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Biomedical subjects

Mark Thomas

Publications and source records attributed to Mark Thomas.

At least 19 recordsLinked to original sources
PubMed2007

Motion sickness as a predictor of postoperative vomiting in children aged 1-16 years.

BACKGROUND: Motion sickness (MS) may be a risk factor for postoperative vomiting (POV), but its independent predictive value in children is not known. METHODS: A convenience sample of 70 consecutive patients aged 1-16 years scheduled for elective surgery were questioned, a history of MS was sought and patients were observed for the subsequent development of POV. RESULTS: The overall incidence of POV was 29%. Fourteen children (20%) had a history of MS; MS-positive children were more likely to vomit than those who were MS-negative (P < 0.01). The type of surgery, use of opioids or prophylactic antiemetics did not differ significantly between the groups. The sensitivity of MS as a predictor of POV is 45% and the specificity 90%, giving a positive predictive value of 64.3% and a negative predictive value of 80.4%. CONCLUSION: Motion sickness is associated with POV in this group of children, but its positive predictive value is fairly low.

Adolescent↗
PubMed2006

A functional transsulfuration pathway in the brain links to glutathione homeostasis.

Oxidative stress and diminished glutathione pools play critical roles in the pathogenesis of neurodegenerative diseases, including Alzheimer and Parkinson disease. Synthesis of glutathione, the most abundant mammalian antioxidant, is regulated at the substrate level by cysteine, which is synthesized from homocysteine via the transsulfuration pathway. Elevated homocysteine and diminished glutathione levels, seen in Alzheimer and Parkinson disease patients suggest impairments in the transsulfuration pathway that connects these metabolites. However, the very existence of this metabolic pathway in the brain is a subject of controversy. The product of the first of two enzymes in this pathway, cystathionine, is present at higher levels in brain as compared with other organs. This, together with the reported absence of the second enzyme, gamma-cystathionase, has led to the suggestion that the transsulfuration pathway is incomplete in the brain. In this study, we incubated mouse and human neurons and astrocytes and murine brain slices in medium with [35S]methionine and detected radiolabel incorporation into glutathione. This label transfer was sensitive to inhibition of gamma-cystathionase. In adult brain slices, approximately 40% of the glutathione was depleted within 10 h following gamma-cystathionase inhibition. In cultured human astrocytes, flux through the transsulfuration pathway increased under oxidative stress conditions, and blockade of this pathway led to reduced cell viability under oxidizing conditions. This study establishes the presence of an intact transsulfuration pathway and demonstrates its contribution to glutathione-dependent redox-buffering capacity under ex vivo conditions in brain cells and slices.

Animals↗
PubMed2006

Myostatin negatively regulates the expression of the steroid receptor co-factor ARA70.

Myostatin is a transforming growth factor-beta (TGF-beta) superfamily member and a key negative regulator of embryonic and postnatal muscle growth. In order to identify downstream target genes regulated by Myostatin, we performed suppressive subtraction hybridization (SSH) on cDNA generated from the biceps femoris muscle of wild-type and myostatin-null mice. Sequence analysis identified several known and unknown genes as Myostatin downstream target genes. Here, we have investigated the regulation of gene expression of an androgen receptor (AR) binding co-factor, androgen receptor associated protein-70 (ARA70), by Myostatin. We show that in mouse there are two isoforms of ARA70 with high homology (79%) to human ARA70; an alpha-isoform which is a canonical ARA70 and a beta-isoform which has a 9 consecutive amino acid deletion and 6 amino acid substitutions in the carboxyl-terminal portion. Reverse Northern analysis on the differentially expressed cDNA library indicated that there is increased expression of ARA70 in the muscles of myostatin-null mice. In addition, Northern blot, together with semi-quantitative PCR analysis, confirmed that there is increased expression of ARA70 in myostatin-null biceps femoris muscle when compared to wild-type muscle. In corroboration of these results, addition of exogenous Myostatin results in down-regulation of ARA70 expression confirming that Myostatin is a negative regulator of ARA70 gene expression. Expression analysis further confirmed that ARA70 is up-regulated during myogenesis and that peak expression of ARA70 is observed following the peak expression of MyoD in differentiating myoblasts. Given that lack of Myostatin and increased expression of AR leads to hypertrophy, we propose that absence of Myostatin, at least in part, induces the hypertrophy phenotype by increasing the activity of AR by up-regulating the expression of ARA70, a known stimulating co-factor of AR.

Amino Acid Sequence↗
PubMed2006

Myostatin auto-regulates its expression by feedback loop through Smad7 dependent mechanism.

Myostatin, a secreted growth factor, is a member of the TGF-beta superfamily and an inhibitor of myogenesis. Previously, we have shown that myostatin gene expression is regulated at the level of transcription and that myostatin is a downstream target gene of MyoD. Here we show that myostatin gene expression is auto-regulated by a negative feedback mechanism. Northern blot analysis indicated that there are relatively higher levels of myostatin mRNA in the biceps femoris muscle of cattle that express a non- functional myostatin allele (Belgian Blue) as compared to normal cattle. In contrast, addition of exogenous myostatin decreases endogenous myostatin mRNA. Consistent with this result, wild type myostatin protein is able to repress myostatin promoter activity via Activin type IIb receptor (ActRIIB) and ALK5 (P < 0.001). However, non-functional myostatin (Piedmontese) failed to repress the myostatin promoter suggesting that myostatin auto-regulates its promoter by negative feedback inhibition. Auto-regulation by myostatin appears to be signaled through Smad7, since the expression of the inhibitory Smad7 is induced by myostatin and the over-expression of Smad7 in turn inhibits the myostatin promoter activity (P < 0.001). In contrast down regulation of Smad7 by siRNA results in increased myostatin mRNA indicating that Smad7 is a negative regulator of myostatin gene expression. Consistent with these results, a decrease in Smad7 mRNA and concomitant increase in myostatin expression is seen in myotubes that express non functional myostatin. In addition, interference with myostatin signaling prevents the induction of Smad7 promoter activity by myostatin. Based on these results, we propose that myostatin auto-regulates its gene expression through a Smad7 dependent mechanism in myogenic cells.

Animals↗
PubMed2006

Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism.

Myostatin, a transforming growth factor-beta (TGF-beta) super-family member, has been well characterized as a negative regulator of muscle growth and development. Myostatin has been implicated in several forms of muscle wasting including the severe cachexia observed as a result of conditions such as AIDS and liver cirrhosis. Here we show that Myostatin induces cachexia by a mechanism independent of NF-kappaB. Myostatin treatment resulted in a reduction in both myotube number and size in vitro, as well as a loss in body mass in vivo. Furthermore, the expression of the myogenic genes myoD and pax3 was reduced, while NF-kappaB (the p65 subunit) localization and expression remained unchanged. In addition, promoter analysis has confirmed Myostatin inhibition of myoD and pax3. An increase in the expression of genes involved in ubiquitin-mediated proteolysis is observed during many forms of muscle wasting. Hence we analyzed the effect of Myostatin treatment on proteolytic gene expression. The ubiquitin associated genes atrogin-1, MuRF-1, and E214k were upregulated following Myostatin treatment. We analyzed how Myostatin may be signaling to induce cachexia. Myostatin signaling reversed the IGF-1/PI3K/AKT hypertrophy pathway by inhibiting AKT phosphorylation thereby increasing the levels of active FoxO1, allowing for increased expression of atrophy-related genes. Therefore, our results suggest that Myostatin induces cachexia through an NF-kappaB-independent mechanism. Furthermore, increased Myostatin levels appear to antagonize hypertrophy signaling through regulation of the AKT-FoxO1 pathway.

Animals↗
PubMed2006

An analysis of the UNOS liver transplant registry: high serum alpha-fetoprotein does not justify an increase in MELD points for suspected hepatocellular carcinoma.

The current United Network for Organ Sharing (UNOS) criteria for liver transplantation gives priority to patients with elevated serum alpha-fetoprotein (AFP; > or = 500 ng/mL) in the absence of radiologic evidence of a hepatic mass. Reports have shown that an elevated serum AFP is a poor diagnostic indicator for hepatocellular carcinoma (HCC) in patients with cirrhosis. Our aim was to determine if an AFP level above 500 ng/mL, in the absence of a liver mass by imaging study, correlates with the presence of HCC. Using the UNOS database we identified all patients transplanted for HCC in the United States between February 2002 and October 2005 based on these criteria. The data collected included: patient demographics, clinical information, and pathological outcomes. The data was analyzed using a chi-squared t-test and confirmed by logistic regression modeling. A total of 22 patients received a cadaveric liver transplant, while 1 received a living donor transplant during the study period. HCC was confirmed posttransplantation in only 6 patients (26%). There was no difference in race, gender, etiology of liver disease, or AFP level between patients with and without HCC but a significant difference in age (59.8 yr for HCC patients vs. 51.3 yr for the non-HCC group; P = 0.01). In conclusion, the majority of the patients who received extra Model for End-Stage Liver Disease (MELD) points based on an elevated AFP did not have HCC. Older age was a significant predictor for the presence of HCC in patients with a serum AFP greater than 500 ng/mL. These results demonstrate the poor correlation of serum AFP with the presence of HCC in patients awaiting liver transplantation.

Adult↗
PubMed2006

Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design.

The cyclin-dependent kinases (CDKs) have been characterized in complex with a variety of inhibitors, but the majority of structures solved are in the inactive form. We have solved the structures of six inhibitors in both the monomeric CDK2 and binary CDK2/cyclinA complexes and demonstrate that significant differences in ligand binding occur depending on the activation state. The binding mode of two ligands in particular varies substantially in active and inactive CDK2. Furthermore, energetic analysis of CDK2/cyclin/inhibitors demonstrates that a good correlation exists between the in vitro potency and the calculated energies of interaction, but no such relationship exists for CDK2/inhibitor structures. These results confirm that monomeric CDK2 ligand complexes do not fully reflect active conformations, revealing significant implications for inhibitor design while also suggesting that the monomeric CDK2 conformation can be selectively inhibited.

Crystallography, X-Ray↗
PubMed2006

Pain management in fulminating ulcerative colitis.

BACKGROUND: Toxic megacolon is a life-threatening complication of ulcerative colitis (UC) characterized by systemic toxicity, loss of blood per rectum and severe pain. Pain management is challenging in these patients because nonsteroidal anti-inflammatory drugs may exacerbate bleeding and opioids are contraindicated because they adversely affect bowel peristalsis causing an increased risk of colonic perforation. METHODS: We describe three episodes of fulminating UC in two children in whom ketamine analgesia was used. Our protocol for a low-dose continuous ketamine infusion with either nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) bolus administration is presented and a review of the literature regarding the use of ketamine analgesia in children is discussed. RESULTS: Low-dose ketamine N/PCA with a continuous background infusion provided satisfactory analgesia and none of our children reported adverse effects. CONCLUSIONS: We have demonstrated the safe and effective use of ketamine analgesia in children with toxic megacolon, a condition in which the child is in severe pain and morphine is contraindicated.

Analgesia, Patient-Controlled↗
PubMed2005

I.V. admixture contamination rates: traditional practice site versus a class 1000 cleanroom.

PURPOSE: The contamination rates associated with the preparation of medium-risk i.v. admixtures in a traditional practice site and in a class 1000 cleanroom were compared. METHODS: Simulated product media fills served as the samples. Each investigator, a pharmacist and a pharmacy technician, prepared 500 vials and 500 small-volume parenteral (SVP) bags in five separate runs at a traditional practice site and in a cleanroom. United States Pharmacopeia chapter 797 medium-risk compounding procedures were followed, and strict adherence to aseptic technique was employed. Single-strength tryptic soy broth was substituted for the drug and diluent in the admixtures. Positive and negative controls were also prepared and stored for the duration of the study. The pharmacist and technician prepared a total of 4057 samples: 2027 samples (1014 vials and 1013 SVP bags) were prepared in a class 1000 cleanroom, and 2030 (1014 vials and 1016 SVP bags) were prepared at a traditional practice site. RESULTS: Contamination rates did not significantly differ between the traditional practice site (0.296%) and the cleanroom environment (0.344%) (p = 1.0). A significant difference in the number of contaminated samples was found between the two investigators (2 of 2057 were contaminated by the pharmacist and 11 of 2000 were contaminated by the technician) (p = 0.012). Contamination rates by the pharmacist (p = 1.0) and technician (p = 1.0) did not significantly differ between sites. CONCLUSION: The most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in which the drugs were compounded.

Asepsis↗
PubMed2005

Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice.

Numerous stimulatory growth factors that can influence muscle regeneration are known. Recently, it has been demonstrated that neutralization of muscle growth inhibitory factors, such as myostatin (Mstn; also known as growth differentiation factor 8, Gdf8), also leads to increased muscle regeneration in mdx mice that are known to have cycles of degeneration. However, the precise mechanism by which Mstn regulates muscle regeneration has not yet been fully determined. To investigate the role of Mstn in adult skeletal muscle regeneration, wild-type and myostatin-null (Mstn-/-) mice were injured with notexin. Forty-eight hours after injury, accelerated migration and enhanced accretion of myogenic cells (MyoD1+) and macrophages (Mac-1+) was observed at the site of regeneration in Mstn-/- muscle as compared with wild-type muscle. Inflammatory cell numbers decreased more rapidly in the Mstn-/- muscle, indicating that the whole process of inflammatory cell response is accelerated in Mstn-/- mice. Consistent with this result, the addition of recombinant Mstn reduced the activation of satellite cells (SCs) and chemotactic movements of both myoblasts and macrophages ex vivo. Examination of regenerated muscle (28 days after injury) also revealed that Mstn-/- mice showed increased expression of decorin mRNA, reduced fibrosis and improved healing as compared with wild-type mice. On the basis of these results, we propose that Mstn negatively regulates muscle regeneration not only by controlling SC activation but also by regulating the migration of myoblasts and macrophages to the site of injury. Thus, antagonists of Mstn could potentially be useful as pharmacological agents for the treatment of disorders of overt degeneration and regeneration.

Animals↗
PubMed2005

Proteolytic processing of myostatin is auto-regulated during myogenesis.

Myostatin, a potent negative regulator of myogenesis, is proteolytically processed by furin proteases into active mature myostatin before secretion from myoblasts. Here, we show that mature myostatin auto-regulates its processing during myogenesis. In a cell culture model of myogenesis, Northern blot analysis revealed no appreciable change in myostatin mRNA levels between proliferating myoblasts and differentiated myotubes. However, Western blot analysis confirmed a relative reduction in myostatin processing and secretion by differentiated myotubes as compared to proliferating myoblasts. Furthermore, in vivo results demonstrate a lower level of myostatin processing during fetal muscle development when compared to postnatal adult muscle. Consequently, high levels of circulatory mature myostatin were detected in postnatal serum, while fetal circulatory myostatin levels were undetectable. Since Furin proteases are important for proteolytically processing members of the TGF-beta superfamily, we therefore investigated the ability of myostatin to control the transcription of furin and auto-regulate the extent of its processing. Transfection experiments indicate that mature myostatin indeed regulates furin protease promoter activity. Based on these results, we propose a mechanism whereby myostatin negatively regulates its proteolytic processing during fetal development, ultimately facilitating the differentiation of myoblasts by controlling both furin protease gene expression and subsequent active concentrations of mature myostatin peptide.

Animals↗
PubMed2005

Soil-transmitted helminth infection, skin infection, anaemia, and growth retardation in schoolchildren of Taveuni Island, Fiji.

AIM: To estimate the prevalence of hookworm, ascaris, and trichuris infection; as well as anaemia, growth retardation, scabies, and impetigo; in schoolchildren of Taveuni Island, Fiji. METHODS: Schoolchildren from five villages on Taveuni Island were examined and had their haemoglobin concentration measured on a finger-prick blood sample. In addition, they had a faecal sample examined for the presence of helminth ova. RESULTS: 258 children aged 5-15 years were surveyed. The overall prevalence of infection was: hookworm 14%, ascaris 33%, trichuris 17%, scabies 32%, and impetigo 2%. Eight percent of children were anaemic, while 8% and 6% of children were on or below the third centile for weight and height respectively. CONCLUSIONS: The relatively low overall prevalence of hookworm infection and of anaemia suggests that regular anthelminthic treatment of schoolchildren would only provide modest health benefits. Further study is needed to identify the reasons why Taveuni Island schoolchildren weigh less than expected for their age.

Adolescent↗
PubMed2005

Deprivation and dialysis: pathways to kidney failure in Australian Aborigines.

Rates of end-stage renal disease among Australian Aboriginal people have been increasing over the past 2 decades, particularly in the northern and more remote areas of Australia, and especially in disadvantaged communities. Proteinuria predicts the rate of loss of kidney function; it is common in young adults and virtually universal in those over 50 years of age. Cumulative independent risk factors include low birth weight, recurrent skin infections, adult obesity, diabetes or its precursors, smoking, excessive alcohol intake, and a family history of renal disease. A plausible theory is that intrauterine malnutrition permanently reduces total nephron numbers, which are then overworked in adulthood by the metabolic stresses of obesity (from excess alcohol and poor diet), by higher blood pressures, and by infections, while starved of blood supply because of smoking. Although kidney disease is often only detected when already well established, active medical intervention offers great rewards. Control of blood pressure (preferentially using angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (AIIRBs) in combination) can often stop or even reverse kidney damage, even if ongoing diabetes control is poor. Adequately funded kidney health programs with active Aboriginal health worker involvement are enormously cost-effective: tight blood pressure control at least halves the rate of disease progression, and every year of dialysis deferred for 1 patient could fund the appointment of 2 health workers. Addressing the underlying social causes for this epidemic is critical.

Australia↗
PubMed2005

Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: a matched control study.

BACKGROUND: Liver transplant recipients are at high risk for multi-drug resistant infections because of broad-spectrum antibiotic and immunosuppression. This study evaluates the clinical and financial impact of vancomycin resistant Enterococcus (VRE) in liver transplant recipients. METHODS: Liver transplant recipients with VRE from 1995 to 2002 were identified and matched (age, gender, UNOS status, liver disease and transplant date) to controls. Demographics, clinical factors, co-infections, antibiotic use, length of stay, abdominal surgeries, biliary complications, survival and resource utilization were compared with matched controls. RESULTS: Nineteen patients were found to have 28 VRE infections via evaluation of microbiologic culture results of all liver transplant patients in the transplant registry. Thirty-eight non-VRE patients served as matched controls. The four most common sites VRE was cultured from included blood (35%), peritoneal fluid (35%), bile (20%), and urine (12%). Median time from transplant to infection was 48 d (range of 4-348). No significant differences in demographics were observed. The VRE group had a higher incidence of prior antibiotic use than the non-VRE group (95% vs. 34%; p < 0.05). The VRE group also experienced more abdominal surgery (20/19 vs. 3/38; p = 0.029), biliary complications (9/19 vs. 9/38; p = 0.018) and a longer length of stay (42.5 vs. 21.7 d; p = .005). Survival in the VRE group was lower (52% vs. 82%; p = 0.048). Six of the 19 VRE patients were treated with linezolid for eight infection episodes, and four of six patients survived. Eight patients were treated with quinupristin/dalfopristin for nine infections, and two of eight survived. Increased cost of care was observed in the VRE group. Laboratory costs were higher in the VRE group (6500 dollars vs. 1750; p = 0.02) as well. CONCLUSION: VRE was associated with prior antibiotic use, multiple abdominal surgeries, biliary complications and resulted in decreased survival compared to non-VRE control patients. VRE patients also utilized more hospital resources. Linezolid showed a trend toward improved survival.

Enterococcus↗
PubMed2005

Involvement of streptococcal mitogenic exotoxin Z in streptococcal toxic shock syndrome.

We report a nonfatal case of streptococcal toxic shock syndrome (STSS) caused by a Streptococcus pyogenes emm118 strain encoding a novel variant of streptococcal mitogenic exotoxin Z (SMEZ-34). This variant was responsible for the major mitogenic activity in the cell culture supernatant. Patient sera showed seroconversion toward SMEZ, implying a role for this toxin in STSS.

Adult↗
PubMed2005

Patients' perception of military doctors in fracture clinics--does the wearing of uniform make a difference?

We performed a study during our Trauma Week when patients who were referred from the accident department with fractures were reviewed in our fracture clinic. During our Trauma Week, Mister Thomas, Consultant Orthopaedic and Trauma Surgeon or Surgeon Lieutenant Commander McLean, Specialist Registrar in Orthopaedic and Trauma Surgery reviewed a total of 93 patients in fracture clinic. All patients were given an anonymous questionnaire regarding their perceptions of their attending clinician, 77 were completed. Forty-nine questionnaires regarding Surgeon Lieutenant Commander McLean and 28 regarding Mister Thomas were available for analysis. During the Trauma Week all patients were seen in the same location in identical cubicles by either of the two clinicians, consultations were typically brief lasting about five minutes. Throughout the week the clinicians, one military and one civilian, wore differing attire. The military uniform comprised Royal Navy number four action working dress. The civilian attire comprised 'dog-robbers' (jacket, shirt with tie and smart trousers). The hypothesis tested was that the use of military uniform might alter patients' perceptions of their attending clinician. Our results appear to demonstrate that the attire of the attending clinician does not adversely influence patients' perceptions of their attending clinician.

Adolescent↗
PubMed2004

National survey of palliative care in end-stage renal disease in the UK.

BACKGROUND: Palliative care for patients with end-stage renal disease (ESRD) is a neglected aspect of nephrology. We carried out this survey to establish the current pattern of provision of palliative care for ESRD in the UK. METHODS: An anonymous but numbered questionnaire concerning local palliative care provision was sent to clinical directors of all 69 UK renal units. RESULTS: All the questionnaires were returned. Only 27 (39%) units employ nursing or Professions Allied to Medicine (PAM) staff with palliative care for ESRD patients as a specified part of their role. In 19 of these units, staff spend <4 h per week concerned with palliative care and only five units have staff working for >12 h a week in this role. Fifty-five (80%) units do not have a written protocol for palliative care. Anaemic ESRD patients with an expected survival of >3 months receive blood transfusion in 59 (86%) units, intravenous iron in 61 (88%) units and erythropoietin in 63 (91%) units. Only 37 (54%) units kept a record of patients seen by the unit staff but deemed not suitable for dialysis. CONCLUSION: There is a significant variation in provision of palliative care services across the UK. In some areas, access to palliative care is restricted to patients with malignant disease, and ESRD patients are excluded.

Anemia↗