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Biomedical subjects

A Blackburn

Publications and source records attributed to A Blackburn.

At least 19 recordsLinked to original sources
PubMed2006

Perinuclear localisation of cellular retinoic acid binding protein I mRNA.

Retinoids are important metabolic and developmental regulators that act through nuclear receptors. The cellular retinoic acid binding protein CRABPI has been suggested to play a role in trafficking of retinoic acid but its exact functions and subcellular localisation remain unclear. Here we show that in CHO cells both exogenous CRABPI transcripts and tagged CRABPI protein have a perinuclear distribution that depends upon the 3'UTR of the mRNA. The CRABPI 3'UTR conferred perinuclear localisation on globin reporter transcripts. Deletion analysis indicated that the first 123nt of CRABPI 3'UTR are necessary for localisation of both CRABPI mRNA and protein. We propose that CRABPI mRNA is localised by a signal within its 3'UTR and that this partly determines the distribution of CRABPI protein.

3' Untranslated Regions↗
PubMed2001

Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer.

PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 10(11) particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication > or = 22 days after injection. CONCLUSION: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.

Adenovirus E1B Proteins↗
PubMed2001

Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity.

Although genetically engineered adenoviruses hold promise for the treatment of cancer, clinical trial reports have utilized intratumoral injection to date. To determine the feasibility of intravenous delivery of ONYX-015, an E1B-55kD gene-deleted replication selective adenovirus with demonstrated clinical safety and antitumoral activity following intratumoral injection, we performed a clinical trial in patients with metastatic solid tumors. ONYX-015 was infused intravenously at escalating doses of 2 x 10(10) to 2 x 10(13) particles via weekly infusion within 21-day cycles in 10 patients with advanced carcinoma metastatic to the lung. No dose-limiting toxicity was identified. Mild to moderate fever, rigors and a dose-dependent transient transaminitis were the most common adverse events. Neutralizing antibody titers significantly increased within 3 weeks in all patients. IL-6, gamma-IFN, TNF-alpha and IL-10 increased within 24 h following treatment. Evidence of viral replication was detectable in three of four patients receiving ONYX-015 at doses > or = 2 x 10(12) particles and intratumoral replication was confirmed in one patient. In conclusion, intravenous infusion of ONYX-015 was well tolerated at doses up to 2 x 10(13) particles and infection of metastatic pulmonary sites with subsequent intratumoral viral replication was seen. The intravenous administration of genetically altered adenovirus is a feasible approach.

Adenocarcinoma↗
PubMed2001

Trends over time in the management of subarachnoid haemorrhage in newcastle: review of 1609 patients.

This article reviews trends in the management of subarachnoid haemorrhage (SAH) at the Regional Neurosurgery Unit in Newcastle over 9 years. This is a comprehensive analysis of prospectively collected data on patients with SAH. We review the changes in clinical therapy and outcome with regards to conservative (non-surgical), surgical and endovascular therapy. Since 1990, the demographic and management/outcome details of patients with SAH have been recorded systematically. This study involves patients admitted over the 9 years, from January 1990 to December 1998. The data were computerized using Microsoft Access (Microsoft Inc. USA), and analysed using SPSS statistical package. A total of 1609 had aneurysmal SAH confirmed with CT, lumbar puncture and/or angiography. Sixty-seven per cent (1,073 patients) were female with a female to male ratio of 2:1. This ratio was maintained from 1990 to date. The mean age has slowly increased from 49 years in 1990 to 55 years of age in 1998, (range 18-91). Overall, 53.9% (from 66.3% in 1990 to 35.3% in 1998) were surgically treated, 8.1% had embolization (range 0.6-18.4%) and 38% (range 28.2-46.4%) were managed without surgical intervention for the aneurysm. The proportion of patients undergoing surgery has decreased since 1994 with improvements in endovascular therapy, participation in the ISAT trial and increased admission of poor grade patients (WFNS grades 4 and 5, from 17% in 1990 to 31% in 1998). The mortality rate has doubled over the years under review (18-32%). The percentage of severely disabled patients has remained constant at about 7% with none in a vegetative state. Only 54% had a favourable outcome in 1998 compared with 78% in 1990. Total morbidity and mortality has increased particularly during the last 3 years. This has been associated with double the number of admissions in grade 5. Favourable outcome occurred in 90% of good grade patients (WFNS 1 and 2) with 6.2% mortality in surgical candidates and 5.5% in patients treated endovascularly. The mortality for poor grade (WFNS 4 and 5) patients was 64%.

Adolescent↗
PubMed2000

The selectin superfamily: the role of selectin adhesion molecules in delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage.

Cerebral ischaemia and reperfusion injury may be exacerbated by leukocyte recruitment and activation. Adhesion molecules play a pivotal role in leukocyte recruitment. We report a prospective study of the potential role of the selectin family of adhesion molecules (E-, P- and L-selectin) in delayed cerebral ischaemia (DID) following aneurysmal subarachnoid haemorrhage. In patients with good grade SAH, we have compared serum concentrations of E-, P- and L-selectin, between patients who do, and do not develop delayed cerebral ischaemia. There was no difference in E-selectin concentration between the two groups (44.0 ng/ml vs. 37.4 ng/ml). Serum P-selectin concentration was significantly higher in patients with DID compared to those patients without DID (149.5 ng/ml vs. 112.9 ng/ml, p = 0.039). Serum L-selectin concentrations were significantly lower in patients with DID (633.8 ng/ml vs 897.9 ng/ml, p = 0.013). We conclude that P- and L-selectin are involved in the pathogenesis of DID following aneurysmal subarachnoid haemorrhage. The results of this study do not elucidate the exact role of each selectin in DID.

Brain↗
PubMed2000

Database analysis and gene discovery in pharmacogenetics.

The global genome research effort has resulted in the creation of extensive DNA and protein sequence databases that are a valuable resource for the identification of new genes and polymorphic variants of enzymes of pharmacogenetic interest. Previously undescribed members of gene families with novel functions and substrate specificities can be identified by database searching and sequence alignment strategies. Since the expressed sequence tag (EST) database contains sequences from many individuals, it can be searched for evidence of polymorphisms that can significantly influence enzyme function. The different approaches to these forms of analysis are reviewed and illustrated with examples from the glutathione transferase gene family.

Animals↗
PubMed2000

Acyl-CoA dehydrogenase activity in pea cotyledon tissue during germination and initial growth.

Acyl-CoA dehydrogenase activity has been measured in homogenates of post-imbibition to 14-day-old hydroponically grown pea seeds at daily intervals, using C(4), C(12) and C(16) acyl-CoA substrates. The activity peaks of the different chain-length acyl-CoA dehydrogenases did not transpose at all points and the ratios of the chain-length activities were not constant. It therefore has to be concluded that more than one dehydrogenase is present in pea mitochondria. There was a post-imbibition initial surge of activity with short- and mid-chain-length substrates. The C(16)-handling enzyme first peaked at 3-4 days, which coincided with the onset of plumule unfurling and greening. Further peaks were observed with all three substrates, coinciding with secondary root formation and leaf enlargement and later with cotyledon degeneration. Overall activity showed that the long-chain acyl-CoA dehydrogenase was much more active than the short-chain acyl-CoA dehydrogenase.

Acyl-CoA Dehydrogenase↗
PubMed1998

Polymorphism of phase II enzymes: identification of new enzymes and polymorphic variants by database analysis.

The Phase II enzymes of xenobiotic metabolism are characterized by a high level of substrate diversity and genetic polymorphism. Genetic polymorphism of the Phase II enzymes can be of substantial clinical significance as some variants have differences in substrate specificity, stability and levels of expression. Variation in these factors can give rise to abnormal drug metabolism and susceptibility to carcinogens and toxins. A new approach to the discovery of additional members of Phase II enzyme families and the identification of polymorphic variants using searches of the EST databases has been investigated. The examples provided demonstrate that relatively simple search strategies can be highly productive.

Amino Acid Sequence↗
PubMed1998

Aminopyrimidines with high affinity for both serotonin and dopamine receptors.

A series of [4-[2(4-arylpiperazin-1-yl)alkyl]cyclohexyl]pyrimidin-2-ylamine s was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.

Animals↗
PubMed1997

Relationship of polymorphisms in the renin-angiotensin system and in E-selectin of patients with early severe coronary heart disease.

Previous association studies between angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) polymorphisms and several cardiovascular diseases have reported variable results. Therefore we examined the association of the DNA variants of ACE and AGT with early, severe coronary heart disease (CHD). In addition, we compared the genotypes of both polymorphisms and the recently discovered polymorphism in the E-selectin gene in both patients and an unselected population. This study included 113 patients with severe CHD (50 years old or less) and up to 197 control subjects. The frequencies of the ACE I/D variants were 48% I and 52% D in the controls and 46% I and 54% D in the patients. The frequencies of the AGT-M235T polymorphism were 60.8% M and 39.2% T in controls and 49.1% M and 50.9% T in the patients. The frequencies of the S128R polymorphism of the E-selectin were 91.3% S and 8.7% R in controls and 84.5% S and 15.5% R in the patients. In our studies the DD genotype of ACE was not associated with early severe CHD. We found a correlation between the M235T molecular variant of AGT and the S128R variant of E-selectin to early severe CHD.

Adult↗
PubMed1997

Actions and interactions of growth hormone and insulin-like growth factor-II: body and organ growth of transgenic mice.

To characterize long-term actions and interactions of growth hormone (GH) and insulin-like growth factor-II (IGF-II) on postnatal body and organ growth, hemizygous phosphoenolpyruvate carboxykinase (PEPCK)-human IGF-II transgenic mice were crossed with hemizygous PEPCK-bovine GH transgenic mice. The latter are characterized by two-fold increased serum levels of IGF-I and exhibit markedly increased body, skeletal and organ growth. Four different genetic groups were obtained: mice harbouring the IGF-II transgene (I), the bGH transgene (B), or both transgenes (IB), and non-transgenic controls (C). These groups of mice have previously been studied for circulating IGF-I levels (Wolf et al., 1995a), whereas the present study deals with body and organ growth. Growth curves (week 3 to 12) were estimated by regression with linear and quadratic components of age on body weight and exhibited significantly (p < 0.001) greater linear coefficients in B and IB than in I and C mice. The linear coefficients of male I and C mice were significantly (p < 0.001) greater than those of their female counterparts, whereas this sex-related difference was absent in the bGH transgenic groups. The weights of internal organs as well as the weights of abdominal fat, skin and carcass were recorded from 3.5- to 8-month-old mice. In addition, organ weight-to-body weight-ratios (relative organ weights) were calculated. Except for the weight of abdominal fat, absolute organ weights were as a rule significantly greater in B and IB than in I and C mice. IGF-II overproduction as a tendency increased the weights of kidneys, adrenal glands, pancreas and uterus both in the absence and presence of the bGH transgene. Analysis of relative organ weights demonstrated significant (p < 0.05) effects of elevated IGF-II on the relative growth of kidneys (males and females) and adrenal glands (females), confirming our previous report on organ growth of PEPCK-IGF-II transgenic mice. In females, IGF-II and GH overproduction were additive in stimulating the growth of spleen and uterus, providing evidence for tissue-specific postnatal growth promoting effects by IGF-II in the presence of elevated IGF-I.

Abdomen↗
PubMed1997

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice.

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

Animals↗
PubMed1996

Clinical observations with real timing.

This article describes the hemodynamic effects of IABC therapy on patients supported with real timing. Criteria used to assess "proper" timing are discussed and challenged as they relate to the limited research available on the subject and to the cases in this article. It is important that clinicians who time the IAB consoles and assess therapeutic benefit of this therapy are aware of the different timing modalities and their potential benefits or ill effects in certain patient populations. The observations made by the authors strongly suggest the need for clinical research, case reports, and further evidence of valid assessment criteria to develop a research-based theory for practice of IABC timing and to provide criteria for selecting timing modalities for specific patient populations.

Adult↗
PubMed1995

Balanced analgesia with intravenous ketorolac and patient-controlled morphine following lower abdominal surgery.

STUDY OBJECTIVE: To investigate the efficacy, opioid-sparing effects and any reduction in adverse events of a continuous intravenous (i.v.) infusion of ketorolac following lower abdominal surgery. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Inpatient elective gynecologic surgical patients. PATIENTS: 60 ASA physical status I or II patients aged 18 to 70 years scheduled for elective abdominal hysterectomy. INTERVENTIONS: Following standardized preparation and anesthesia, continuous i.v. infusions of either ketorolac or placebo were administered for 24 hours postoperatively with a patients' standardized postoperative protocol. Supplementary analgesia was administered by an i.v. patient-controlled analgesia (PCA) system. MEASUREMENTS AND MAIN RESULTS: A significantly lower proportion of the patients in the ketorolac group (6%) rated their pain at 24 hours as moderate or severe compared with patients in the placebo group (34%) (p = 0.04). Mean 24-hour morphine consumption was significantly lower in the ketorolac group (43 mg; SEM 5 mg) compared with the placebo group (55 mg SEM 5 mg) (p = 0.02). There was no significant difference in the incidence of postoperative hypoxemia between the groups with respect to mean times per hour spent with oxygen saturation (SPO2) less than 85%, more than 85% but less than 90%, or more than 90% but less than 94%, mean hourly SPO2, or the incidence and duration of severe hypoxemic episodes. Nausea and vomiting were the only significant adverse events, and they occurred in 30% of patients in both groups. CONCLUSION: Intravenous infusion of ketorolac combined with morphine delivered via a PCA device would appear to be a valuable method of providing balanced analgesia following lower abdominal surgery.

Adolescent↗
PubMed1995

Arterial and jugular venous bulb blood propofol concentrations during induction of anesthesia.

The aim of this study was to show that blood propofol concentrations at loss of consciousness vary with the rate of administration. Eighteen patients were allocated to receive a propofol infusion at 6 or 12 mg.kg-1.h-1 (approximately 8 and 15 mg/min) for induction of anesthesia. Propofol concentrations were analyzed from simultaneous arterial and jugular bulb venous blood samples. There were no significant differences in the dose of propofol administered to induce anesthesia (0.52 mg/kg both groups). However there were significant differences between the groups in the mean induction times (309 and 156 s), and in median arterial and venous concentrations at induction. Arterial concentrations were 1.93 and 2.70 and venous 1.11 and 1.51 micrograms/mL. There were no significant differences between the groups in the area between the arterial and venous time concentration curves from start of infusion to loss of consciousness (3.14 and 3.05 micrograms.mL-1.min-1). This study confirms that a target blood concentration of propofol cannot be identified with loss of consciousness under nonsteady state conditions. Both arterial and venous blood propofol concentrations at loss of consciousness depend on the rate of administration.

Anesthesia↗
PubMed1995

Can we judge the strength of a drink?

Using the method of direct magnitude estimation, ten subjects each judged by taste the strength of ten rum/water mixtures; these ranged from 10% to 100% rum. Mean judgements of the concentration of rum were highly accurate (r = .99) and showed no tendency towards underestimation or overestimation at any concentration.

Alcohol Drinking↗