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Biomedical subjects

J Winter

Publications and source records attributed to J Winter.

At least 73 records · Page 4Linked to original sources
PubMed2000

Respiratory syncytial virus infection and G and/or SH protein expression contribute to substance P, which mediates inflammation and enhanced pulmonary disease in BALB/c mice.

A distinct clinical presentation of respiratory syncytial virus (RSV) infection of humans is bronchiolitis, which has clinical features similar to those of asthma. Substance P (SP), a tachykinin neuropeptide, has been associated with neurogenic inflammation and asthma; therefore, we chose to examine SP-induced inflammation with RSV infection. In this study, we examined the production of pulmonary SP associated with RSV infection of BALB/c mice and the effect of anti-SP F(ab)(2) antibodies on the pulmonary inflammatory response. The peak production of pulmonary SP occurred between days 3 and 5 following primary RSV infection and day 1 after secondary infection. Treatment of RSV-infected mice with anti-SP F(ab)(2) antibodies suggested that SP may alter the natural killer cell response to primary and secondary infection. In mice challenged after formalin-inactivated RSV vaccination, SP appears to markedly enhance pulmonary eosinophilia as well as increase polymorphonuclear cell trafficking to the lung. Based on studies with a strain of RSV that lacks the G and SH genes, the SP response to RSV infection appears to be associated with G and/or SH protein expression. These data suggest that SP may be an important contributor to the inflammatory response to RSV infection and that anti-SP F(ab)(2) antibodies might be used to ameliorate RSV-associated disease.

Animals↗
PubMed2000

Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3)

During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development. Intervillous blood flow increases around 10 to 12 weeks of gestation and results in exposure of trophoblast cells to increased oxygen tension. Before this time, low oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. Using human villous explants of 5-8 weeks' gestation, we found that low oxygen tension triggered trophoblast proliferation, fibronectin synthesis, alpha(5) integrin expression, and gelatinase A activity. These biochemical markers were barely detectable under oxic conditions. We therefore examined the placental expression of hypoxia-inducible factor-1 (HIF-1), a master regulator of oxygen homeostasis, and determined that expression of HIF-1alpha subunit during the first trimester of gestation parallels that of TGFbeta(3), an inhibitor of extravillous trophoblast differentiation. Expression of both molecules is high in early pregnancy and falls around 9 weeks of gestation, when placental pO(2) levels are believed to increase. Increasing oxygen tension induced a similar decrease in expression in cultured explants. Moreover, antisense inhibition of HIF-1alpha expression in hypoxic explants inhibited expression of TGFbeta(3), arrested cell proliferation, decreased alpha(5) expression and gelatinase A activity, and triggered biochemical markers of an invasive trophoblast phenotype such as alpha(1) integrin and gelatinase B expression. These data suggest that the oxygen-regulated early events of trophoblast differentiation are in part mediated by TGFbeta(3) through HIF-1 transcription factors.

Cell Differentiation↗
PubMed2000

A health visitor for older people in an accident and emergency department.

Published studies indicate that older people have special needs on discharge from accident and emergency (A&E) departments that are not always fully met. The literature reflects that although a significant proportion of older people have a decrease in functional independence and an increased need for services following discharge from A&E, social and functional assessment by A&E staff can be inadequate, as can the arrangement of follow-up community services. As part of a wider study into the organization of care for older people in A&E, a health visitor for older people was funded to work part-time in the A&E department of a large NHS Trust. The health visitor identified potential clients through reviewing the A&E documentation of patients aged 75 years or over discharged directly from A&E. Telephone calls or home visits were used to follow up those individuals deemed to be vulnerable by the health visitor. Interventions included health education, referral to other agencies and patient or family counselling. None of the clients followed up by the health visitor (n = 212) had been referred by A&E to a specialist in gerontology, which suggests that these clients would otherwise not have received the potential benefit of specialist intervention. The pilot study described here highlights a number of practical issues in relation to the health visitor post for older people in A&E, including the importance of dedicated office space and access to a telephone. Data collected during the study, plus the positive evaluation of the role by a small group of A&E staff confirm the claims made in other studies (e.g. Runciman et al, 1996) that health visitors for older people may be of value in meeting the post-discharge needs of these people.

Accidental Falls↗
PubMed2000

[14-year experience with implantable cardioverter/defibrillators: determination of prognosis and discharge behavior].

BACKGROUND: The treatment of life threatening ventricular arrhythmias with implantable cardioverter/defibrillators (ICD) has become the therapy of choice; the survival benefit of ICD treatment compared to drug therapy in patients with aborted sudden cardiac death (SCD) and hemodynamically unstable ventricular tachycardia has been proven. In addition for the primary prevention of SCD in high risk patients, ICD therapy is gaining growing acceptance. PATIENTS AND METHODS: We analyzed the long-term follow-up of 274 consecutive patients (211 male, 63 female, age 59 +/- 12 years, left ventricular ejection fraction 39 +/- 15%) provided with an ICD between 1984 and 1998. The aim of the study was to ascertain the survival rate in different subgroups and to discover determining factors of ICD discharge and prognosis. RESULTS: Long-term survival probability at 10 resp. 14 years was 84 resp. 65% for the total collective, and the freedom of event probability (neither shocks nor antitachycardiac pacing from the ICD) to 28% each. The risk to die from SCD was below 3% over time. The most pronounced differences regarding prognosis ensued from dividing the collective into heart insufficiency stages. Thus in NYHA class I and II versus III and IV, the cumulative event rate was 61% vs 82% at 5 years, and survival rate amounted to 94 vs 63% at 5 years and 87% vs 30% at 14 years (p < 0.001). Calculating the relative benefit of ICD therapy survival benefit provided by the ICD was shown to decrease significantly after 5 years for patients in NYHA class III/IV, while it increased progressively for patients in NYHA class I/II up to 10 years. Additional determinants of prognosis and ICD discharge rate were identified left ventricular ejection fraction, age and tendency for the basic cardiac disease, however neither the result of electrophysiological testing nor the results of non-invasive risk stratification. In patients with ischemic heart disease, revascularization procedures improved prognosis only in tendency, while the effect of ICD therapy was significant. In patients with the non-obstructive form of hypertrophic cardiomyopathy ICD, discharges occurred in about 50% of patients; in contrast patients with surgical myectomy for obstructive cardiomyopathy showed no events during follow-up. In patients with chronic inflammatory heart disease and normal left ventricular function (LVF), a very low event rate was expected if patients were treated by immunosuppressive drugs. Patients with dilated cardiomyopathy did not differ from patients with ischemic heart disease with respect to prognosis and ICD discharge rate. CONCLUSION: Significant determinants of prognosis and ICD discharge rate are left ventricular function, age and with limitations the basic cardiac disease. In contrast to patients with better LVF relative survival benefit decreases significantly after 5 years in patients with a worse LVF. Patients with aborted SCD and preserved LVF experience half the ICD discharges compared to patients with poor LVF and gain at the same time a normalization of life expectancy. Causative treatment of the basic disease has an impact on the overall prognosis and event rate, but should in general not influence the decision for IDC implantation in high risk patients.

Adult↗
PubMed1999

Glial cell line derived neurotrophic factor (GDNF) regulates VR1 and substance P in cultured sensory neurons.

Many nociceptive dorsal root ganglion (DRG) sensory neurons express the high affinity nerve growth factor (NGF) receptor TRKA, and respond to NGF. However, many do not express TRKA but are thought to respond to glial cell-derived neurotrophic factor (GDNF) and related molecules. We therefore cultured DRG neurons in the presence of GDNF, and looked at the expression of substance P and of the capsaicin receptor, VR1, two nociceptive properties already known to be NGF regulated. Using several different approaches we demonstrated that GDNF produced clear increases in expression of both properties, comparable in magnitude to increases seen with NGF. Following axotomy, aberrant expression of substance P in A fibres may be involved in the generation of neuropathic pain. Factors regulating substance P and other properties in the absence of retrogradely transported NGF may therefore be of significance in neuropathic pain states.

Animals↗
PubMed1999

Cloning of a cDNA encoding a novel cytochrome P450 from the insect Locusta migratoria: CYP6H1, a putative ecdysone 20-hydroxylase.

The biosynthesis of the steroidal molting hormone, 20-hydroxyecdysone, of arthropods involves a series of cytochrome P450-catalyzed hydroxylations. None of the many sequences of insect cytochromes P450, known to date, is related to ecdysteroid pathways. Here, we report the cloning and sequencing of a full-length cDNA of a new cytochrome P450, classified as CYP6H1, from malpighian tubules of the locust, Locusta migratoria. The 1854 bp DNA contained an open reading frame coding for a protein of 542 amino acids, a 5'-leader sequence and a 3'-untranslated region containing a polyadenylation signal and a poly(A) tail. The encoded protein had been isolated as an ecdysone-binding cytochrome P450 from microsomes of the same tissue in previous work. The closest homolog of CYP6H1 was CYP6A2 from Drosophila with 42.1% identity. According to Northern analysis, CYP6H1 is predominantly expressed at larval instars and in malpighian tubules. Evidence is presented for a functional assignment of CYP6H1 to microsomal ecdysone 20-hydroxylase of the locust.

Amino Acid Sequence↗
PubMed1999

Safety and efficacy of implantable defibrillator therapy with programmed shock energy at twice the augmented step-down defibrillation threshold: results of the prospective, randomized, multicenter Low-Energy Endotak Trial.

Whether the safety and efficacy of implantable cardioverter defibrillator (ICD) therapy can be assured with lower output devices is an important question. The purpose of this study was to evaluate whether programming the device output at twice the augmented defibrillation threshold was as safe and effective as using the maximum energy. Patients indicated for ICD therapy, but without slow monomorphic ventricular tachycardia (MVT), who achieved an augmented defibrillation threshold (DFT plus) < or = 15 joules (J) with a single endocardial lead system and a biphasic defibrillator were included in the study. Prior to ICD implantation, patients were randomized into 2 groups. The shock energies in test group patient were set as follows: first shock at twice DFT plus, the second to fifth shocks at maximum output (34 J). In control group patients, all shocks were programmed at 34 J. The study population consisted of 166 consecutive patients (mean age 57.4 +/- 12.1 years, mean left ventricular ejection fraction 36.8 +/- 13.8%). Mean DFT plus was 9.6 +/- 3.2 J in test group patients and 10.1 +/- 3.5 J in control group patients (p = 0.36). During a mean follow-up of 24.2 +/- 9.6 months, 736 arrhythmia episodes were analyzed. The first shock efficacy was 98.3% in the test group patients versus 97.4% in the control group (p = 0.45). Total mortality was 6%, equally distributed in both study groups. The results of this study prove that the method of doubling the defibrillation energy at the DFT plus level provides an adequate safety margin in defibrillator therapy.

Adult↗
PubMed1999

The role of the pedunculopontine region in basal-ganglia mechanisms of akinesia.

The akinesia of Parkinsonism is relieved by pallidotomy and subthalamic nucleotomy, but not by thalamotomy. Therefore, this disabling symptom probably depends upon connections other than the pallidalthalamocortical tracts, possibly efferents of the medial pallidum descending to the upper brainstem. We have previously demonstrated akinesia in the normal monkey following radiofrequency lesioning in the region of the pedunculopontine nucleus (PPN), one of the primary targets for descending pallidal outflow. Here, we confirm that selectively destroying neurones in the PPN area, whilst sparing fibres of passage, results in an akinetic state in normal macaques.

Alfaxalone Alfadolone Mixture↗
PubMed1999

[Large pseudoaneurysm of the left ventricle after posterolateral wall infarct].

Pseudoaneurysms of the left ventricle are rare complications after acute myocardial infarction. We report on a 69 year old patient with a large false aneurysm located in the posterolateral ventricular wall. It became clinically apparent during an episode of severe left heart failure. Echocardiography and left ventriculography allowed an accurate determination of localization and dimension of the pseudoaneurysm; coronary angiography revealed a proximal occlusion of the left circumflex coronary artery. Because of the high risk of rupture, a rapid surgical repair of the false aneurysm was indicated.

Aged↗
PubMed1999

Peripheral inflammation increases the capsaicin sensitivity of dorsal root ganglion neurons in a nerve growth factor-dependent manner.

Inflammation results in a local increase in nerve growth factor production which potentially can modify the properties of nerve growth factor-responsive sensory neurons innervating the inflamed tissue. The sensitivity of primary sensory neurons to the neurotoxin capsaicin is regulated in vitro by nerve growth factor and we have now investigated the effect of complete Freund's adjuvant-induced inflammation on the capsaicin sensitivity of adult rat sensory neurons. Dorsal root ganglion neurons innervating inflamed tissue were identified in vivo by retrograde labelling with the dye Fast Blue. Neuronal capsaicin sensitivity was measured in vitro with a quantitative cobalt-uptake densitometric technique, and was shown to increase significantly five days after inflammation. This increase in sensitivity was dependent on nerve growth factor as it could be inhibited by systemic treatment with nerve growth factor neutralizing antibodies. The enhanced capsaicin sensitivity that results from Freund's adjuvant injection may contribute to inflammatory hyperalgesia.

Amidines↗
PubMed1999

Combinatorial discovery process yields antimicrobial peptoids.

N-alkylated glycine trimers are generically referred to as peptoids. The identification of antimicrobial peptoids from a statistically unbiased diverse combinatorial chemistry library led to the design of the optimization peptoid library that we describe in this manuscript. This optimization library was designed using structural information from the most active peptoids in the unbiased library. Screening of the optimization library for antimicrobial activity identified a single pool of peptoids with activity against both Staphylococcus aureus and Escherichia coli. The active peptoids from this pool were active against drug sensitive and drug resistant organisms and represent novel antibacterial compounds.

Anti-Bacterial Agents↗
PubMed1999

Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection.

The role of immune mechanisms in the pathogenesis of Ebola hemorrhagic fever (EHF) remains to be elucidated. In this report, the serum cytokine levels of patients who died of EHF were compared with those of patients who recovered and those of control patients. A marked elevation of interferon (IFN)-gamma levels (>100 pg/mL) was observed in sequential serum samples from all fatal EHF cases compared with patients who recovered or controls. Markedly elevated serum levels of interleukin (IL)-2, IL-10, tumor necrosis factor (TNF)-alpha, and IFN-alpha were also noted in fatal EHF cases; however, they had a greater degree of variability. No differences were noted in serum levels of IL-4 and IL-6. mRNA quantitation from blood clots of the same patients showed relatively elevated levels of TNF-alpha and IFN-alpha in samples from EHF patients. Taken together, these results suggest that a high degree of immune activation accompanies and potentially contributes to a fatal outcome in EHF patients.

Cytokines↗
PubMed1999

Characterization of novel antimicrobial peptoids.

Peptoids differ from peptides in that peptoids are composed of N-substituted rather than alpha-carbon-substituted glycine units. In this paper we report the in vitro and in vivo antibacterial activities of several antibacterial peptoids discovered by screening combinatorial chemistry libraries for bacterial growth inhibition. In vitro, the peptoid CHIR29498 and some of its analogues were active in the range of 3 to 12 microg/ml against a panel of gram-positive and gram-negative bacteria which included isolates which were resistant to known antibiotics. Peptoid antimicrobial activity against Staphylococcus aureus was rapid, bactericidal, and independent of protein synthesis. beta-Galactosidase and propidium iodide leakage assays indicated that the membrane is the most likely target of activity. Positional isomers of an active peptoid were also active, consistent with a mode of action, such as membrane disruption, that does not require a specific fit between the molecule and its target. In vivo, CHIR29498 protected S. aureus-infected mice in a simple infection model.

Animals↗
PubMed1999

Respiratory syncytial virus G and/or SH protein alters Th1 cytokines, natural killer cells, and neutrophils responding to pulmonary infection in BALB/c mice.

BALB/c mice sensitized to vaccinia virus expressed G protein of respiratory syncytial virus (RSV) develop a Th2-type cytokine response and pulmonary eosinophilia when challenged with live RSV. In this study, BALB/c mice were immunized or challenged with an RSV mutant lacking the G and SH proteins or with DNA vaccines coding for RSV G or F protein. F or G protein DNA vaccines were capable of sensitizing for pulmonary eosinophilia. The absence of the G and/or SH protein in the infecting virus resulted in a consistent increase both in pulmonary natural killer cells and in gamma interferon and tumor necrosis factor expression, as well as, with primary infection, a variable increase in neutrophils and CD11b(+) cells. The development of pulmonary eosinophilia in formalin-inactivated RSV-vaccinated mice required the presence of the G and/or SH protein in the challenge virus. These data show that G and/or SH protein has a marked impact on the inflammatory and innate immune response to RSV infection.

Animals↗
PubMed1998

Capsaicin sensitivity is associated with the expression of the vanilloid (capsaicin) receptor (VR1) mRNA in adult rat sensory ganglia.

A vanilloid receptor (VR1) has recently been cloned and shown to be a target for capsaicin, the excitotoxic component of capsicum peppers (Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D. and Julius, D., Nature, 389 (1997) 816-824). The effects of capsaicin appear to be selective for a subset of sensory neurones which includes polymodal nociceptors. The present study describes the distribution of VR1 mRNA, together with measurements of capsaicin sensitivity, in sensory nerve ganglia of different embryological origins and a single sympathetic ganglion, the superior cervical ganglion (SCG). In situ hybridisation revealed the expression of VR1 mRNA in small-to-medium-sized neurones of the dorsal root, trigeminal and vagal ganglia. No hybridisation signal was observed in the SCG neurones. This pattern of expression correlated with capsaicin sensitivity measured by whole-cell voltage clamp where, in similar sized cells, over 80% of neurones from dorsal root and vagal ganglia were capsaicin sensitive, but all SCG neurones were insensitive to capsaicin.

Animals↗
PubMed1998

Depolarization stimulates lamellipodia formation and axonal but not dendritic branching in cultured rat cerebral cortex neurons.

Electric activity is known to have profound effects on growth cone morphology and neurite outgrowth, but the nature of the response varies strongly between neurons derived from different species or brain areas. To establish the role of electric activity in neurite outgrowth and neuronal morphogenesis of rat cerebral cortex neurons, cultured neurons were depolarized for up to 72 h and quantitatively analyzed for changes in axonal and dendritic morphology. Depolarization with 25 mM potassium chloride induced a rapid increase in lamellipodia in almost all growth cones and along both axons and dendrites. Lamellipodia formation was dependent on an influx of extracellular calcium through L-type voltage-sensitive calcium channels. Prolonged depolarization for 24 h induced an increase in total axonal length, mainly due to an increase in branching. After three days of depolarization axonal outgrowth was largely the same as in control neurons, suggesting accommodation of the growth cones to chronic depolarization. Dendrites showed very little change during the first three days in culture, and dendritic length or branching were not affected by depolarization. Thus, in early cerebral cortex neurons depolarization specifically stimulates axonal outgrowth through increased branching. This increase in branching may be a consequence of the earlier increase in lamellipodia formation. In contrast, early dendrites seem to be unable to translate the increase in lamellipodia into changes in outgrowth or branching. This difference between axons and dendrites could be due to differences in the stabilization of the tubulin cytoskeleton.

Animals↗
PubMed1998

Brain derived neurotrophic factor, but not nerve growth factor, regulates capsaicin sensitivity of rat vagal ganglion neurones.

Dorsal root ganglion (DRG) sensory neurones are depolarised by the excitotoxin capsaicin. This ability to respond to capsaicin is dependent on nerve growth factor (NGF) in dissociated, cultured, adult rat DRG neurones. We tested the ability of NGF (50 ng/ml) to regulate capsaicin sensitivity in a different group of sensory neurones, namely those of the vagal ganglia. Capsaicin sensitivity, measured in populations of neurones by capsaicin-evoked 45Ca uptake, or in single neurones using a cobalt staining method, was apparent in vagal ganglion neurones after 1 day in culture, but after 5 days in the presence or the absence of NGF, capsaicin-stimulated 45Ca uptake was essentially abolished. As some vagal ganglion neurones exhibit responses to brain derived neurotrophic factor (BDNF), we grew cells in BDNF (1 microg/ml) and found that the capsaicin sensitivity was now apparent at 5 days. Therefore BDNF but not NGF, regulates capsaicin sensitivity in adult rat vagal ganglion neurone cultures. BDNF cannot, however, substitute for NGF in DRG neurone cultures.

Animals↗