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Biomedical subjects

C Hay

Publications and source records attributed to C Hay.

At least 19 recordsLinked to original sources
PubMed2004

Inhibitors in haemophilia: clinical aspects.

Inhibitor development continues to be a severe complication worldwide of haemophilia therapy. Given the difficulties associated with the treatment of inhibitors in both the developed and the developing world, prediction and prevention of inhibitors following exposure to factor VIII or IX in the young child has become a management priority. Two different clinical approaches to minimizing or delaying inhibitor development are highlighted in this manuscript. Challenges in the therapy of existing inhibitors persist. However, the nature of the issues faced by physicians in the developed and developing worlds vary considerably. Both are discussed in this manuscript by representatives of both worlds, who face these challenges on a daily basis.

Blood Coagulation Factors↗
PubMed2001

Phosphole-containing pi-conjugated systems: from model molecules to polymer films on electrodes.

Two series of 2,5-dipyridyl- and 2,5-dithienylphosphole derivatives containing sigma3- or sigma4-P atoms were prepared, and their optical (UV/Vis absorption, fluorescence spectra) and electrochemical properties were systematically evaluated. These physical properties depend mainly on the natures of the 2,5-substituents and of the phosphorus moiety, and they revealed that these compounds contain extended pi-conjugated systems. Structure-property relationships were established on the basis of these experimental data and ab initio calculations on the parent molecules. The limited aromatic character and low-lying LUMO of the phosphole ring appear to be crucial for achieving a highly delocalised pi system. Electrooxidation of 2,5-dithienylphosphole derivatives affords electroactive films with low optical band gaps. As observed for the corresponding monomers, the optical and electrochemical properties of the polymers can be varied over a wide range by modifying the nature of the phosphorus moiety.

Journal Article↗
PubMed2001

Differential cell cycle progression patterns of infiltrating leukocytes and resident cells after balloon injury of the rat carotid artery.

The heterogeneous nature of the cell populations involved in vascular repair remains a major hurdle for the assessment of the cellular events that take place in injured arteries. The present experiments were designed to estimate the proportions and cell cycle progression of infiltrating leukocytes versus resident vascular cells after balloon injury of the rat common carotid artery. After tissue disaggregation, cell suspension samples from each artery were analyzed by flow cytometry. Cells were stained with anti-CD45 or anti-alpha-smooth muscle actin antibodies to identify leukocytes and smooth muscle cells, respectively. A day after injury, a 12-fold increase in CD45+ leukocytes was found. Double labeling with CD45 and CD-3, ED-1, or granulocyte markers revealed that most infiltrating cells were monocytes and granulocytes. Approximately 14% of infiltrating leukocytes were found to enter apoptosis at day 1, and 17% entered S phase at day 3. In contrast, the highest proliferation rate of resident alpha-smooth muscle actin-positive cells was observed at day 7 (19%). The present results demonstrate that infiltrating leukocytes and resident vascular smooth muscle cells have dissimilar cell cycle profiles. Furthermore, our study demonstrates the feasibility of using flow cytometry to quantitatively determine the cell types and their relative activation state in injured arteries.

Animals↗
PubMed2000

Vetting requests for body computed tomography.

The aim of this study was to assess the process and outcome of hospitalised patients (inpatients) for whom whole-body CT was requested but not performed. For 6 months the reasons why CT was not performed were recorded, together with relevant discussions with clinicians. Subsequent referrals for alternative investigations were noted. The eventual outcome of the patients was monitored via the patients' records. Eighty-three (8%) of 1001 inpatient requests were identified for which body CT was not performed after an electronically generated request. Fifty-five requests were not accepted by the radiology department during the vetting process for a variety of reasons (often more than one): criteria used for rejection often overlapped and included referrals outside national guidelines (n = 20), better alternative investigations (n = 29), time constraints (n = 19), over-zealous requests (n = 17) and clinicians' erroneous interpretation of preceding imaging investigations (n = 9). Sixteen CT exams were cancelled by a clinician. An additional 12 exams were not performed for miscellaneous non-medical reasons. In no case could a patient's death be ascribed to CT not being performed. Most (981 of 1001, 98%) CT requests comply with current guidelines, disproving a perception that many radiological referrals are inappropriate. In our health care system radiologists have to turn down some appropriate CT referrals due to a lack of CT capacity. Although lack of CT contributed to delay in diagnosis, no patient died as a direct result of not having CT.

Adolescent↗
PubMed1999

A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma.

Transducing and distributing a vector throughout a tumor mass are presently insufficient for effective cancer gene therapy. To overcome these difficulties an adenoviral vector was designed that would replicate specifically in tumor cells. This tumor-specific replication-restricted adenoviral (TSRRA) vector was constructed by requiring that the essential E1A gene be expressed from a tumor-specific promoter, namely, the alpha-fetoprotein (AFP) gene promoter. This promoter was chosen since the AFP gene is highly expressed in 70-80% of patients with hepatocellular carcinoma (HCC) but not in normal adults. HCC is one of the major worldwide causes of cancer death. A vector was constructed (AvE1a04i) and demonstrated to replicate in human AFP-producing HCC cell lines. However, little replication was observed in seven other, non-AFP-producing human cell lines, as well as primary cultures of normal human lung epithelial and endothelial cells. In addition, AvE1a04i was shown to prevent tumor growth of an ex vivo-transduced AFP-expressing HCC cell line but not a non-AFP-expressing cell line. Finally, in situ administration of AvE1a04i into preestablished tumors resulted in a greater than 50% long-term survival rate. This novel TSRRA vector for HCC demonstrated both specificity and efficacy in vitro and in vivo.

Adenoviruses, Human↗
PubMed1999

Efficient processing of the immunodominant, HLA-A*0201-restricted human immunodeficiency virus type 1 cytotoxic T-lymphocyte epitope despite multiple variations in the epitope flanking sequences.

Immune escape from cytotoxic T-lymphocyte (CTL) responses has been shown to occur not only by changes within the targeted epitope but also by changes in the flanking sequences which interfere with the processing of the immunogenic peptide. However, the frequency of such an escape mechanism has not been determined. To investigate whether naturally occurring variations in the flanking sequences of an immunodominant human immunodeficiency virus type 1 (HIV-1) Gag CTL epitope prevent antigen processing, cells infected with HIV-1 or vaccinia virus constructs encoding different patient-derived Gag sequences were tested for recognition by HLA-A*0201-restricted, p17-specific CTL. We found that the immunodominant p17 epitope (SL9) and its variants were efficiently processed from minigene expressing vectors and from six HIV-1 Gag variants expressed by recombinant vaccinia virus constructs. Furthermore, SL9-specific CTL clones derived from multiple donors efficiently inhibited virus replication when added to HLA-A*0201-bearing cells infected with primary or laboratory-adapted strains of virus, despite the variability in the SL9 flanking sequences. These data suggest that escape from this immunodominant CTL response is not frequently accomplished by changes in the epitope flanking sequences.

Adolescent↗
PubMed1999

Mutations in von Willebrand factor multimerization domains are not a common cause of classical type 1 von Willebrand disease.

Type 1 von Willebrand disease (vWD) is an autosomal dominant bleeding disorder of variable penetrance. It is characterised by a mild to moderate bleeding tendency and a quantitative deficiency of von Willebrand factor (vWF) with the full range of vWF multimers. Few mutations have been described which account for the mode of inheritance in dominant vWD type 1. We screened the vWF multimerization domains (regions D1-D3 of the vWF gene) of 12 unrelated patients with dominant vWD type 1 to investigate the hypothesis that multimerization of vWF sub-units may be inhibited or reduced by a "dominant negative" mechanism. Platelet-derived RNA was reverse transcribed and the resulting vWF cDNA amplified by the polymerase chain reaction (PCR) in a series of overlapping fragments. These were subjected to a combination of single-strand conformation polymorphism (SSCP) and heteroduplex analysis. This approach identified mobility shifts on acrylamide gels that represented 12 distinct SSCP and/or heteroduplex patterns in our patient group. DNA sequencing of the region encompassing each mobility shift showed these variants to represent previously described polymorphisms within the vWF coding sequence. Examination in all 12 patients for the previously described G3389T and T3445C mutations proved negative. The molecular pathology of classical type 1 vWD remains enigmatic, mutations having been identified in only a small minority of patients. A common mechanism underlying this disease state has still to be elucidated.

Amino Acid Substitution↗
PubMed1999

Pharmacokinetics of recombinant factor VIII (recombinate) using one-stage clotting and chromogenic factor VIII assay.

In a study designed to demonstrate the safety and pharmacokinetics of a recombinant factor VIII (Recombinate) manufactured in Andover, MA and Thousand Oaks, CA, two different methods of factor VIII assay (one-stage clotting and Chromogenic substrate) were compared in vivo. The study was performed in four centres in the UK: London, Oxford, Cardiff and Manchester. Two pharmacokinetic studies, at least one week apart, were performed in 30 patients with severe haemophilia A (VIII:C < 2 IU/dl). A dose of 50 IU/kg was administered with sampling pre-infusion, and +0.25, 0.5, 1, 3, 6, 9, 12 and 24 h post-infusion. The aggregate 60 pharmacokinetic study showed a half-life of 12.7 and 13.0 h (p = 0.28) and recovery of 127 and 161 IU/dl (p = 0.0001) using one-stage clotting or chromogenic substrate respectively. In a supplementary experiment, 20 post-infusion samples were re-assayed by 1-stage and chromogenic assay using two plasma (20th British plasma standard and an "in-house" pooled normal plasma) and two concentrate standards, derived from the same type, but different batch of infused concentrate (Recombinate) and pre-diluted in either individual pre-infusion sample or in pooled commercial haemophilic plasma. The use of the Recombinate concentrate standard overcame the significant difference in FVIII levels between 1-stage and chromogenic assay methods when a plasma standard was used (p <0.0001). It is concluded that where potency dosing designation is carried out by an assay system different to that used in the clinical situation, the use of the recombinant concentrate as a standard in post-infusion plasma samples is likely to give more reliable and reproducible results.

Biological Assay↗
PubMed1999

An Internet implementation of an international clinical study.

This paper describes a clinical study that is being conducted in 15 countries world-wide via the internet. The study concerns the removal of Factor VIII inhibitors in haemophilic children. The suitability of the Internet for this type of study is explored together with the technology (Active Server Pages, Secure Sockets Layer) that is involved in the creation of such a system.

Child↗
PubMed1998

The geography of mental health in Dunedin, New Zealand.

The process of deinstitutionalization of people with chronic mental disabilities in Western countries has often produced a spatial concentration of ex-psychiatric patients, and of mental health services, in inner city urban neighbourhoods. In this paper, the geography of mental health services and patients in Dunedin is examined, and it is shown that a concentration does exist in one neighbourhood. The history and characteristics of this neighbourhood are described. The key factors in contemporary New Zealand that have generated this spatial pattern are then considered, and Dunedin's centralized mental health geography is contrasted with the North American "zone of dependence" phenomenon. The paper concludes by considering to what extent Dunedin's emergent geography of mental health provides a supportive environment for people with mental illnesses, and exploring the policy implications for health care planners and service providers.

Community Mental Health Centers↗
PubMed1997

Carrageenan-induced hyperalgesia is associated with increased cyclo-oxygenase-2 expression in spinal cord.

The discovery of the inducible form of cyclo-oxygenase, known as cyclo-oxygenase-2 (COX-2), has provided insight into the mechanisms involved in the inflammatory response. Peripheral inflammation induced by intraplantar injection of carrageenan is associated with a marked increase in COX-2 mRNA and prostaglandins in the surrounding tissue and the accompanying oedema is sensitive to COX-2-selective drugs. In this study, we investigated whether COX-2 in spinal cord was similarly induced by carrageenan and whether the associated development of altered pain sensitivity, hyperalgesia was affected by the COX-2 selective inhibitor DuP 697. Intraplantar injection of carrageenan caused a marked hyperalgesia at 4 h which was significantly attenuated by treatment with DuP 697 (10 mg kg-1). At the same time levels of COX-2 mRNA in lumbar spinal cord were significantly increased two-fold by carrageenan treatment. However, DuP 697 potentiated COX-2 mRNA induction, which indicates the existence of a potential regulatory mechanism to overcome COX-2 inhibition.

Animals↗
PubMed1996

What do cancer patients mean when they complain of concentration and memory problems?

Cognitive function items are increasingly included in quality of life measures, and complaints of concentration and memory difficulties are often reported by cancer patients. The aim of this study was to examine the factors influencing patients' level of complaint by comparing subjective reports with objective test performance of a sample of adult lymphoma patients, disease-free and > or = 6 months after treatment. There was no significant difference between complainers and non-complainers in sociodemographic or clinical characteristics or in their performance on standard neuropsychometric tests of concentration and memory. Those reporting concentration and memory difficulties had significantly higher scores on measures of anxiety, depression and fatigue. This calls into question the validity of including cognitive function items in self-report quality of life measures. Patients who report concentration and memory difficulties should be screened for clinically significant and potentially remediable mood disorder. Objective testing remains the method of choice for assessing higher mental function.

Adult↗
PubMed1995

Changes in expression of NR-1 and c-jun mRNA in rat lumbar spinal cord after neonatal common peroneal nerve crush.

We have examined the expression of the NR-1 subunit of the glutamate NMDA receptor and the immediate early gene c-jun in lumbar spinal cord following neonatal common peroneal nerve crush. The expression of these two genes was studied up to 12 days post-injury (crush occurring at neonatal day P2). The levels of both NR-1 and c-jun mRNA were increased in spinal cord ipsilateral to the site of crush, the induction of mRNA was shown to occur in a time-dependent manner, peaking at 5 days post-injury. The level of NR-1 mRNA showed the most substantial change following nerve crush, increasing 5 times from 4 h to 5 days post-crush. An increase in expression of NR-1 was also observed in spinal cord contralateral to the injury, although quantitatively this was a smaller effect. These results indicate that early postnatal injury causes a significant increase in the expression of NR-1 mRNA which is most marked at 5 days after injury. This period coincides with that of maximum cell death and indicates that the selective induction of NR-1 could underlie the mechanism of this cell death.

Animals↗