Search PubMed⌕ Search

Biomedical subjects

J Hughes

Publications and source records attributed to J Hughes.

At least 181 records · Page 10Linked to original sources
PubMed1998

Genetic immunization of chimpanzees chronically infected with the hepatitis B virus, using a recombinant retroviral vector encoding the hepatitis B virus core antigen.

Cytotoxic T lymphocyte (CTL) activity and CD4+ helper T cell responses to the hepatitis B virus (HBV) core antigen (HBcAg) have been implicated in clearance of acute and chronic HBV infections. We showed that intramuscular injections of a novel recombinant retroviral vector expressing an HBcAg-neomycin phosphotransferase II (HBc-NEO) fusion protein induces HBc/eAg-specific antibodies and CD4+ and CD8+ T cell responses in mice and rhesus monkeys. We have now immunized three chronically infected chimpanzees, each with 10(10) CFU of nonreplicating retroviral vector particles expressing the HBc-NEO fusion protein. Of two immunized chimpanzees examined for CTL responses, one developed HBcAg-specific CTLs and showed marginal, transient elevations of alanine aminotransferase (ALT) levels following injection. However, both chimpanzees remained positive for serum HBeAg, negative for anti-HBe antibody by conventional assays, and displayed no change in HBV viral load throughout the study. In contrast, the third chimpanzee exhibited a traditional seroconversion evidenced by a loss of serum HBeAg and the subsequent emergence of anti-HBe antibodies within 24 weeks after the first injection. Simultaneously, two transient ALT flares and a significant decrease in the serum HBV DNA levels were noted. Despite its limitations, the present study demonstrates (1) the safety of treatment with high titers of retroviral vector in chimpanzees, (2) the capability of a retroviral vector expressing HBcAg to stimulate immune responses in HBV chronic carrier chimpanzees, and (3) that retroviral vector immunization may be therapeutically beneficial in the treatment of chronic HBV infection.

Amino Acid Sequence↗
PubMed1998

Evaluation of PD 154075, a tachykinin NK1 receptor antagonist, in a rat model of postoperative pain.

PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph) is a selective tachykinin NK1 receptor antagonist. Its effect on development and maintenance of thermal and mechanical hypersensitivity was examined in a rat model of surgical pain. When administered 30 min before surgery, PD 154075 dose-dependently (3-100 mg/kg, s.c.) prevented the development of thermal and mechanical hypersensitivity with respective minimum effective doses of 10 and 30 mg/kg. These antihypersensitivity effects lasted for 72 h. In contrast, the administration of PD 154075 (30 mg/kg, s.c.) after surgery had little or no effect on these nociceptive responses. PD 154075 antagonised thermal hypersensitivity induced by intrathecal administration of substance P, over the same dose range that blocked surgical hypersensitivity. However, it only partially blocked the thermal hypersensitivity induced by the selective NK2 receptor agonist [betaAla8]neurokinin A-(4-10). Morphine dose-dependently (1-6 mg/kg, s.c.) lengthened isoflurane and pentobarbitone-induced sleeping time in the rat. In contrast, PD 154075 (3-100 mg/kg, s.c.) did not interact with these anaesthetics. It is suggested that tachykinin NK1 receptor antagonists, such as PD 154075, may possess therapeutic potential as pre-emptive antihypersensitive agents.

Anesthetics↗
PubMed1998

The neuroprotective effects of the recombinant interleukin-1 receptor antagonist rhIL-1ra after excitotoxic stimulation with kainic acid and its relationship to the amyloid precursor protein gene.

The cytokine interleukin-1 (IL-1) and its endogenous antagonist (IL-1ra) have important functions in the central nervous system. Recent experimental observations have suggested that recombinant IL-1RA (rhIL-1ra) has neuroprotective properties in ischaemia, excitotoxicity, and trauma. We wished to see what effect rhIL-1ra had on kainic acid-induced neuronal death and to investigate how this might relate to changes in expression of the amyloid precursor protein gene (APP) and glial fibrillary acid protein (GFAP) using in situ hybridization. Wistar rats were treated by intracerebroventricular administration with rhIL-1ra at doses of 10, 20 and 40 microg given 10 min before and 10 min after intraperitoneal kainic acid 10 mg/kg. Behaviour was measured and, after 10 days, the brains were removed for histology and in situ hybridization. There were no anticonvulsant effects on kainic acid-induced wet dog shakes or limbic motor seizures. There were no differences in the effects of rhIL-1ra at all doses tested on hippocampal temperature, blood pressure, blood gases, pH, and glucose in comparison to control. With rhIL-1ra 10 microg given twice, there was significant protection of neurons in the CA1 and CA3 field of the hippocampus and dorsal thalamus, but not in the primary olfactory cortex-amygdaloid region. Small, but insignificant, neuroprotective effects were observed in the same anatomical regions with a dose of 20 microg given twice, and no neuroprotective effects were observed with 40 microg. The enhanced neuronal survival in CA1, CA3 and the dorsal thalamus was associated with preservation of APP 695 mRNA (neuronal form) and lack of stimulation of APP 770 (glial form) and GFAP messages. Where there was no neuroprotection APP 695 mRNA was reduced and stimulation of both APP 770 and GFAP mRNAs was observed. In conclusion, rhIL-1ra has dose- and region-dependent effects on neuronal survival after kainic acid and prevents damage-induced changes in APP and GFAP mRNAs.

Amyloid beta-Protein Precursor↗
PubMed1998

Characterization of a pH-sensitive surfactant, dodecyl-2-(1'-imidazolyl) propionate (DIP), and preliminary studies in liposome mediated gene transfer.

The inefficiency of non-viral gene delivery systems, relative to viral systems, is likely due, in part, to the failure of endosomes to release DNA before reaching degradative lysosomes. A solution is to incorporate compounds in a delivery vector that will selectively increase the release of endosomally encapsulated DNA. To meet the above criteria, we designed, synthesized, and characterized the physicochemical and biological properties of such a compound, dodecyl-2-(1'-imidazolyl) propionate (DIP) to enhance cationic liposome mediated gene delivery. Several surface active techniques were used to characterize DIP lysing membranes. The critical micelle concentration of DIP was between 0.10-0.18 mM and the effective release and solubilization ratios were 1.0 and 4.0, respectively. DIP facilitated membrane disruption in both a pH and concentration dependent manner. In the presence of esterase at pH 7.0, the hydrolysis rate increased 32-fold indicating DIP can be degraded in the biological milieu. Toxicity of DIP by MTT assay in the SKnSH cell line demonstrated an ID50 of 1.2 mM, which is 30-fold higher than the concentration of DIP used to enhance gene transfection. When incorporated into cationic-liposomes, DIP enhanced transgene expression in vitro by 5-fold. The results of the study indicate that DIP may be a useful adjuvant to increase non-viral gene delivery to cells.

Fluoresceins↗
PubMed1998

Dermatological uses of high-dose intravenous immunoglobulin.

High-dose intravenous immunoglobulin (hdIVIg) is increasingly used to treat a range of inflammatory and autoimmune diseases. The current dermatological uses of hdIVIg include the treatment of dermatomyositis and the autoimmune bullous disorders, epidermolysis bullosa acquisita, pemphigoid, and pemphigus. Numerous immunomodulatory mechanisms for hdIVIg have been proposed, and they are discussed alongside treatment protocols and adverse effects. Increasing use of this therapy has helped to establish its excellent safety record, without the many adverse effects of steroids and other immunosuppressive agents. This safety record makes hdIVIg an attractive therapeutic option; however, in view of the time required to administer the infusions, the cost, and the urgent need for controlled trials of hdIVIg in patients with specific dermatological disorders such as pemphigus, patients must be carefully selected. Unfortunately, current dermatological uses of hdIVIg have been limited to either uncontrolled trials or anecdotal case reports, except for a single controlled trial of hdIVIg as adjunctive therapy in patients with dermatomyositis, which documented a significant benefit. Further trials in dermatomyositis should be established to confirm these data and to clarify the dose and frequency of therapy required for patients with dermatomyositis. When using hdIVIg, liaison between the dermatologist and the immunologist is helpful because it allows the use of both the nursing and the medical expertise of an existing immunotherapy unit. If appropriate, the patient may be entered into an hdIVIg home therapy training program, such as the one that exists for primary immunodeficiency and some neurologic indications, with clear benefits in quality of life and inpatient costs.

Adjuvants, Immunologic↗
PubMed1998

Blue light- and genetically-reversed gravitropic response in protonemata of the moss Ceratodon purpureus.

In darkness, protonemal filaments of Ceratodon purpureus (Brid.) grow negatively gravitropically (upwards). Red light induces a positive phototropic response mediated by the photoreceptor phytochrome. A red light treatment also has an inhibitory effect on the gravitropic response, an effect also mediated by phytochrome. In this study the effects of blue light on phototropism and on gravitropism were analysed. Unilateral blue light resulted in only a weak phototropic response, but markedly randomised growth direction. Blue light given together with a gravitropic stimulus reversed the gravitropism, changing it from negative to positive (filaments grow downward). The effect of blue light was also analysed with the mutant ptr116, which is defective in the biosynthesis of the phytochrome chromophore, and in a newly isolated mutant wwr2, which is positively gravitropic in darkness. Blue light induced the same reversal of gravitropism in ptrll6 as in the wild type, indicating that phytochrome is not involved in this process. In wwr2 the direction of gravitropism was unaltered by the blue light treatment. Light also affects chlorophyll content and the size of plastids, potential statoliths for gravitropism. Red light induced an increase in plastid size and chlorophyll content in the wild type but not in ptr116. Blue light induced a similar change in wild type plastids. It seems as though light-induced alterations of gravitropism are not simply mediated by alterations in plastid properties, and that red light and blue light evoke fundamentally different responses.

Bryopsida↗
PubMed1998

Parental anxiety due to abnormal behaviour following withdrawal of sedation.

Abnormal behaviour has been previously reported on withdrawal of sedation in critically-ill children. This description of a child who had prolonged withdrawal symptoms lasting almost 2 weeks includes a report on his parent's comments in relation to the anxiety they felt while he was behaving abnormally. Health professionals need to be aware of the severe nature of this withdrawal reaction and its effect on the parents.

Adult↗
PubMed1998

DQAsomes: a novel potential drug and gene delivery system made from Dequalinium.

PURPOSE: Dequalinium, a drug known for over 30 years, is a dicationic amphiphile compound resembling bolaform electrolytes. The purpose of our work was to determine the state of aggregation of dequalinium in aqueous medium and to investigate both, its ability to bind DNA and its potential to serve as a novel non-viral transfection vector. METHODS: The form of aggregation was determined employing electron microscopic techniques. The DNA binding capacity of dequalinium was assayed using SYBR Green I stain. For in vitro cell transfection experiments plasmid DNA encoding for firefly luciferase was used. RESULTS: Dequalinium forms in aqueous medium liposome-like aggregates, which we term DQAsomes. These dequalinium vesicles bind DNA and they are able to transfect cells in vitro with an efficiency comparable to Lipofectin. CONCLUSIONS: Based on the intrinsic properties of dequalinium such as the in vivo selectivity for carcinoma cells and selective accumulation in mitochondria we propose DQAsomes as a novel and unique drug and gene delivery system.

Animals↗
PubMed1998

The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury.

The cyclin-dependent kinase inhibitor p27Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27Kip1 also safeguards against excessive cell proliferation in specific pathophysiologic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27-/- mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27-/- mice following ureteral obstruction. p27Kip1 may have a general role in protecting cells and tissues from inflammatory injury.

Animals↗
PubMed1998

Timing of removal of the laryngeal mask airway.

Previous studies reported that complications associated with removal of the laryngeal mask were more frequent in awake patients than in anaesthetised patients; however, these studies did not comply with the method described in the manufacturer's instruction manual. The reported incidences of regurgitation during the use of the laryngeal mask also differ considerably between studies. We studied these factors in 66 patients in whom the method described in the manual was used. After induction of anaesthesia, the laryngeal mask and a pH probe were inserted and the cuff of the mask was inflated with a minimum volume of air. Anaesthesia was maintained with nitrous oxide and isoflurane in oxygen. At the end of the operation, we randomly allocated patients to one of two groups and the laryngeal mask was removed either while they were still deeply anaesthetised or after they had regained consciousness. No apparent regurgitation occurred in any patient during operation, but one patient in the anaesthetised group regurgitated immediately after removal of the mask. The incidence of complications during or after removal of the laryngeal mask was significantly greater in the anaesthetised group than that in the awake group (p << 0.001; difference [95% CI]: 48.5 [30.5-66.5]%). Therefore, the laryngeal mask can be safely left in place until the patient has regained consciousness after emergence from anaesthesia.

Adolescent↗
PubMed1998

Dentine hypersensitivity: the effects of brushing desensitizing toothpastes, their solid and liquid phases, and detergents on dentine and acrylic: studies in vitro.

Dentine exhibiting symptoms of dentine hypersensitivity has tubules open at the dentine surface and patent to the pulp. The mechanisms whereby dentinal tubules are exposed is ill understood but probably involves a variety of abrasive and/or erosive agents. This study in vitro examined the quantitative and qualitative effects of toothpastes, their solid and liquid phases and detergents on dentine and acrylic. Abrasion of dentine and acrylic were measured by surfometry. Morphological changes to dentine were assessed by scanning electron microscopy. Abrasion of dentine and acrylic by toothpastes increased with increasing brushstrokes with marked differences in the extent of abrasion between different pastes. Brushing dentine with water or detergents produced progressive abrasion but which appeared to plateau around 2 microm loss. Water and detergents produced minimal effects on acrylic. At 5000 strokes dentine abrasion by solid phases was less than the parent toothpastes but the ranking order of abrasivity was the same as the parent toothpastes. Loss of dentine produced by liquid phases was minimal and in the order of 1-2 microm. Observationally, all toothpastes removed at least the dentine smear layer to expose many tubules; with one desensitizing product leaving a particulate deposit occluding most tubules. The solid phases of the toothpaste produced identical morphological changes to the parent paste. The liquid phases and detergents all exposed dentinal tubules by 5000 strokes. Water had little or no effect on the dentine smear layer. It is concluded that toothpastes, solid phase, liquid phase and detergents have the potential to abrade or erode dentine to a variable degree and result in tubule exposure. The effects of the liquid phases and detergents appear limited to the removal of the smear layer. Such detrimental effects seen in vitro could have relevance to the aetiology and management of dentine hypersensitivity. Toothpaste formulations which despite exposing tubules have ingredients capable of occluding tubules may be an area of development for such products.

Acrylic Resins↗
PubMed1998

The TAPS Project 42: the last to leave hospital--a profile of residual long-stay populations and plans for their resettlement. Team for the Assessment of Psychiatric Services.

This study aims to assess the service needs of residual hospital populations and the adequacy of the alternative facilities provided for them following the closure of psychiatric hospitals. The remaining 368 long-stay patients in four representative English hospitals scheduled for closure within 1 year were assessed by means of a standardized schedule devised to rate problem behaviours. The residual populations consisted predominantly of elderly, male and very long-stay patients. The most frequent problem behaviours were hostility, physical aggression and incontinence. The one hospital which allowed new admissions to continue indefinitely had the highest proportion of problematic patients. Alternative care facilities were provided by a diverse range of agencies. Large residential homes were the predominant type of provision for most patients, and private nursing homes often accommodated mixed groups of elderly people. NHS trusts catered for most of the 'difficult to place' patients within specialized facilities, based in the community. There were some indications that compromises led to insufficient and understaffed specialist facilities. In view of the increasing demand for long-term intensively staffed facilities, this policy might put an extra burden on the local health services.

Adult↗
PubMed1998

Recombinant phytochrome of the moss Ceratodon purpureus: heterologous expression and kinetic analysis of Pr-->Pfr conversion.

The phytochrome-encoding gene Cerpu;PHY;2 (CP2) of the moss Ceratodon purpureus was heterologously expressed in Saccharomyces cerevisiae as a polyhistidine-tagged apoprotein and assembled with phytochromobilin (P phi B) and phycocyanobilin (PCB). Nickel-affinity chromatography yielded a protein fraction containing approximately 80% phytochrome. The holoproteins showed photoreversibility with both chromophores. Difference spectra gave maxima at 644/716 nm (red-absorbing phytochrome [Pr]/far-red-absorbing phytochrome [Pfr]) for the PCB adduct, and 659/724 nm for the P phi B-adduct, the latter in close agreement with values for phytochrome extracted from Ceratodon itself, implying that P phi B is the native chromophore in this moss species. Immunoblots stained with the antiphytochrome antibody APC1 showed that the recombinant phytochrome had the same molecular size as phytochrome from Ceratodon extracts. Further, the mobility of recombinant CP2 holophytochrome on native size-exclusion chromatography was similar to that of native oat phytochrome, implying that CP2 forms a dimer. Kinetics of absorbance changes during the Pr-->Pfr photoconversion of the PCB adduct, monitored between 620 and 740 nm in the microsecond range, revealed the rapid formation of a red-shifted intermediate (I700), decaying with a time constant of approximately 110 microseconds. This is similar to the behavior of phytochromes from higher plants when assembled with the same chromophore. When following the formation of the Pfr state, two major processes were identified (with time constants of 3 and 18 ms) that are followed by slow reactions in the range of 166 ms and 8 s, respectively, albeit with very small amplitudes.

Avena↗
PubMed1998

Xenografting: ethical issues.

This paper considers the ethical issues raised by xenotransplantation under four headings: interfering with nature; effects on the recipient; effects on other humans; and effects on donor animals. The first two issues raise no insuperable problems: charges of unnaturalness are misguided, and the risks that xenotransplantation carries for the recipient are a matter for properly informed consent. The other two issues raise more serious problems, however, and it is argued that if we take seriously the risk of transferring new infectious agents from animal to human populations and the interests of donor animals, then a moratorium on xenotransplantation is called for. The paper finds that the recent Nuffield Council and Department of Health reports on xenotransplantation are insufficiently cautious in the conclusions that they draw from these considerations.

Animal Experimentation↗
PubMed1998

Urinary neopterin as a prognostic index of survival time in HIV-1 infection.

A prospective semi-longitudinal study was undertaken to determine if urinary neopterin was a predictor for survival in HIV-positive patients. One hundred and one HIV-positive subjects attending a department of genitourinary medicine over a 41-month period were included. Survival data were analysed 6 months after the end of recruitment. Ninety-two subjects were followed up for a minimum of 6 months. Survival figures at 1 and 2 years were 93% (SE 3%) and 79% (SE 5%). There was an inverse relationship between urinary neopterin excretion and 1 and 2-year survival. Two-year survival fell from 70% (SE 6%) for neopterin levels > or = 300 mmol/mol creatinine to 25% (SE 9%) for levels > or = 700 mmol/mol creatinine (P < 0.001). Urinary neopterin may be a useful non-invasive technique in predicting survival in HIV-positive patients.

CD4 Lymphocyte Count↗