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Biomedical subjects

J Hughes

Publications and source records attributed to J Hughes.

At least 199 records · Page 11Linked to original sources
PubMed1998

Impact of tracheotomy on colonization and infection of lower airways in children requiring long-term ventilation: a prospective observational cohort study.

STUDY OBJECTIVES: Determination of the following: (1) colonization and infection rates in children requiring long-term ventilation initially via a transtracheal tube and subsequently via a tracheotomy; (2) the number of infection episodes per 1,000 ventilation days, during both types of artificial airways; and (3) routes of colonization/infection of the lower airways, ie, whether the pathogenesis was endogenous (via the oropharynx) or exogenous (via the transtracheal tube or tracheotomy). DESIGN: Observational, cohort, prospective study over 2 1/2 years. SETTING: Pediatric ICU (PICU), Royal Liverpool Children's National Health Service Trust of Alder Hey, a tertiary referral center. PATIENTS: Twenty-two children requiring long-term mechanical ventilation initially transtracheally and subsequently via a tracheotomy. INTERVENTION: Nil. RESULTS: The lower airways were colonized in 71% of children during transtracheal ventilation; posttracheotomy, this was 95% (p=0.03). Children developed significantly fewer infections following colonization with a microorganism posttracheotomy (8/15 pretracheotomy vs 6/21 posttracheotomy; p=0.013). Throughout the study, there were a total of 17 episodes of infection, all of which were preceded by colonization. Haemophilus influenzae, Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa were the same four causative pathogens during mechanical ventilation both transtracheally and via tracheotomy. Forty-nine episodes of colonization were observed, 15 pretracheotomy and 34 posttracheotomy; of these, 12 (80%) and 19 episodes (56%), respectively, were primary endogenous, ie, present in the oropharynx on hospital admission and subsequently at tracheotomy. Only one colonization episode (7%) of exogenous pathogenesis was observed during transtracheal intubation, while 12 (35%) (p=0.02) occurred after tracheotomy. An equal number of secondary endogenous colonization episodes (two and three, ie, acquired in the oropharynx after PICU admission and after tracheotomy, respectively, were recorded. CONCLUSIONS: (1) Despite a high level of hygiene, exogenous colonization without subsequent infection was common. (2) Although all patients were colonized, the infection rate was lower after tracheotomy. This may be due to enhanced immunity (medically stable) and improved tracheobronchial toilet. (3) Microorganisms in children with tracheotomy differ from those in adults.

Adult↗
PubMed1998

Fluorescence and photochemistry of recombinant phytochrome from the cyanobacterium Synechocystis.

Fluorescence and photochemical properties of phytochrome from the cyanobacterium Synechocystis were investigated in the temperature interval from 293 to 85 K. The apoprotein was obtained by overexpression in Escherichia coli and assembled to a holophytochrome with phycocyanobilin (PCB) and phytochromobilin (P phi B), Syn(PCB)phy and Syn(P phi B)phy, respectively. Its red-absorbing form, Pr, is characterized at 85 K by the emission and excitation maxima at 682 and 666 nm in Syn(PCB)phy and at 690 and 674 nm in Syn(P phi B)phy. At room temperature, the spectra are blue shifted by 5-10 nm. The fluorescence intensity dropped down by approximately 15-20-fold upon warming from 85 to 293 K and activation energy of the fluorescence decay was estimated to be ca 5.4 and 4.9 kJ mol-1 in Syn(PCB)phy and Syn(P phi B)phy, respectively. Phototransformation of Pr upon red illumination was observed at temperatures above 160-170 K in Syn(PCB)phy and above 140-150 K in Syn(P phi B)phy with a 2-3 nm shift of the emission spectrum to the blue and increase of the intensity of its shorter wavelength part. This was interpreted as a possible formation of the photoproduct of the meta-Ra type of the plant phytochrome. At ambient temperatures, the extent of the Pr phototransformation to the far-red-absorbing form, Pfr, was ca 0.7-0.75 and 0.85-0.9 for Syn(PCB)phy and Syn(P phi B)phy, respectively. Fluorescence of Pfr and of the photoproduct similar to lumi-R was not observed. With respect to the photochemical parameters, Syn(PCB)phy and Syn(P phi B)phy are similar to each other and also to a small fraction of phyA (phyA") and to phyB. The latter were shown to have low photochemical activity at low temperatures in contrast to the major phyA pool (phyA'), which is distinguished by the high extent (ca 50%) of Pr phototransformation at 85 K. These photochemical features are interpreted in terms of different activation barriers for the photoreaction in the Pr excited state.

Cyanobacteria↗
PubMed1998

Emerging models of care management for older people and those with mental health problems in the United Kingdom.

Care management has emerged as a central component in the development of community-based care in many countries. It has been government policy for providers of social services to develop care management systems in the United Kingdom since 1993. This paper examines the extent to which it is possible to begin to discern models of care from the different care management arrangements which are now emerging. First, the background to changes in policy and the role of care management in the UK social care system are discussed; second, evidence from the early phases of care management development in the UK is also examined; and third, based upon the pilot phase of a major national study of care management, the key dimensions of variation in care management through which models may be constituted are identified.

Aged↗
PubMed1998

Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat.

Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 microg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9, Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]et hyl ]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in diabetes-induced hypersensitivity.

Animals↗
PubMed1998

Improving the fit: adolescents' needs and future programs for sexual and reproductive health in developing countries.

Demand is growing in developing countries for sexual and reproductive health programs for young people. However, little scientifically based evidence exists about which program approaches are most effective in shaping healthy behaviors. Careful evaluation and research must be increased, but meanwhile, planners need guidance as they expand programming. Research indicates that current programs often do not match the needs and health-seeking behaviors of young people. Behavioral theories and expert opinion agree that adolescents must be taught generic and health-specific skills necessary for adopting healthy behaviors. Constraints on financial and human resources, coupled with the great size of the youth population, highlight the need to find less costly ways to reach young people. These observations generate six programming principles to help planners and communities experiment with a wide variety of programming approaching.

Adolescent↗
PubMed1998

Harnessing peer networks as an instrument for AIDS prevention: results from a peer-driven intervention.

OBJECTIVE: Since 1985, community outreach efforts to combat acquired immunodeficiency syndrome (AIDS) among injecting drug users (IDUs) in the United States have overwhelmingly depended on a provider-client model that relies on staffs of professional outreach workers. We report on a comparison of this traditional outreach model with an innovative social network model, termed "a peer-driven intervention" (PDI). The latter provides IDUs with guidance and structured incentives that permit them to play a much more active role in the outreach process, thereby harnessing peer pressure on behalf of human immunodeficiency virus (HIV) prevention efforts. METHODS: We compare the performance of a traditional outreach intervention (TOI) and a PDI that were implemented in medium-sized towns in eastern and central Connecticut. Comparisons are based on the number and representativeness of IDUs recruited at each site, the effectiveness of HIV prevention education, compliance rates with AIDS risk reduction recommendations, and relative cost. The analyses are based on 522 initial interviews and 190 six-month follow-up interviews conducted during the first two years of each intervention's operation. RESULTS: Both interventions produced significant reductions in HIV risk behaviors, as measured using self-reports. The PDI outperformed the traditional intervention with respect to the number of IDUs recruited, the ethnic and geographic representativeness of the recruits, and the effectiveness of HIV prevention education. In addition, the costs of recruiting IDUs into the intervention and educating them about HIV in the community was only one-thirtieth as much in the PDI as in the traditional intervention. CONCLUSIONS: The findings suggest that given guidance and nominal incentives, IDUs can play a more extensive role in community outreach efforts than the traditional model allows. The findings also suggest that both interventions reduce HIV-associated risk behaviors, but the PDI reaches a larger and more diverse set of IDUs, and does so at much less expense.

Adult↗
PubMed1997

The anticonvulsant properties of antisense c-fos oligodeoxynucleotides in kainic acid-induced seizures.

Evidence has accumulated that the immediate early gene c-fos has important physiological and pharmacological properties in the central nervous system. The role of c-fos in seizures and, in particular, kainic acid-induced seizures, is unclear. It is unknown if c-fos stimulation after kainic acid is a consequence of neuronal activation, or an intrinsic critical component of the metabolic pathways leading to seizure. To elucidate this problem we have pretreated male Wistar rats with antisense c-fos and nonsense c-fos oligodeoxynucleotides 12 h prior to kainic acid 10 mg/kg intraperitoneal. Antisense c-fos inhibited the number of wet dog shakes and the appearance of limbic motor seizures, effects not seen with nonsense or vehicle. The anticonvulsant effects were associated with reduction of both Fos and NGFI-A immunoreactivity and neuroprotection in the hippocampus, thalamus and primary olfactory cortex-amygdaloid region. Four days after antisense c-fos limbic motor seizures were not inhibited, and there was no decrease in Fos or NGFI-A immunoreactivity and no neuroprotection, indicating that the anticonvulsant effects were not secondary to a toxic effect. Sense oligonucleotides had no anticonvulsant effects when given 12 h prior to kainic acid and did not influence immunoreactivity or neuronal survival. In conclusion, these findings suggest a role for c-fos in the generation of kainic acid-induced limbic seizures and neuronal death.

Animals↗
PubMed1997

Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection.

BACKGROUND: Early in human immunodeficiency virus type 1 (HIV-1) infection there is a decline in viral replication that has been attributed to host immunity, but the components of this response, particularly the ability of cytotoxic T lymphocytes to control viral burden and influence the outcome of disease, are poorly understood. METHODS: We prospectively studied 33 patients with primary HIV-1 infection for HIV-specific activated cytotoxic T lymphocytes and memory cytotoxic T lymphocytes and compared these lymphocyte responses with changes in viral load and clinical status over the subsequent 18 to 24 months. RESULTS: Soon after infection, activated HIV-specific cytotoxic T lymphocytes, mediated primarily by CD8+ cells, were detected in 17 of 23 patients (74 percent). Memory cytotoxic T lymphocytes were found in 6 of 6 patients tested (100 percent) during the first three months of infection and in 17 of 21 patients (81 percent) tested during the first six months. The frequencies of memory cytotoxic T lymphocytes varied markedly over time, but overall they declined over the first 6 to 8 months and then stabilized over the next 12 to 18 months. The patients with higher frequencies of Env-specific memory cytotoxic T lymphocytes had a median level of plasma HIV-1 RNA about one third that of the patients with lower frequencies, (median number of RNA copies per milliliter, 22,000 vs. 62,000; P=0.006). Patients with low frequencies of Env-specific memory cytotoxic T lymphocytes (or none) in early infection had a more rapid decline to less than 300 CD4+ cells per cubic millimeter (P = 0.05). CONCLUSIONS: In early HIV-1 infection, the induction of memory cytotoxic T lymphocytes, particularly those specific for Env, helps control viral replication and is associated with slower declines in CD4+ cell counts. Host cytolytic effector responses appear to delay the progression of HIV-1 disease.

Adult↗
PubMed1997

Raman spectroscopic and light-induced kinetic characterization of a recombinant phytochrome of the cyanobacterium Synechocystis.

A phytochrome-encoding cDNA from the cyanobacterium Synechocystis has been heterologously expressed in Escherichia coli and reconstituted into functional chromoproteins by incubation with either phycocyanobilin (PCB) or phytochromobilin (PPhiB). These materials were studied by Raman spectroscopy and nanosecond flash photolysis. The Raman spectra suggest far-reaching similarities in chromophore configuration and conformation between the Pfr forms of Synechocystis phytochrome and the plant phytochromes (e.g. phyA from oat), but some differences, such as torsions around methine bridges and in hydrogen bonding interactions, in the Pr state. Synechocystis phytochrome (PCB) undergoes a multistep photoconversion reminiscent of the phyA Pr --> Pfr transformation but with different kinetics. The first process resolved is the decay of an intermediate with red-shifted absorption (relative to parent state) and a 25-micros lifetime. The next observable intermediate grows in with 300 (+/-25) micros and decays with 6-8 ms. The final state (Pfr) is formed biexponentially (450 ms, 1 s). When reconstituted with PPhiB, the first decay of this Synechocystis phytochrome is biexponential (5 and 25 micros). The growth of the second intermediate is slower (750 micros) than that in the PCB adduct whereas the decays of both species are similar. The formation of the Pfr form required fitting with three components (350 ms, 2.5 s, and 11 s). H/D Exchange in Synechocystis phytochrome (PCB) delays, by an isotope effect of 2.7, both growth (300 micros) and decay rates (6-8 ms) of the second intermediate. This effect is larger than values determined for phyA (ca. 1.2) and is characteristic of a rate-limiting proton transfer. The formation of the Pfr state of the PCB adduct of Synechocystis phytochrome shows a deuterium effect similar as phyA (ca. 1.2). Activation energies of the second intermediate in the range 0-18 degrees C are 44 (in H2O/buffer) and 48 kJ mol-1 (D2O), with essentially identical pre-exponential factors.

Apoproteins↗
PubMed1997

Characterization of recombinant phytochrome from the cyanobacterium Synechocystis.

The complete sequence of the Synechocystis chromosome has revealed a phytochrome-like sequence that yielded an authentic phytochrome when overexpressed in Escherichia coli. In this paper we describe this recombinant Synechocystis phytochrome in more detail. Islands of strong similarity to plant phytochromes were found throughout the cyanobacterial sequence whereas C-terminal homologies identify it as a likely sensory histidine kinase, a family to which plant phytochromes are related. An approximately 300 residue portion that is important for plant phytochrome function is missing from the Synechocystis sequence, immediately in front of the putative kinase region. The recombinant apoprotein is soluble and can easily be purified to homogeneity by affinity chromatography. Phycocyanobilin and similar tetrapyrroles are covalently attached within seconds, an autocatalytic process followed by slow conformational changes culminating in red-absorbing phytochrome formation. Spectral absorbance characteristics are remarkably similar to those of plant phytochromes, although the conformation of the chromophore is likely to be more helical in the Synechocystis phytochrome. According to size-exclusion chromatography the native recombinant apoproteins and holoproteins elute predominantly as 115- and 170-kDa species, respectively. Both tend to form dimers in vitro and aggregate under low salt conditions. Nevertheless, the purity and solubility of the recombinant gene product make it a most attractive model for molecular studies of phytochrome, including x-ray crystallography.

Apoproteins↗
PubMed1997

Expression of LIM protein genes Lmo1, Lmo2, and Lmo3 in adult mouse hippocampus and other forebrain regions: differential regulation by seizure activity.

The LIM domain is a zinc-binding amino acid motif that characterizes various proteins which function in protein-protein interactions and transcriptional regulation. Expression patterns of several LIM protein genes are compatible with roles in vertebrate CNS development, but little is known about the expression, regulation, or function of LIM proteins in the mature CNS. Lmo1, Lmo2, and Lmo3 are LIM-only genes originally identified as putative oncogenes that have been implicated in the control of cell differentiation and are active during CNS development. Using in situ hybridization for mRNA and immunohistochemical detection of reporter protein expression in transgenic mice, we found that Lmo1, Lmo2, and Lmo3 show individually unique but partially overlapping patterns of expression in several regions of the adult mouse forebrain, including hippocampus, caudate putamen, medial habenula, thalamus, amygdala, olfactory bulb, hypothalamus, and cerebral cortex. In the hippocampal formation, Lmo1, Lmo2, and Lmo3 show different combinatorial patterns of expression levels in CA pyramidal and dentate granule neurons, and Lmo1 is present in topographically restricted subpopulations of astrocytes. Kainic acid-induced limbic seizures differentially regulated Lmo1, Lmo2, and Lmo3 mRNA levels in hippocampal pyramidal and granule neurons, such that Lmo1 mRNA increased, whereas Lmo2 and Lmo3 mRNAs decreased significantly, with maximal changes at 6 hr after seizure onset and return to baseline by 24 hr. These findings show that Lmo1, Lmo2, and Lmo3 continue to be expressed in the adult mammalian CNS in a cell type-specific manner, are differentially regulated by neuronal activity, and may thus be involved in cell phenotype-specific regulatory functions.

Animals↗
PubMed1997

Venepuncture.

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Anesthetics, Local↗
PubMed1997

Activation of c-fos mRNA in the brain by the kappa-opioid receptor agonist enadoline and the NMDA receptor antagonist dizocilpine.

Using in situ hybridization, we have shown that the kappa-opioid receptor agonist enadoline (CI-977) and the non-competitive NMDA receptor antagonist dizocilpine (MK-901) induced the immediate early gene c-fos in dorsal medial thalamic nuclei. Dizocilpine, and not enadoline, also induced c-fos in the posterior cingulate cortex and retrosplenial cortex. Enadoline's stimulation of c-fos mRNA was dose and time dependent and completely inhibited by pretreatment with naltrexone. Morphine did not stimulate c-fos in the thalamus. It is suggested that the stimulation of c-fos with enadoline represents a specific kappa-opioid receptor effect.

Analysis of Variance↗
PubMed1997

Human glomerular mesangial cell phagocytosis of apoptotic neutrophils: mediation by a novel CD36-independent vitronectin receptor/thrombospondin recognition mechanism that is uncoupled from chemokine secretion.

In this study we examined the mechanisms by which glomerular mesangial cells ingest apoptotic cells and the mesangial cell response to this event, since there is in vivo evidence that such semiprofessional phagocytes participate in phagocytic clearance of both apoptotic leukocytes and apoptotic resident cells from inflamed glomeruli, thereby promoting resolution of glomerulonephritis. Mesangial cell phagocytosis of apoptotic neutrophils in vitro was not affected by inhibitors of lectin-like receptors, phosphatidylserine receptors, the 61D3 Ag, and beta1 and beta2 integrins, receptors which have been implicated in phagocytosis of apoptotic cells by particular populations of semiprofessional and professional phagocytes. However, the specific inhibitory effects of cationic aminosugars, Arg-Gly-Asp-Ser (RGDS) peptide, and mAbs to phagocyte alpha(v)beta3 vitronectin receptor integrin and "bridging" thrombospondin 1 (TSP1) indicated that mesangial cell phagocytosis of apoptotic cells involved an alpha(v)beta3/TSP mechanism akin to that described for human monocyte-derived macrophages (Mphi) in which Mphi CD36 plays an important role in binding "bridging" TSP1. However, mesangial cells did not express CD36 and there was no evidence for involvement of alternative phagocyte receptors for TSP1, heparan sulfate proteoglycan and sulfatides. Nevertheless, phagocytosis of apoptotic neutrophils by either mesangial cells or Mphi failed to elicit secretion of IL-8 and MCP-1, representatives of each major class of proinflammatory chemotactic cytokines. We conclude that mesangial cell phagocytosis of apoptotic neutrophils involves a novel CD36-independent, alpha(v)beta3/TSP-mediated mechanism that is uncoupled from chemokine secretion, emphasizing the injury-limiting potential of mesangial cell phagocytosis of apoptotic cells.

Apoptosis↗
PubMed1997

The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret.

The activity of a selective tachykinin NK1 receptor antagonist, PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph), was examined in radioligand binding studies, in a [Sar9,Met(O2)11]substance P-induced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies, PD 154075 showed nanomolar affinity for the human, guinea-pig, gerbil, dog and ferret NK1 receptors with an approximate 300 times lower affinity for the rodent NK1 receptor. Using NK2,NK3 receptors and a range of other receptor ligands, PD 154075 was shown to exhibit a high degree of selectivity and specificity for the human type NK1 receptor. Following subcutaneous administration PD 154075 dose dependently (1-100 mg/kg) antagonised the centrally mediated [Sar9,Met(O2)11] substance P-induced foot tapping in the gerbil with a minimum effective dose (MED) of 10 mg/kg. The ability of PD 154075 to readily penetrate into the brain following oral administration was confirmed by its extraction and high performance liquid chromatography assay from the rat brain. PD 154075 was shown to achieve a relatively fast and sustained brain concentration (brain/plasma ratios ranged from 0.27 to 0.41 during the time period of 0.25-12 h). Further pharmacokinetic studies revealed that the absolute oral bioavailability of PD 154075 in the rat was (mean +/- S.D.) 49 +/- 15%. PD 154075 (1-30 mg/kg, i.p.) dose dependently antagonised the acute vomiting and retching in the ferret measured for 4 h following administration of cisplatin (10 mg/kg, i.p.) with a MED of 3 mg/kg. The administration of a lower dose of cisplatin (5 mg/kg, i.p.) in the ferret induces both an acute (day 1) and delayed (days 2 and 3) phase of emesis. The i.p. administration of PD 154075, 10 mg/kg three times a day for 3 days, almost completely blocked both the acute and delayed emetic responses. In the same study, the 5-HT3 receptor antagonist ondansetron (1 mg/kg, i.p., t.i.d.) was also very effective against the acute emetic response observed during the first 4 h following cisplatin, but it was only weakly active against the delayed response. In conclusion, PD 154075 is a selective and specific high affinity NK1 receptor antagonist with good oral bioavailability which is effective against both acute and delayed emesis induced by cisplatin in the ferret.

Animals↗