha expression affects hepatic injury following experimental paracetamol poisoning; anti-TNFalpha therapies are therefore unlikely to be effective in the corresponding clinical situation.

Acetaminophen↗

PubMed2000

Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2.

Monocyte chemoattractant protein-1 is one of the major C-C chemokines that has been implicated in liver injury. The C-C chemokine receptor, CCR2, has been identified as the primary receptor that mediates monocyte chemoattractant protein-1 (MCP-1) responses in the mouse. Accordingly, the present study addressed the role of CCR2 in mice acutely challenged with acetaminophen (APAP). Mice genetically deficient in CCR2 (CCR2(-/-)) and their wild-type counterparts (CCR2(+/+)) were fasted for 10 hours before receiving an intraperitoneal injection of APAP (300 mg/kg). Liver and serum samples were removed from both groups of mice before and at 24 and 48 hours post APAP. Significantly elevated levels of MCP-1 were detected in liver samples from CCR2(+/+) and CCR2(-/-) mice at 24 hours post-APAP. Although CCR2(+/+) mice exhibited no liver injury at any time after receiving APAP, CCR2(-/-) mice exhibited marked evidence of necrotic and TUNEL-positive cells in the liver, particularly at 24 hours post-APAP. Enzyme-linked immunosorbent assay analysis of liver homogenates from both groups of mice at the 24 hours time point revealed that liver tissue from CCR2(-/-) mice contained significantly greater amounts of immunoreactive IFN-gamma and TNF-alpha. The in vivo immunoneutralization of IFN-gamma or TNF-alpha significantly attenuated APAP-induced liver injury in CCR2(-/-) mice and increased hepatic IL-13 levels. Taken together, these findings demonstrate that CCR2 expression in the liver provides a hepatoprotective effect through its regulation of cytokine generation during APAP challenge.

Acetaminophen↗

PubMed2000

The role of chemokines in the immunopathology of the liver.

Chemokines are small protein inflammatory mediators that were classically known for their elicitation of inflammatory cells out of the vasculature. However, more contemporary studies show that these ubiquitous factors impinge on many facets of biology, including hematopoiesis, angiogenesis, and mitogeneis. The elucidation of mechanisms involved in the immunopathogenesis of liver disease has magnified the importance of chemokines in this organ. Accordingly, a number of in vitro and in vivo studies have highlighted the importance of chemokine biology in both acute and chronic liver disease, and a variety of liver diseases have been shown to involve chemokines and their receptors during the initiation and main tenance of liver pathology. A greater understanding of the role chemokines play during liver disease may permit the employment of therapies that target or enhance chemokines in the liver. This review will highlight the current clinical and experimental research in the immunopathogenesis of acute and chronic liver diseases.

Animals↗

PubMed2000

Pretransplantation tumor necrosis factor-alpha production predicts acute rejection after liver transplantation.

Immunosuppressive therapy has many adverse effects in both the short and longer term. Tailoring immunosuppression might be possible if pretransplantation parameters predicted rejection. We investigated production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory cytokine, interleukin-10 (IL-10), pretransplantation to determine whether there is a relation with acute rejection. Peripheral-blood mononuclear cells were obtained from patients with chronic liver disease on the waiting list for orthotopic liver transplantation and healthy controls. Cells (0.5 x 10(6)) were stimulated with 200 ng of lipopolysaccharide. Preincubation for 30 minutes with tacrolimus, cyclosporine, and dexamethasone at concentrations of 10 and 100 ng was also performed. TNF-alpha and IL-10 levels were measured by enzyme-linked immunosorbent assay. Acute rejection was defined on clinical and histological grounds. Pretransplantation in vitro production of TNF-alpha significantly (P <.05) increased in the group of patients with acute rejection (n = 9) compared with those who did not develop rejection (n = 12). Preincubation with dexamethasone significantly (P <.001) reduced TNF-alpha and IL-10 production in both patients and controls (n = 8). IL-10 production pretransplantation was not different in those who developed acute rejection (n = 9) compared with those who did not (n = 9). Preincubation with tacrolimus augmented (P <.05) the production of IL-10 in patients (n = 18), but not controls (n = 6). Pretransplantation TNF-alpha production is increased in patients who go on to develop acute rejection posttransplantion.

Acute Disease↗

PubMed2000

Serum hyaluronan--a non-invasive test for diagnosing liver cirrhosis.

INTRODUCTION: Hyaluronan is a glucosaminoglycan synthesized by the mesenchymal cells and degraded by hepatic sinusoidal endothelial cells by a specific receptor-mediated process. Elevated levels are associated with the sinusoidal capillarization that is seen in cirrhosis. METHODOLOGY: Serum hyaluronan was measured, using a radiometric assay (Pharmacia, Sweden) in 221 patients with biopsy-proven chronic liver disease of a variety of aetiologies (alcohol n = 70, autoimmune chronic active hepatitis n = 23, primary biliary cirrhosis n = 17, hepatitis C n = 69, cryptogenic n = 15, various n = 27). All patients were fasted, and their liver function tests, full blood count, prothrombin time and Child-Pugh score were assessed at the time of the liver biopsy. RESULTS: Hyaluronan levels (microg/l) were significantly higher in patients with liver cirrhosis (cirrhosis n = 127, mean 440, 95% CI 367-515) (P < 0.0001) compared with hepatic fibrosis (n = 23, mean 144, 95% CI 69-190), chronic hepatitis (n = 60, mean 63, 95% CI 37-91) and fatty liver (n = 11, mean 107, 95% CI 37-177). Within the cirrhotic population, there was no significant difference in hyaluronan levels between different aetiologies, but hyaluronan level increased proportionally to the severity of cirrhosis. Overall, a hyaluronan level > 100 microg/l had a 78% specificity and 83% sensitivity for diagnosing cirrhosis, while the specificity was increased to 96% for all patients with hyaluronan levels > 300 microg/l. The highest specificity and sensitivity were seen at a cut-off value of 100 microg/l in patients with alcohol-associated liver disease (89%, 87%) and hepatitis C (93%, 72%) respectively. Within patient cohorts, there was a significant correlation (P < 0.01) between hyaluronan and albumin, platelet count and bilirubin, but not with alanine aminotransferase. CONCLUSION: Measurement of fasted serum hyaluronan reliably differentiated cirrhotic from non-cirrhotic liver disease and can be regarded as a useful test in the diagnosis of liver cirrhosis, particularly when a liver biopsy is contraindicated.

Biopsy↗

PubMed2000

Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis.

AIMS: To investigate the associations between the Rsa I, Dra I, and Taq I genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease or to hepatocellular carcinoma. METHODS: DNA samples isolated from 61 patients with alcoholic liver disease, 46 patients with hepatocellular carcinoma, and 375 healthy controls were subjected to polymerase chain reaction amplification followed by digestion with the endonucleases Rsa I, Dra I, or Taq I. Meta-analysis was performed using data from previous studies of Rsa I polymorphism and the risk of alcoholic liver disease. RESULTS: No association was found between any of the three polymorphisms and susceptibility to hepatocellular carcinoma. The distributions of Rsa I and Dra I alleles among the patients with alcoholic liver disease were not significantly different from those among the control group. Meta-analysis of this data and previous data concerning Rsa I polymorphism and alcoholic liver disease risk failed to demonstrate any significant association between the two. However, the alcoholic liver disease group in this study showed a significantly lower frequency of the less common Taq I allele compared with the healthy control group (odds ratio, 0.33; 95% confidence interval, 0.12 to 0.78). CONCLUSIONS: Possession of the less common Taq I cytochrome p4502E1 allele is associated with reduced susceptibility to alcoholic liver disease. There is no existing evidence that the Taq I polymorphism is directly associated with altered alcohol metabolism, but it might be in linkage disequilibrium with as yet unidentified protective factors.

Adult↗

PubMed1999

Foot landing position during gait influences ground reaction forces.

OBJECTIVE: The purpose of this study was to determine how foot landing position influenced the ground reaction forces of two coordinate systems during gait. DESIGN: Values of ground reaction forces components as expressed in two coordinate systems (room, foot) were used to compare ground reaction forces of different foot landing position. BACKGROUND: Non-neutral foot landing position during gait could influence the mechanics of the whole body motion and/or the foot-ankle complex and produce different ground reaction forces patterns compared to a neutral foot landing position. METHODS: Thirty females were assigned to a foot landing group: toe-out, toe-in or neutral. Each participant walked 10 trials across a force platform while three-dimensional motion was captured. RESULTS: No differences were observed for vertical or anteroposterior ground reaction forces variables between groups for either coordinate system. For medio-lateral forces of both coordinate systems, toe-out participants exhibited greater first lateral and second medial maximum forces and exhibited greater impulses. CONCLUSION: For toe-out participants, greater medio-lateral ground reaction forces of the room coordinate system indicate excessive forces are generated by toe-out participants that do not contribute to moving the participant forward. Furthermore, medio-lateral loading on the foot increases proportionally with the degree of toe-out. RELEVANCE: Establishing norms for clinical populations requires understanding of factors that can influence ground reaction force (GRF). Foot landing position (FLP) only affects the medio-lateral forces. Excessive toe-out landing has been surmised to be related to injury. Greater forces acting medio-laterally to the foot's long axis may have a relevant effect on in/eversion loading of the foot.

Ankle Joint↗

PubMed1999

The whey acidic protein family: a new signature motif and three-dimensional structure by comparative modeling.

Whey acidic proteins (WAP) from the mouse, rat, rabbit, camel, and pig comprise two "four-disulfide core" domains. From a detailed analysis of all sequences containing this domain, we propose a new PROSITE motif ([KRHGVLN]-X-¿PF¿-X-[CF]-[PQSVLI]-X(9,19)-C-¿P¿-X-[DN]-X-¿N¿ -[CE]-X(5)-C-C) to accurately identify new four-disulfide core proteins. A consensus model for the WAP proteins is proposed, based on the human mucous proteinase inhibitor crystal structure. This article presents a detailed atomic model for the two-domain porcine WAP sequence by comparative modeling. Surface electrostatic potential calculations indicate that the second domain of the pig WAP model is similar to the functional human mucous proteinase inhibitor domains, whereas the first domain may be nonfunctional.

Amino Acid Sequence↗

PubMed1999

Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury.

Profound hepatocellular injury is often a consequence of adenovirus-mediated gene therapy or acetaminophen ingestion. The aim of the present study was to examine the role of a CXC chemokine, macrophage inflammatory protein-2 (MIP-2), in the hepatotoxic response by mice infected with adenovirus and challenged with acetaminophen. CD1 mice that received a replication-defective human type 5 adenovirus vector (Ad70-3) intravenously exhibited hepatic injury that peaked at 24 h after infection. In contrast, mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hepatic injury at any time after infection. The combination of Ad70-3 infection and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fatal in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetaminophen were similarly affected. Furthermore, AdMIP-2 mice had significantly lower hepatic injury and serum aminotransaminases compared with the Ad70-3 group. However, AdMIP-2 infection in mice lacking the CXC chemokine receptor that binds MIP-2, CXCR2, did not attenuate any of the markers of liver injury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltration into the liver and an earlier increase in hepatic 3H-thymidine incorporation compared with the control group. Taken together, these data demonstrate that MIP-2 has a protective role in both adenovirus- and acetaminophen-mediated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic regeneration following acute hepatic injury.

Acetaminophen↗

PubMed1999

Review article: mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications.

The social use of ecstasy (methylenedioxymethampheta-mine, MDMA) and amphetamines is widespread in the UK and Europe, and they are popularly considered as 'safe'. However, deaths have occurred and hepatotoxicity has featured in many cases of intoxication with amphetamine or its methylenedioxy analogues such as ecstasy. Recreational use of these drugs presents an important but often concealed cause of hepatitis or acute liver failure, particularly in young people. The patterns of liver damage and multiple putative mechanisms of injury are discussed. Recognition of the aetiological agent requires a high index of suspicion. Optimum management of the resultant liver damage, including the controversial role of liver transplantation for fulminant hepatic failure, is also discussed.

Amphetamine↗