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Biomedical subjects

J Rose

Publications and source records attributed to J Rose.

At least 91 records · Page 5Linked to original sources
PubMed1998

Evaluation of a candidate human immunodeficiency virus type 1 (HIV-1) vaccine in macaques: effect of vaccination with HIV-1 gp120 on subsequent challenge with heterologous simian immunodeficiency virus-HIV-1 chimeric virus.

Human immunodeficiency virus type 1 (HIV-1) envelope vaccines can now be evaluated for efficacy in macaques by challenging with chimeric viruses in which the env, tat and rev genes of simian immunodeficiency virus (SIV) have been replaced by those of HIV-1. Most experiments have so far been conducted using gp120 molecules derived from T-cell-adapted LAI or MN strains of HIV-1, which predominantly use the CXCR-4 co-receptor. These vaccines protect against infection by apathogenic chimeric virus carrying the same envelope sequences. In the experiment described here, four macaques were vaccinated with W61D gp120 derived from a low passage Dutch isolate and capable of inhibiting the binding of MIP1beta to the co-receptor CCR-5. This vaccine was potent, inducing high titres of binding and neutralizing antibodies against the homologous HIV-1 and tenfold lower titres against a heterologous challenge virus (SHIV(SF33)) in which the env, tat and rev genes of SIV had been replaced by those of a San Francisco isolate, HIV-1(SF33). Despite strong immune responses to the vaccine there was no evidence that it protected against challenge with this chimeric virus. The antigenic divergence between vaccine and challenge virus or the increased virulence of the challenge virus may be responsible for the inability of this vaccine to protect against infection by SHIV(SF33).

AIDS Vaccines↗
PubMed1997

Locality commissioning. The long and winding road.

It is unlikely that locality commissioning, as it stands, could respond to any future government policy that identifies it as the way forward. The size of localities should remain flexible. The government has indicated that it wishes to support pilots where localities have delegated budgetary responsibility, but it is unclear whether this will emerge as a preferred model.

Benchmarking↗
PubMed1997

Contrast echocardiography for assessment of myocardial perfusion.

It has been suggested that the myocardial perfusion can be qualitatively and quantitatively assessed by different ultrasound contrast techniques. It has been reported that the intracoronary or intraaortic administration of the ultrasound contrast agents can be used to visualize perfusion defects or to analyze the coronary flow reserve. The perfusion analysis after intracoronary injection of ultrasound contrast agents seems to be established, but there are a lot of open questions. A topographic (qualitative) perfusion analysis with visualization of perfusion defects and perfusion areas or analysis of collaterals has been demonstrated. A quantitative analysis of myocardial blood flow has been described but the existing studies are inconsistent. It is not known which parameters of the contrast wash-out curves should be used for perfusion analysis and if the Stewart-Hamilton curve analysis can be transferred to all ultrasound contrast agents as a model for quantitative myocardial blood flow assessment. The development of the transpulmonary contrast agents for echocardiographic evaluation of left ventricular cavity has the impact for myocardial perfusion imaging. The increase of myocardial intensity does not mean that a qualitative or quantitative perfusion analysis can be clinically used. In this field we have to differentiate between the possibilities of qualitative discrimination of perfusion defects and quantitative perfusion (myocardial blood flow) analysis. The different scanning conditions, the poor transthoracic ultrasound window and insufficient enhancement of the myocardial intensity make it problematic to quantify the myocardial perfusion. At the moment myocardial intensity will be increased after intravenous injection of transpulmonary contrast agents, but the value for perfusion analysis has not been shown. New ultrasound technologies such as second harmonic imaging, power-mode and raw data analysis have to show the clinical importance of these techniques for perfusion analysis in daily clinical routine. The open questions of the perfusion analysis by contrast echocardiography will be discussed in this review article.

Contrast Media↗
PubMed1997

The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold.

The first structure of an aldehyde dehydrogenase (ALDH) is described at 2.6 A resolution. Each subunit of the dimeric enzyme contains an NAD-binding domain, a catalytic domain and a bridging domain. At the interface of these domains is a 15 A long funnel-shaped passage with a 6 x 12 A opening leading to a putative catalytic pocket. A new mode of NAD binding, which differs substantially from the classic beta-alpha-beta binding mode associated with the 'Rossmann fold', is observed which we term the beta-alpha,beta mode. Sequence comparisons of the class 3 ALDH with other ALDHs indicate a similar polypeptide fold, novel NAD-binding mode and catalytic site for this family. A mechanism for enzymatic specificity and activity is postulated.

Aldehyde Dehydrogenase↗
PubMed1997

Allogeneic bone marrow transplant for chronic myelogenous leukemia in a patient with multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system in which immune mechanisms appear to be an important component of the pathophysiology. Although the clinical manifestations are variable, a subset of patients develops a progressive clinical course associated with marked neurologic impairment and significant morbidity. BMT has been proposed as treatment for such patients based on preclinical data as well as clinical observations in other autoimmune diseases. We report clinical and MRI findings in an MS patient, later diagnosed with CML, and treated with an allogeneic BMT.

Bone Marrow Transplantation↗
PubMed1997

Mechanisms of protection induced by attenuated simian immunodeficiency virus. I. Protection cannot be transferred with immune serum.

To evaluate its role in protection, immune serum was collected from four macaques which were chronically infected with live attenuated simian immunodeficiency virus (SIVmacC8) and had resisted challenge with wild-type SIVmacJ5. The immune serum was transferred to two naive cynomolgus macaques by intraperitoneal injection (11 ml/kg). Four control macaques received an intraperitoneal injection of normal saline. One day later, all macaques were challenged with 10 MID50 of the J5M challenge stock of SIV. After challenge, all macaques became infected as determined by virus co-culture and diagnostic PCR. Virus loads in PBMC at 2 weeks post-challenge were indistinguishable between the two groups of macaques. Thus, the failure of passive immunization to transfer protection indicates that serum components alone are not sufficient to mediate the potent protection obtained using live attenuated vaccines. This is the first time that serum has been transferred from animals known to be protected against superinfection.

Animals↗
PubMed1997

Psychological well-being of staff working with people who have challenging behaviour.

The present survey explored stress in direct-care staff working with people who have learning disabilities and challenging behaviour. A total of 78 (82.7% response rate) staff working in 14 small community houses participated. Houses were selected on the basis of 'expert' (Head of Psychology Services) knowledge of houses where residents were known to display challenging behaviour and houses where there was no known history of challenging behaviour. Residents were assessed by key workers for adaptive behaviour, challenging behaviour and mental health using partially validated questionnaires. Staff completed self-report questionnaires on job demands, anxiety and depression, staff support, and information on the presence/absence of challenging behaviour in their home. Staff working in houses with residents who showed challenging behaviour were significantly more anxious than staff working in houses with no challenging behaviour; they also reported feeling significantly less supported, were less clear about the identification of risk situations and had lower job satisfaction. No differences were found on measures of job demands and depression. Regression analyses exploring the relationships between these variables are discussed along with the implications of the findings.

Adult↗
PubMed1997

Cardioprotection by ACE inhibitors in myocardial ischaemia/reperfusion. The importance of bradykinin.

Myocardial ischaemia, when severe and sustained for more than 40 minutes, results in irreversible damage, i.e. myocardial infarction. However, with early reperfusion, damage is reversible. Complete recovery of contractile function requires some time, despite fully or almost fully restored blood flow. This phenomenon has been termed myocardial stunning. There is experimental evidence showing that angiotensin converting enzyme (ACE) inhibitors limit the development of infarct size, reduce the incidence of ischaemic and reperfusion arrhythmias, and enhance the recovery of contractile function of stunned myocardium. These cardioprotective effects of ACE inhibitors are mediated by an attenuated degradation of bradykinin.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Use of ultrasonography in the patient with acute abdominal trauma.

The purpose of this study was to assess the use of ultrasonography in patients with acute abdominal trauma. Five hundred prospective patients, who came to the Emergency Department with acute trauma, were evaluated with ultrasonography and included in this study. The ultrasonographic examination focused on detection of free fluid but included evaluation of parenchymal organs for injury. The physical examination was not used in the statistical analysis of the sonographic findings. In comparing ultrasonography to computed tomography, diagnostic peritoneal lavage, or operative findings, we obtained 24 true positive, 79 true negative, four false positive, and 14 false negative results. Sensitivity of ultrasonography in detecting free fluid in comparison to computed tomography, diagnostic peritoneal lavage, and surgery was 63%, specificity was 95%, accuracy was 85%, positive predictive value was 86%, and negative predictive value was 85%. The most common reason for false negative sonographic results was identification of free fluid in the pelvis on computed tomograms but not on ultrasonograms owing to lack of a full bladder. In none of these instances were the sonographic false negative results of clinical significance. Ultrasonography allowed detection of solid organ injury of the liver in one of seven cases, of the kidney in one of four cases, and in the bowel in zero of three cases. In the three instances of bowel injury, free fluid was noted on ultrasonograms. Ultrasonography fared better in cases of splenic laceration, permitting detection in nine of 14 cases. The emergent ultrasonogram may be used to detect free fluid in the abdomen of the acutely traumatized patient. However, sonography is limited in detecting free fluid in the pelvis using the present technique and does not allow visualization of organ injury. Limitations of this examination should be recognized for appropriate triage of the acutely traumatized patient.

Abdomen↗
PubMed1997

EEG spectral analysis of the neuroprotective kappa opioids enadoline and PD117302.

The present study characterized the electroencephalographic (EEG) effects of the neuroprotective kappa opioids enadoline and PD117302 in conscious, freely moving rats with the use of computer-assisted spectral analysis (CASA). Enadoline (25-100 microg/kg) or PD117302 (1.25-5.0 mg/kg) was administered intravenously to rats implanted with cortical EEG electrodes. Although both drugs produced an immediate, mild sedation, there were no signs of head-weaving or ataxia, and there was little visual evidence of opioid-like EEG slow-wave bursts or seizures. Both drugs produced only modest increases in total EEG power that were not dose dependent. In contrast, CASA revealed significant dose-dependent frequency shifts in relative power distributions, thereby identifying distinct kappa opioid alterations in awake EEG activity; EEG power decreased in the 0- to 4-Hz frequency band with concomitant increases in power measured in the 4- to 8-Hz frequency range. The kappa opioids produced a dose-dependent consolidation of the EEG waveform centered about a peak frequency of 5.0 Hz (for enadoline) or 4.8 Hz (for PD117302) and a significant shift in the mean EEG frequency from 6.6 Hz (predrug) to 6.2 Hz (postdrug). Further CASA revealed significant postdrug decreases in the edge frequency, mobility and complexity of the EEG. Both drugs produced moderate increases in the latency to slow-wave sleep (SWS). Overall, enadoline (ED50 = 18 microg/kg) was approximately 94 times more potent than PD117302 (ED50 = 1690 microg/kg) in producing the kappa EEG profile. Because the kappa-induced EEG changes were stereospecific for the (-)-enantiomers and inhibited by norbinaltorphimine (nor-BNI), the EEG "fingerprint" described in this study could be attributed to specific activation of brain kappa opioid receptors.

Animals↗
PubMed1997

Distortions of time in the transference: some clinical and theoretical implications.

The author considers that patients' distortions of time can frequently and readily be observed in clinical psychoanalysis, reflecting both their psychopathology and their reactions to the temporal aspects of the psychoanalytic setting. These phenomena are considered in order to examine the assumptions that can implicitly be made about the nature of space and time in object-relations theory. Two case histories are given to exemplify these clinical phenomena-the first being an example of a fixation and the second one of a psychic retreat. These cases are compared to demonstrate the unconscious processes underlying the particular time distortions being considered, their impact on the patient's lives and their manifestation in the clinical setting. On the basis of these studies, it is suggested that the asymmetry of the 'arrow of time' cannot be assumed in the structure of psychic reality. The clinical evidence suggests that psychic reality has to be seen as discontinuous and that the structure of the discontinuities is revealed by the impact that the temporal aspects of the psychoanalytic setting have on the patient.

Humans↗
PubMed1996

The crystal structure of glutamine-binding protein from Escherichia coli.

The crystal structure of the glutamine-binding protein (GlnBP) from Escherichia coli in a ligand-free "open" conformational state has been determined by isomorphous replacement methods and refined to an R-value of 21.4% at 2.3 A resolution. There are two molecules in the asymmetric unit, related by pseudo 4-fold screw symmetry. The refined model consists of 3587 non-hydrogen atoms from 440 residues (two monomers), and 159 water molecules. The structure has root-mean-square deviations of 0.013 A from "ideal" bond lengths and 1.5 degrees from "ideal" bond angles. The GlnBP molecule has overall dimensions of approximately 60 A x 40 A x 35 A and is made up of two domains (termed large and small), which exhibit a similar supersecondary structure, linked by two antiparallel beta-strands. The small domain contains three alpha-helices and four parallel and one antiparallel beta-strands. The large domain is similar to the small domain but contains two additional alpha-helices and three more short antiparallel beta-strands. A comparison of the secondary structural motifs of GlnBP with those of other periplasmic binding proteins is discussed. A model of the "closed form" GlnBP-Gln complex has been proposed based on the crystal structures of the histidine-binding protein-His complex and "open form" GlnBP. This model has been successfully used as a search model in the crystal structure determination of the "closed form" GlnBP-Gln complex by molecular replacement methods. The model agrees remarkably well with the crystal structure of the Gln-GlnBP complex with root-mean-square deviation of 1.29 A. Our study shows that, at least in our case, it is possible to predict one conformational state of a periplasmic binding protein from another conformational state of the protein. The glutamine-binding pockets of the model and the crystal structure are compared and the modeling technique is described.

Amino Acid Sequence↗
PubMed1996

Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart. Inotropic responses to postextrasystolic potentiation and intracoronary calcium.

BACKGROUND: We tested the hypothesis that decreased calcium responsiveness is responsible for the reduction in contractile function in regional hibernating and stunned myocardium in situ. METHODS AND RESULTS: In 19 anesthetized swine, the left anterior descending coronary artery flow was reduced to decrease anterior myocardial work index (sonomicrometry) by approximately 60%. During 90 minutes of hypoperfusion, creatine phosphate recovered (as determined by biopsy specimens and bioluminescence) and no necrosis developed (as determined by staining with triphenyl tetrazolium chloride). In 10 swine, changes in the intracellular calcium concentration were induced by systematic variation of the postextrasystolic time interval at a constant prematurity. In 9 additional swine, a graded IC calcium infusion was performed. Under control conditions, anterior myocardial work increased with a fully compensated postextrasystolic time interval from 380+/-93 (mean+/-SD) to 523+/-98 mm Hg . mm. IC calcium infusion increased anterior myocardial work under control conditions from 356+/-85 to a maximum of 428+/-93 mm Hg . mm. Although the maximal responses were decreased during postextrasystolic potentiation (222+/-68 versus 523+/-98 mm Hg . mm) and calcium infusion (176+/-32 versus 428+/-93 mm Hg . mm) after 90 minutes of ischemia, the relationships between increases in anterior myocardial work and, respectively, postextrasystolic time interval and IC calcium were not different. The same was true after 30 minutes of reperfusion. CONCLUSIONS: Both regional hibernating myocardium and stunned myocardium in situ are characterized by a decrease in overall myocardial calcium responsiveness; however, there appears to be no significant myocardial desensitization to calcium.

Animals↗
PubMed1996

Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution.

src homology 2 (SH2) domains are modules of about 100 amino acid residues and bind to phosphotyrosine-containing motifs in a sequence-specific manner. They play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. The protein tyrosine kinase p56lck is a member of the src family and is involved in T-cell activation. The crystal structure of its SH2 domain with an 11-residue peptide showed that the phosphotyrosine and the Ile residue at the pY + 3 position are recognized by the SH2 domain. We present here the crystal structure of the SH2 domain of human p56lck in complex with the short phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Ile (pYEEI peptide) at 1.0 A resolution. The structural analysis at atomic resolution reveals that residue Arg134 (alphaA2), which interacts with the phosphotyrosine side-chain, is present in two conformations in the complex. The structure at 1.8 A resolution of the complex with the phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Gly (pYEEG peptide), which is 11 fold less potent, shows another binding mode for the pY + 3 residue as well as rearrangements of the side-chain of Arg196 (EF3) and one of the water molecules at the base of the pY + 3 pocket. The structure of the complex with the short pYEEI peptide at atomic resolution represents a good starting point for the design and optimization of new inhibitors. Comparative structural analysis of many different inhibitor complexes will be an important component of this drug discovery process.

Amino Acid Sequence↗