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Biomedical subjects

Mark Thomas

Publications and source records attributed to Mark Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2004

Prevention of group B meningococcal disease by vaccination: a difficult task.

New Zealand has embarked on an immunisation program to reduce the incidence of disease caused by serogroup B Neisseria meningitidis. Similar immunisation programs in Norway and South America have shown good efficacy in older vaccinees (ie, persons receiving vaccinations), but variable efficacy in younger vaccinees. Protective efficacy correlates well with the ability of the vaccine to stimulate a fourfold rise in serum bactericidal antibodies. Unfortunately, second and third doses of serogroup B N. meningitidis vaccines do not boost serum bactericidal antibody titres to very high levels; consequently protective efficacy wanes within a few years of immunisation. The overall outcome of the immunisation program will reflect both the immunogenicity of the vaccine and the uptake of the vaccine by the target population. The especially high incidence of meningococcal disease in Pacific and Maori children means that particular efforts will need to be made to reach these groups.

Disease Outbreaks↗
PubMed2004

Molecular analysis of fiber type-specific expression of murine myostatin promoter.

Myostatin is a negative regulator of muscle growth, and absence of the functional myostatin protein leads to the heavy muscle phenotype in both mouse and cattle. Although the role of myostatin in controlling muscle mass is established, little is known of the mechanisms regulating the expression of the myostatin gene. In this study, we have characterized the murine myostatin promoter in vivo. Various constructs of the murine myostatin promoter were injected into the quadriceps muscle of mice, and the reporter luciferase activity was analyzed. The results indicate that of the seven E-boxes present in the 2.5-kb fragment of the murine myostatin promoter, the E5 E-box plays an important role in the regulation of promoter activity in vivo. Furthermore, the in vitro studies demonstrated that MyoD preferentially binds and upregulates the murine myostatin promoter activity. We also analyzed the activity of the bovine and murine promoters in murine skeletal muscle and showed that, despite displaying comparable levels of activity in murine myoblast cultures, bovine myostatin promoter activity is much weaker than murine myostatin promoter in mice. Finally, we demonstrate that in vivo, the 2.5-kb region of the murine myostatin promoter is sufficient to drive the activity of the reporter gene in a fiber type-specific manner.

Animals↗
PubMed2004

2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.

Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.

Aniline Compounds↗
PubMed2004

Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway.

Rhabdomyosarcoma (RMS) tumors are the most common soft-tissue sarcomas in childhood. In this investigation, we show that myostatin, a skeletal muscle-specific inhibitor of growth and differentiation is expressed and translated in the cultured RMS cell line, RD. The addition of exogenous recombinant myostatin inhibits the proliferation of RD cells cultured in growth media, consistent with the role of myostatin in normal myoblast proliferation inhibition. However, unlike normal myoblasts, upregulation of p21 was not observed. Rather, myostatin signalling resulted in the specific downregulation of both Cdk2 and its cognate partner, cyclin-E. The analysis of Rb reveals that there was no change in its phosphorylation status with myostatin treatment, consistent with D-type-cyclin-Cdk4/6 complexes being active in the absence of p21. Moreover, the activity of Rb appeared to be unchanged between treated and nontreated RD cells, as determined by the ability of Rb to bind E2F1. The examination of NPAT, a substrate of cyclin-E-Cdk2 involved in the transcriptional activation of replication-dependent histone gene expression, revealed that it undergoes a loss of phosphorylation with myostatin treatment. Supporting this, a downregulation in H4-histone gene expression was observed. These results suggest that myostatin could potentially be used as an inhibitor of RMS proliferation and define a previously uncharacterized, Rb-independent mechanism for the inhibition of muscle precursor cell proliferation by myostatin.

CDC2-CDC28 Kinases↗
PubMed2004

Subcutaneous black fungus (phaeohyphomycosis) infection in renal transplant recipients:three cases.

We describe three cases of subcutaneous phaeohyphomycosis developing in the lower limbs of renal transplant recipients shortly after transplantation. Each case presented with dark-colored nodules that subsequently ulcerated. Histopathologic examination revealed dematiaceous fungal hyphae with a surrounding granulomatous reaction. The fungi were subsequently identified as Alternaria alternatum in two cases and Phialophora richardsiae in one case. In one case, the lesions resolved during a prolonged (6-month) course of itraconazole without the requirement for surgical excision. In the other two cases, combined medical and surgical treatment resulted in cure. A review of the literature on phaeohyphomycosis is presented.

Aged↗
PubMed2004

Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors.

A number of selective inhibitors of the CDK4/cyclin D1 complex have been reported recently. Due to the absence of an experimental CDK4 structure, the ligand and protein determinants contributing to CDK4 selectivity are poorly understood at present. Here, we report the use of computational methods to elucidate the characteristics of selectivity and to derive the structural basis for specific, high-affinity binding of inhibitors to the CDK4 active site. From these data, the hypothesis emerged that appropriate incorporation of an ionizable function into a CDK2 inhibitor results in more favorable binding to CDK4. This knowledge was applied to the design of compounds in the otherwise CDK2-selective 2-anilino-4-(thiazol-5-yl)pyrimidine pharmacophore that are potent and highly selective ATP antagonists of CDK4/cyclin D1. The findings of this study also have significant implications in the design of CDK4 mimic structures based on CDK2.

Adenosine Triphosphate↗
PubMed2004

Mate Aaraikore A Muri Ake Nei: experiences of Maori New Zealanders living with HIV.

BACKGROUND: This paper is drawn from the first comprehensive study in New Zealand of the health and social experiences of HIV positive people and specifically addresses the experiences of HIV positive Maori. METHODS: A total of 226 HIV positive men and women completed an anonymous, self-administered HIV Futures New Zealand questionnaire. Twenty-five Maori completed the survey (17 male, 7 female, 1 transgendered). The majority identified as takataapui (Maori and homosexual) five were heterosexual women, and four identified with other sexualities. RESULTS: Seven respondents indicated that they had received pre-test counselling, and 18 that they had received post-test counselling. The mean CD4 count at most recent test was 462.4 cells/microL. The mean HIV viral load result at most recent test was 558.1 copies/mL. Two-thirds of respondents were currently using antiretroviral treatments, and half had taken a break from them. The most commonly cited source of social support was their doctor. Eight respondents were in full-time work; most received benefits or a pension as their main income source; five were living below the poverty line. Only two respondents did not personally know another person with HIV. All had disclosed their status to someone; fifteen said that unwanted disclosure had occurred. Eight reported experiencing discrimination concerning accommodation, nine in a medical setting and seven in relation to employment. CONCLUSIONS: Maori people in New Zealand have access to a comprehensive health care system, nonetheless it is of concern that a number report discrimination and unwanted disclosure of their HIV status, most particularly within health care settings.

Adult↗
PubMed2004

Gram-negative bacillary meningitis after cranial surgery or trauma in adults.

In order to assess the clinical features, aetiology, treatment and outcome of post-neurosurgical and post-traumatic Gram-negative bacillary meningitis (GNBM) we performed a retrospective review of all adult patients admitted to the Department of Neurosurgery who had Gram-negative bacilli cultured from cerebrospinal fluid (CSF) following a neurosurgical procedure or traumatic head/spinal injury. During the 12 y of the review 33 patients had CSF isolates of Gram-negative bacilli that were thought to be significant. The median patient age was 47 y (range 22-77 y) and 21 (64%) were male. Klebsiella pneumoniae, Enterobacter cloacae and Escherichia coli were the most common isolates. Minimal inhibitory concentrations (MIC) measured for half the patients' isolates resulted in 5 regimen changes, including 2 patients with E. cloacae meningitis in whom cephalosporin susceptibility decreased during cephalosporin treatment. Our recommended initial treatment was intravenous ceftriaxone and amikacin, subsequently tailored by susceptibility results; approximately half the patients remained on the antibiotics they started and half were changed to an alternate regimen, most often a carbapenem. Five patients (15%) died, 1 dying after cure of his GNBM. There were no failures in those who received more than 12 d of appropriate treatment: treatment for at least 14 d after the last positive CSF culture guaranteed cure. Initial ceftriaxone and amikacin subsequently changing to susceptibility driven alternatives, often a carbapenem, resulted in cure of 85% of our patients with GNBM.

Adult↗
PubMed2004

Antecedents of renal disease in Aborigines.

Rates of end-stage renal disease in the Aboriginal community have been increasing over the past two decades, particularly in the northern and more remote areas of Australia, and especially in disadvantaged communities. Proteinuria predicts the rate of loss of renal function and is common in young adults and virtually universal in those over 50 years old. Cumulative independent risk factors include low birthweight, 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), blood pressure and infections, while starved of blood supply through smoking. Although renal disease is often only detected when already established, there are great rewards for active medical intervention. Control of blood pressure (preferentially using angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (AIIRB) in combination) can often stop or even reverse kidney damage, despite ongoing poor diabetic control. Adequately funded kidney health programmes 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 one patient could fund the appointment of two more health workers. Addressing the underlying social causes for this epidemic is critical.

Australia↗
PubMed2003

Prediction of outcome from the chest radiograph appearance on day 7 of very prematurely born infants.

UNLABELLED: Our aim was to determine whether the chest radiograph appearance at 7 days predicted chronic lung disease development (oxygen dependency at 36 weeks post-menstrual age) or death before discharge and if it was a better predictor than readily available clinical data. Two consecutive studies were performed. In both, chest radiographs taken at 7 days for clinical purposes were assessed using a scoring system for the presence of fibrosis/interstitial shadows, cystic elements and hyperinflation and data were collected regarding gestational age, birth weight, use of antenatal steroids and post-natal surfactant and requirement for ventilation at 7 days. Oxygenation indices were calculated in the first study (study A) at 120 h and in the second (study B) at 168 h. In study A, there were 59 infants with a median gestational age of 26 weeks (range 24 to 28 weeks) and in study B, 40 infants with a median gestational age of 27 weeks (range 25-31 weeks). In both studies, infants who developed chronic lung disease had a significantly higher total chest radiograph score, with a higher score for fibrosis/interstitial shadowing than the rest of the cohort. Infants who died before discharge differed significantly from the rest with regard to significantly higher scores for cysts. In both studies, the areas under the receiver operator characteristic curves with regard to prediction of chronic lung disease were higher for the total chest radiograph score compared to those for readily available clinical data. CONCLUSION: In infants who require a chest radiograph for clinical purposes at 7 days, the chest radiograph appearance can facilitate prediction of outcome of infants born very prematurely.

Chronic Disease↗
PubMed2003

Myostatin negatively regulates satellite cell activation and self-renewal.

Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Here we show that myostatin, a TGF-beta member, signals satellite cell quiescence and also negatively regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher numbers of satellite cells are activated as compared with wild type. In contrast, addition of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle analysis confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin negatively regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochemical analysis with CD34 antibodies indicates that there is an increased number of satellite cells per unit length of freshly isolated Mstn-/- muscle fibers. Determination of proliferation rate suggests that this elevation in satellite cell number could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn-/- adult myoblasts. Taken together, these results suggest that Myostatin is a potent negative regulator of satellite cell activation and thus signals the quiescence of satellite cells.

Animals↗
PubMed2003

Three days of intravenous benzyl penicillin treatment of meningococcal disease in adults.

New Zealand has experienced an epidemic of predominantly serogroup B meningococcal disease during the past decade. In a prospective study, we treated adults (age, >15 years) with meningococcal disease with intravenous benzyl penicillin (12 MU [7.2 g] per day) for 3 days. Sixty-one adults with suspected meningococcal disease were consecutively admitted during the 33-month period; 3 patients were excluded. The 58 patients had a mean age (+/- standard deviation [SD]) of 27.9+/-14.5 years (median, 21 years; range, 15-70 years). Forty-four patients had confirmed and 14 patients had probable meningococcal disease. Fifty-seven patients received 12 MU (7.2 g) and 1 received 8 MU (4.8 g) of benzyl penicillin per day. Thirteen patients received additional antibiotics within the first 24 h because of diagnostic uncertainties. Patients received a mean (+/-SD) of 3.0+/-0.5 days of treatment. No patients relapsed. Five patients died. All but 1 death occurred during benzyl penicillin treatment, and the only posttreatment death was not due to meningococcal disease. Three days of intravenous benzyl penicillin is sufficient treatment for adults with meningococcal disease. The usual recommendations for duration of treatment are excessive.

Adolescent↗
PubMed2003

Symptom complaints following aerial spraying with biological insecticide Foray 48B.

AIM: To investigate the effect of aerial Bacillus thuringiensis (Foray 48B) spraying on self-reported symptom complaints, health perceptions, and visits to healthcare providers. METHODS: Two hundred and ninety two residents within the Ministry of Agriculture and Forestry (MAF) West Auckland spray zone were recruited by a door-to-door survey of homes within the most intensively sprayed area ten weeks prior to the first aerial spraying. Participants completed a symptom checklist and a questionnaire measuring health perceptions. Three months after the start of spraying, 181 (62%) of the original participants responded to a similar postal questionnaire. Symptom reports, health perceptions and visits to healthcare providers were compared between the baseline and the follow-up questionnaire. Rates of symptom complaints in respondents with previously diagnosed asthma, hay fever, or other allergies were compared to those in respondents without these prior health conditions. RESULTS: Symptom complaints increased significantly following the aerial spraying, in particular: sleep problems, dizziness, difficulty concentrating, irritated throat, itchy nose, diarrhoea, stomach discomfort, and gas discomfort. Analyses showed a significant increase in symptoms in those participants with a previous history of hay fever. While overall self-ratings of health decreased following the spraying, most residents saw their health as unaffected by the spray programme, and there was no significant increase in visits to general practitioners or alternative healthcare providers. CONCLUSIONS: Aerial spraying with Foray 48B is associated with some adverse health consequences in terms of significant increases in upper airway, gastrointestinal, and neuropsychiatric symptoms, as well as a reduction in overall perception of health in the exposed population./

Adolescent↗
PubMed2003

Summary: the science of genealogy by genetics.

This summary lays out the basic science and methodology used in genetic testing that investigates historical population migrations and the ancestry of living individuals. The genetic markers used in this testing, and the distinction between Y-chromosome, mitochondrial and autosomes analysis, are explained and the shortcomings of these methodologies are explored.

Anthropology↗
PubMed2002

Prolonged ventilation and intact survival in very low birth weight infants.

UNLABELLED: A requirement for prolonged ventilation (>28 days) has been associated with a poor outcome in infants. We postulated that in the present population of infants who usually receive antenatal steroids and post-natal surfactant, prolonged ventilation in discrete episodes, i.e. discontinuous intermittent positive pressure ventilation (IPPV), would have a better outcome than a requirement for prolonged ventilation continuously from birth (continuous IPPV) and, in addition, that an abnormal ultrasound scan appearance would be a reliable predictor of poor outcome in infants requiring prolonged ventilation. All very low birth weight (VLBW) infants ventilated for at least 28 days (prolonged ventilation) were identified from a prospectively maintained database. At 1 year of age, neurodevelopmental status was assessed and abnormal neurodevelopmental outcome diagnosed if the infant's Griffiths developmental quotient was at least two standard deviations below the mean and/or they had impairment with disability. Of 417 VLBW infants, 41 required prolonged ventilation (30 continuous and 11 discontinuous). In the continuous IPPV group, 18 and one in the discontinuous IPPV group died or had abnormal neurodevelopmental outcome ( P<0.01). All eight infants with major cranial ultrasound abnormalities died or had abnormal outcome ( P<0.01). CONCLUSION: prolonged ventilation can be associated with intact survival, but not in very low birth weight infants with evidence of significant brain injury.

Chi-Square Distribution↗
PubMed2002

Myostatin inhibits myoblast differentiation by down-regulating MyoD expression.

Myostatin, a negative regulator of myogenesis, is shown to function by controlling the proliferation of myoblasts. In this study we show that myostatin is an inhibitor of myoblast differentiation and that this inhibition is mediated through Smad 3. In vitro, increasing concentrations of recombinant mature myostatin reversibly blocked the myogenic differentiation of myoblasts, cultured in low serum media. Western and Northern blot analysis indicated that addition of myostatin to the low serum culture media repressed the levels of MyoD, Myf5, myogenin, and p21 leading to the inhibition of myogenic differentiation. The transient transfection of C(2)C(12) myoblasts with MyoD expressing constructs did not rescue myostatin-inhibited myogenic differentiation. Myostatin signaling specifically induced Smad 3 phosphorylation and increased Smad 3.MyoD association, suggesting that Smad 3 may mediate the myostatin signal by interfering with MyoD activity and expression. Consistent with this, the expression of dominant-negative Smad3 rescued the activity of a MyoD promoter-reporter in C(2)C(12) myoblasts treated with myostatin. Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes. Thus we propose that myostatin plays a critical role in myogenic differentiation and that the muscular hyperplasia and hypertrophy seen in animals that lack functional myostatin is because of deregulated proliferation and differentiation of myoblasts.

Animals↗