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D J Roberts

Publications and source records attributed to D J Roberts.

At least 55 records · Page 3Linked to original sources
PubMed1999

Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells.

The malaria parasite Plasmodium falciparum is one of the most successful human pathogens. Specific virulence factors remain poorly defined, although the adhesion of infected erythrocytes to the venular endothelium has been associated with some of the syndromes of severe disease. Immune responses cannot prevent the development of symptomatic infections throughout life, and clinical immunity to the disease develops only slowly during childhood. An understanding of the obstacles to the development of protective immunity is crucial for developing rational approaches to prevent the disease. Here we show that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendritic cells and subsequently reduce their capacity to stimulate T cells. These data demonstrate both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected erythrocytes.

Animals↗
PubMed1999

Plasmodium falciparum: analysis of the antibody specificity to the surface of the trophozoite-infected erythrocyte.

Current opinion supports the view that immunity to the surface of the trophozoite-infected erythrocyte (IE) is to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1). Here we provide further evidence using the mutant cell line 1776/C10 which no longer expresses PfEMP-1 at the IE surface, due to a subtelomeric deletion in chromosome 9. We have measured antibody reactivity to this mutant in comparison to it's intact isogenic parent line 1776, which does express PfEMP-1, using the sensitive technique of flow cytometry. IgG-specific antibodies (subclass IgG1) in the plasma of hyperimmune adults, reacted to 1776 but never to the 1776/C10 mutant. Antibody subclasses were also measured in individual plasma samples to the surface of trophozoite-IE. Predominantly IgG1 antibodies were detected, with a few individual plasma having additional IgG3 antibodies. Previous studies have used the agglutination assay to measure sero-conversion to PfEMP-1. Here we show that both agglutination and flow cytometric methods are comparable, suggesting that agglutination of trophozoite-IE is mediated by IgG antibodies. Comparison of the isogenic cell lines 1776 and 1776/C10 differing in expression of PfEMP-1 provides further evidence that IgG antibodies, in particular of the cytophilic subclasses, mediate recognition of PfEMP-1.

Adult↗
PubMed1999

The non-cardiac systemic side-effects of antihistamines: ebastine.

Ebastine and its active metabolite carebastine show potent antagonism of histamine H1-mediated phenomena in a wide variety of in vitro and in vivo non-clinical experimental models. By contrast, activity is not seen against histamine H2- or H3-mediated, nor acetylcholine- or serotonin-mediated phenomena, and both compounds are virtually without effect in models measuring pharmacological effects on the central nervous system (CNS). Explanation of these observations is found in their high selectivity for the histamine H1 receptor and in their low in vivo potency in displacing [3H]-mepyramine from central histamine H1 receptors, indicating that they do not readily pass the blood-brain barrier. These findings have been mirrored in clinical experimental models where oral doses of ebastine (1-30 mg) showed clear dose-related inhibition of intradermal histamine-induced weal and flare responses, whereas doses of 90 mg were without anticholinergic effects on salivary flow, cardiovascular reflexes or pilocarpine-induced miosis. Furthermore, in an extensive series of controlled studies in specific clinical models for measuring objective effects on the CNS, ebastine in single doses of 10-90 mg and repeated doses of 10-30 mg once daily, had no clinically relevant effects on cognitive performance and visual co-ordination tests, nor on simulated car-tracking tests and real car-driving tests. Nor was their any interaction with ethanol or diazepam. On subjective test parameters (questionnaires and visual analogue scales) there were only a few isolated and random incidences of minor increases in some indices of sedation at the highest doses. Not surprisingly, therefore, the clear therapeutic benefit seen during the extensive and international use of ebastine (5-20 mg once daily) in the treatment of seasonal and perennial rhinitis and chronic idiopathic urticaria, has not been accompanied by signs of drug-induced anticholinergic effects (dry mouth, disturbances of visual accommodation) or sedation, making it an effective and well-tolerated first-line treatment alternative to other second-generation antihistamines.

Animals↗
PubMed1999

A review of the cardiac systemic side-effects of antihistamines: ebastine.

The cardiac safety of ebastine, a long-acting, non-sedating antihistamine, has been thoroughly assessed in phase I-III clinical studies. Ebastine alone at the recommended doses of 10 mg and 20 mg has no clinically relevant effect on QTc interval in adults and in special patient populations (elderly, children or subjects with hepatic or renal impairment). Ebastine administered at 60 and 100 mg/day (3-5 times the maximum recommended dose) for 1 week had statistically significantly smaller effects (3.7 and 10.3 msec, respectively) on the QTc interval than terfenadine (18 msec) at three times the recommended dose (360 mg/day). The mean QTc interval prolongation observed with ebastine 100 mg/day was small and not clinically meaningful, although the results were statistically significant vs. placebo. The effect of ebastine 60 mg/day was not statistically different from placebo. Steady-state drug interaction studies demonstrated that the co-administration of ebastine 20 mg with ketoconazole or erythromycin produced significant increases in systemic exposure for ebastine, which were accompanied by small increases in QTc (approximately 10 msec above ketoconazole or erythromycin alone). Results from individual studies suggest that, when coadministered with ketoconazole, ebastine produces similar changes in QTc interval measurements compared to loratadine and cetirizine. Pooled data from clinical efficacy trials of ebastine 1-30 mg/day administered for 2-3 weeks showed no clinically relevant cardiac effects as assessed by serial electrocardiographs and Holter monitoring. The overall cardiac safety profile based on currently available information suggests that ebastine, like loratadine and cetirizine, has a lower potential for causing adverse cardiovascular effects than terfenadine.

Adult↗
PubMed1999

Computer-assisted comparison of the structural and electronic dispositions of ebastine and terfenadine.

OBJECTIVE: Ebastine and terfenadine are both marketed nonsedating H1 histamine receptor antagonists. Although apparently similar in chemical structure, the compounds have different pharmacological profiles, particularly with respect to cardiac effects. These effects are consistently observed in a wide range of experimental models with terfenadine, but not with ebastine, despite the fact that the latter is more potent as an antihistamine. The objective of this study was to provide a structural basis to explain such differences. DESIGN: A complete computer-assisted conformational and electronic characterisation was made for both drugs. RESULTS: The preferred 3-dimensional spatial orientations were found to be different, as were the molecular locations of the highest occupied and lowest unoccupied molecular orbitals. Furthermore, for terfenadine, additional points of interaction as a hydrogen bond donor were found, which were not evident in ebastine or other noncardiotoxic antihistamines. These extra points of interaction were also found in other compounds that have shown cardiac effects similar to those of terfenadine.

Butyrophenones↗
PubMed1998

Cerebral effects of aortic clamping during coarctation repair in children: a transcranial Doppler study.

OBJECTIVE: Haemodynamic changes as a consequence of application and release of aortic clamps for surgical repair of aortic coarctation are compensated by cerebrovascular autoregulation. Transcranial Doppler was used to study the effect of these haemodynamic changes upon brain circulation in children during aortic coarctation repair. METHOD: A 2-MHz transcranial Doppler system continuously recorded mean cerebral blood flow velocities from the left middle cerebral artery in 13 children (aged from 5 days to 14 years) during repair of their coarctation. Measurements were performed: prior to aortic clamping (baseline); during the first 5 min after clamp application; 1 min before declamping; at 1, 2, 4 and 6 min after the release of both proximal and distal aortic clamps; and at initial chest closure. A contralateral upper-limb non-invasive blood pressure cuff measured systemic blood pressures. Haemodynamic and anaesthetic parameters were monitored. Patients were stratified by age into two groups: age < 6 months (group A) and age > 6 months (group B). RESULTS: With aortic clamping, systemic blood pressures (range from: -16 to +54%) and cerebral blood flow velocities (range from -40 to +19%) changed slightly (P > 0.05) from initiation to end of aortic clamping. In group A, release of aortic clamps resulted in moderate fluctuations in systemic blood pressures (range from -34 to +15%) (P > 0.05) and a marked reduction in cerebral blood flow velocities (range from -63 to -33%) (P < 0.01). At the time of surgical closure, flow velocities had improved in all infants except one. Group B did not show major reductions in either cerebral blood flow velocity or systemic blood pressures throughout all measurements (P > 0.05). During aortic clamp release, young infants responded with lower brain blood flow velocities as compared to older children (r = 0.68; P < 0.05). CONCLUSION: Transient central nervous system hypotension results as a consequence of flow redistribution during aortic declamping in young infants. Older children usually show a faster autoregulatory compensation to these haemodynamic changes. The observed age-related physiologic differences, suggest that young infants may require higher systemic blood pressures during declamping to prevent the cerebral blood flow reduction. Transcranial Doppler appears to be a valuable monitor of these cerebral haemodynamic changes.

Adolescent↗
PubMed1998

Epithelial-mesenchymal signaling during the regionalization of the chick gut.

The development of the vertebrate gut requires signaling between the endoderm and mesoderm for establishing its normal anteroposterior (AP) axis and for tissue-specific differentiation. Factors implicated in positional specification of the AP regions of the gut include endodermally expressed Sonic hedgehog (Shh), mesodermally expressed Bmp4 and members of the Hox gene family. We have investigated the roles of these factors during AP regional specification of the chick embryonic gut. Early in gut development, the endoderm sends inductive signals to the mesoderm. Shh has been implicated as one of these signals. We find a differential response to exposure of the inductive influence of Shh along the AP axis of the gut. Virally mediated misexpression of Shh results in ectopic upregulation of its receptor Ptc and a cellular proliferation throughout the gut mesoderm. Although ectopic Shh can induce Bmp4 in the mesoderm of the midgut and hindgut, Bmp4 is not induced in the stomach region of the foregut. The stomach region has a thicker layer of mesoderm than the rest of the gut suggesting that the normal function of Bmp4 could be to limit mesodermal growth in the non-stomach regions of the gut. Ectopic Bmp4 expression in the stomach results in a reduction of the mesodermal component consistent with this hypothesis. In addition to the regional restriction on Bmp4 induction, Shh can only induce Hoxd-13 in the mesoderm of the hindgut. These findings suggest that a prepattern exists in the primitive gut mesoderm prior to expression of Shh in the endoderm. The gut mesoderm is subsequently responsible for inducing region-specific differentiation of its overlying endoderm. We tested the role of Hoxd-13, normally restricted in its mesodermal expression to the most posterior region of the hindgut (cloaca), in controlling adjacent endodermal differentiation. When virally mediated Hoxd-13 is misexpressed in the primitive midgut mesoderm, there is a transformation of the endoderm to the morphology and mucin content of the hindgut. Thus, the positionally restricted expression of a Hox gene in the gut mesoderm influences the inductive signaling that leads to regionally specific differentiation of gut endoderm.

Animals↗
PubMed1997

Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo.

Recently, a pathway of genes which are part of a cascade regulating the side on which the heart forms during chick development was characterized (M. Levin et al., 1995, Cell 82, 1-20). Here we extend these previous studies, showing that manipulation of at least one member of the cascade, Sonic hedgehog (Shh), can affect the situs of embryonic rotation and of the gut, in addition to the heart. Bilateral expression of Shh, which is normally found exclusively on the left, does not result in left isomerism (a bilaterally symmetrical embryo having two left sides) nor in a complete situs inversus phenotype. Instead, misexpression of Shh on the right side of the node, which in turn leads to bilateral nodal expression, produces a heterotaxia-like condition, where different aspects of laterality are determined independently. Heart situs has previously been shown to be altered by ectopic Shh and activin. However, the most downstream gene identified in the LR pathway, nodal, had not been functionally linked to heart laterality. We show that ectopic (right-sided) nodal expression is able to affect heart situs, suggesting that the randomization of heart laterality observed in Shh and activin misexpression experiments is a result of changes in nodal expression and that nodal is likely to regulate heart situs endogenously. The first defined asymmetric signal in the left-right patterning pathway is Shh, which is initially expressed throughout Hensen's node but becomes restricted to the left side at stage 4(+). It has been hypothesized that the restriction of Shh expression may be due to repression by an upstream activin-like factor. The involvement of such an activin-like factor on the right side of Hensen's node was suggested because ectopic activin protein is able to repress Shh on the left side of the node, as well as to induce ectopic expression of a normally right-sided marker, the activin receptor cAct-RIIa. Here we provide further evidence in favor of this model. We find that a member of this family, Activin betaB, is indeed expressed asymmetrically, only on the right side of Hensen's node, at the correct time for it to be the endogenous asymmetric activin signal. Furthermore, we show that application of follistatin-loaded beads eliminates the asymmetry in Shh expression, consistent with an inhibition of an endogenous member of the activin-BMP superfamily. This combined with the previous data on exogenous activin supports the model that Activin betaB functions in the chick embryo to initiate Shh asymmetry. While these data extend our understanding of the early signals which establish left-right asymmetry, they leave unanswered the interesting question of how the bilateral symmetry of the embryo is initially broken to define a consistent left-right axis. Analysis of spontaneous chick twins suggests that, whatever the molecular mechanism, left-right patterning is unlikely to be due to a blastodermal prepattern but rather is initiated in a streak-autonomous manner.

Animals↗
PubMed1997

Chromatographic and hyphenated methods for elemental speciation analysis in environmental media.

This review discusses chromatographic techniques that permit the analysis of speciated metals in the environment using conventional detectors, such as UV, and element-specific detectors, such as flame atomic absorption spectrometry, electrothermal atomic absorption spectrometry and inductively coupled plasma mass spectrometry. The importance of determining precise elemental forms in hazardous waste-contaminated soil, water and biota in terms of toxicity is outlined. Previous reviews on this subject are described and recent research on this subject is discussed. Most of the work cited has been performed in the 1990s and a table summarizing the chromatographic method and the detector system used, including brief comments on the work, is included to enable quick reference.

Animals↗
PubMed1997

Perphenazine decreases vomiting by children after tonsillectomy.

PURPOSE: To test the hypothesis that perphenazine decreases the incidence of vomiting by children after tonsillectomy. METHODS: Healthy children (n = 260) aged 2-12 yr undergoing elective tonsillectomy on a day care surgical basis were studied in this randomised. stratified, blocked, double-blind investigation. General Anaesthesia was induced intravenously with propofol or by inhalation with halothane and N2O. Perphenazine 70 micrograms.kg-1 up to 5 mg or placebo i.v. was administered before surgery. Management of perioperative fluids, emesis and pain were all standardised. RESULTS: The groups were similar with respect to demographic data. There was less vomiting after perphenazine during the first 24 hr after surgery 42% (95% CI = 34%-50%) vs 57% (95% CI = 48%-66%, placebo), P < 0.01. On the day of surgery, both in and out-of hospital emesis were decreased by perphenazine. The perphenazine treated patients required fewer rescue antiemetics than the control group, P < 0.05. Each episode of in-hospital vomiting delayed discharge by 20 +/- 7 min (mean +/- SD), P = 0.007. CONCLUSION: The prophylactic administration of perphenazine decreases vomiting by children after tonsillectomy.

Antiemetics↗
PubMed1997

Vomiting after strabismus surgery in children: ondansetron vs propofol.

PURPOSE: To compare the antiemetic efficacy and costs associated with two anaesthetic regimens in children undergoing strabismus surgery. One regimen contained halothane, nitrous oxide and ondansetron, while the other contained propofol and nitrous oxide. METHODS: Three hundred children aged 2-14 yr undergoing strabismus surgery were enrolled into this single-blind, randomized, stratified, blocked study with a balanced design. Anaesthesia was induced by inhalation with halothane/N2O/O2 (Group O) or with 2.5-3.5 mg.kg-1 propofol + 0.5 mg.kg-1 lidocaine i.v. (Group P). Group O patients were administered 0.15 mg.kg-1 ondansetron (maximum dose 8 mg) i.v. and all patients received atropine 20 micrograms.kg-1 i.v. immediately after induction of anaesthesia. Anaesthesia was maintained with N2O and halothane (Group O) or N2O and propofol (Group P). Patients were followed for 24 hr after their operation primarily to assess the incidence of postoperative vomiting. For each case, the costs of the anaesthetic drugs administered and their associated intravenous administration tubing were determined. Drug costs were those prevailing at the study site at the time of the investigation. Fixed costs, such as the cost of the anaesthetic equipment were not assessed. RESULTS: Groups were similar with respect to demographic data. The incidence of vomiting in both groups was 11% while in-hospital and 23% after discharge. Each episode of in-hospital vomiting prolonged discharge by 17 +/- 4 min, P < 0.001. Mean cost per case for anaesthetic drugs was less in Group O, 18 +/- 8 vs 21 +/- 10, CDN$, mean +/- SD, P < 0.01. CONCLUSION: The two methods of antiemetic prophylaxis were equally effective. Propofol-based anaesthesia was more expensive.

Adolescent↗
PubMed1997

The pursuit of colostomy continence.

The lifelong management required by patients with permanent colostomies leads to dissatisfaction with quality of life for many. Through the years, multiple techniques have been attempted to improve the quality of life by pursuing colostomy continence. Such endeavors include surgical interventions, nonsurgical devices and management, and behavior modification techniques. Efforts in research and development continue, and the desire to achieve continence of the stoma remain common cause among persons with on ostomy and those involved in their care.

Colostomy↗
PubMed1997

Prophylaxis for vomiting by children after tonsillectomy: dexamethasone versus perphenazine.

UNLABELLED: The effects of dexamethasone and perphenazine on vomiting after tonsillectomy in children were compared in 226 healthy children aged 2-12 yr. The study was randomized, stratified, blocked, and double-blind. Anesthesia was induced intravenously (I.V.) with propofol or by inhalation with halothane and N2O. Dexamethasone 150 microg/kg or perphenazine 70 microg/kg was administered I.V. after the induction of anesthesia in a double-blind fashion. Perioperative management of emesis, pain, fluids, and patient discharge was all standardized. The groups had similar demographic characteristics. Perphenazine significantly reduced the incidence of in-hospital vomiting compared with dexamethasone (13% vs 36%, P < 0.001). The incidence of out-of-hospital vomiting was almost identical. Overall, the incidence was significantly different for perphenazine vs dexamethasone (33% vs 46%, P = 0.04) using logistic regression analysis. Of note, sex and induction technique were significant predictors of postoperative vomiting (P < 0.05) using logistic regression analysis, with male patients and those patients undergoing I.V. induction vomiting less. In conclusion, perphenazine more effectively decreases vomiting by children after tonsillectomy in an ambulatory hospital setting compared with dexamethasone. IMPLICATIONS: Postoperative vomiting can have many debilitating effects, and children undergoing tonsillectomy are at particular risk. We compared the effects of dexamethasone and perphenazine on vomiting after tonsillectomy in 266 children. We found perphenazine more effective than dexamethasone before discharge from hospital but that the two drugs have similar effects after discharge.

Anesthesia↗