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Biomedical subjects

A Morgan

Publications and source records attributed to A Morgan.

At least 91 records · Page 5Linked to original sources
PubMed1997

Foscarnet for prevention of cytomegalovirus infection in allogeneic marrow transplant recipients unable to receive ganciclovir.

Cytomegalovirus (CMV) disease can be prevented by administration of ganciclovir prophylactically post-transplant. However, up to 30% of patients discontinue use of ganciclovir as a result of profound neutropenia and may subsequently develop CMV infections while unprotected. To prevent reactivation of CMV, we administered foscarnet to 39 adults unable to receive ganciclovir due to delayed engraftment or ganciclovir-induced neutropenia. Twenty-four (62%) of the patients had received T cell-depleted marrow transplants. Foscarnet sodium 60 mg/kg i.v. daily was continued until the neutropenia resolved, at which time ganciclovir was resumed. CMV prophylaxis commenced at a median of 28 days following transplantation. Median time to initiation of foscarnet was day 60 post-transplant, and the median duration of treatment was 22 days. Foscarnet was well-tolerated. Six (15%) patients had CMV detected while receiving prophylaxis, and CMV-related mortality was 5%. Foscarnet is a safe and effective agent for prevention of CMV disease in allogeneic transplant recipients unable to receive ganciclovir.

Actuarial Analysis↗
PubMed1997

Influence of Quillaja saponaria triterpenoid content on the immunomodulatory capacity of Epstein-Barr virus iscoms.

The immune responses to immunostimulating complexes (iscoms) containing recombinant Epstein-Barr virus (EBV) gp340 envelope protein was evaluated in BALB/c (H-2(d)) and CBA (H-2(k)) mice. Gp340-iscoms were used either with a low content of Quillaja triterpenoid adjuvant (L-iscoms) or supplemented with additional Quillaja adjuvant in the form of iscomatrix (S-iscoms). Class and subclass distribution of anti-gp340 antibodies, EBV-neutralizing antibodies, antigen-specific T cell proliferation and cytokine production were determined and these results compared to those obtained by immunization with non-adjuvated gp340. The H-2(d) and H-2(k) mice were characterized as low or high responders in respect to the level of specific anti-gp340 antibodies, secretion of IgG2a isotype, antigen-specific lymphoproliferative capacity, interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) production in the basic immunizations with gp340. While presentation of the antigen in iscom formulations with low levels of Quillaja triterpenoids induces a moderate enhancement of the immune responses in the low responder H-2(d) mice, supplementation with high levels of iscomatrix immunomodulator was required to enhance the immune responses in the high responder H-2(k) mice. In both mouse strains subcutaneous immunization with S-iscoms resulted in a significant increase of IgG1- and IgG2a-specific antibodies, as well as in strong antigen-specific proliferative response confirmed by the simultaneous cytokine production. The enhanced antigen-specific secretion of IL-2 and IFN-gamma together with the abrogation of IL-10 and the absence of IL-4 indicates that the responses were driven towards a Th1-type rather than Th2-type immune response. The S-iscom formulations minimized the differences in immune responses between the two mouse strains, but the capacity of immune sera to neutralize EBV transformation in vitro remained completely strain-dependent. These data indicate that immune responses generated by iscoms can be manipulated by altering the triterpenoid composition of the iscoms and that the levels of triterpenoids can determine whether or not a Th1-type response is made.

Adjuvants, Immunologic↗
PubMed1997

Prevalence of Q fever in a rural practice.

BACKGROUND: Q fever is a world-wide condition caused by the rickettsia Coxiella burnetii. It appears more prevalent in agrarian communities and may have serious sequelae. METHODS: A descriptive, cross-sectional, observational study using a randomly selected group of the adult working practice population in a rural practice in West Wales was devised. An immunofluorescence test, which identified past infection, was used to look for associations between C. burnetii seropositivity and farm-related or social activities, and to compare the findings with those of other studies. An attempt was made to establish a clinical profile for the illness Q fever. RESULTS: Twenty-one subjects were found to be seropositive to C. burnetii. No definite consistent clinical features were identified. Farming was undoubtedly a risk factor for the disease, maybe with other related factors also important. There was a possibility that alcohol had a protective effect. No sinister sequelae were described. CONCLUSIONS: Q fever occurs more frequently in farmers than in non-farmers, but was less common than previously thought. Is Q fever accurately described in medical textbooks? A case is made for a more co-operative approach between primary carers and epidemiologists in the study of illnesses in populations.

Agriculture↗
PubMed1997

Direct demonstration of persistent Epstein-Barr virus gene expression in peripheral blood of infected common marmosets and analysis of virus-infected tissues in vivo.

Epstein-Barr virus (EBV) infection in animal model systems has been studied previously in marmosets and tamarins using serology and PCR of saliva. Here we directly demonstrated long-term persistence of EBV in the peripheral blood of marmosets by assaying EBER RNA expression. A new reverse transcription-PCR assay, able to distinguish a naturally occurring strain polymorphism in EBER 2 that may be useful as a strain marker for monitoring persistence and interactions between multiple strains in the same animal or person, has been developed. In situ hybridization and immunohistochemistry have also been used to search for EBV-infected cells in the animals. The carrier state in the common marmoset is similar to that of humans in that it is asymptomatic, long-lived and displays a very low level of circulating virus-infected cells. It differs from the human in lacking the characteristic antibody response to EBNA 1.

Animals↗
PubMed1997

Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A-mediated entry by Epstein-Barr virus.

Diseases of the nasopharyngeal epithelium due to Epstein-Barr virus (EBV) infection typically occur in chronic virus carriers with preexisting virus-specific antibodies. In vitro studies have shown that EBV-specific immunoglobulin A (IgA) promotes infection of human epithelial cells, otherwise refractory to EBV, via the polymeric immunoglobulin receptor (pIgR). To determine if EBV similarly exploits IgA transport mechanisms in vivo, we examined the fate of IgA-EBV complexes in the blood of mice, where pIgR-mediated transcytosis of IgA immune complexes through hepatocytes eliminates exogenous antigens from the circulation. By PCR analysis we showed hepatobiliary transport of IgA-EBV in viremic mice, but without detectable hepatocellular infection by immunostaining. Because efficient transport of EBV immune complexes might avert an infectious outcome, we modulated the transcytotic pathway in polarized Madin-Darby canine kidney (MDCK) cells transfected with pIgR to determine the effect on viral antigen expression. Like hepatocytes in vivo, MDCK cells in polarized monolayers translocated IgA-EBV from the basal cell face into apical medium without evidence for infection. However, when exposed to IgA-EBV as unpolarized single-cell suspensions, MDCK cells expressed EBV immediate-early and early antigens. These results suggest that pIgR-mediated transcytosis of pIgA-EBV through epithelium facilitates endogenous spread of EBV in long-term virus carriers, with infection being confined to cells with altered polarity from prior cytopathology.

Animals↗
PubMed1996

Similar effects of alpha- and beta-SNAP on Ca(2+)-regulated exocytosis.

Soluble N-ethylmaleimide-sensitive fusion protein attachment proteins (SNAP) proteins function in Ca(2+)-regulated exocytosis. Recent work (Schiavo et al. (1996) Nature 378, 733-736) based on in vitro protein interactions has raised the possibility that alpha- and beta-SNAPs have distinct roles in exocytosis. We have examined this possibility by comparing the activities of recombinant alpha- and beta-SNAPs. Both of these proteins were able to similarly bind NSF and activate its ATPase activity but to a lesser extent than gamma-SNAP. When introduced into digitoninpermeabilised chromaffin cells, both alpha- and beta-SNAP stimulated Ca(2+)-regulated exocytosis in a MgATP-dependent manner. The dose-response relationships for these proteins were essentially the same and addition of both proteins did not lead to any further increase in exocytosis above that due to each protein alone. We conclude that alpha- and beta-SNAPs are interchangeable isoforms with similar functions in regulated exocytosis.

Adenosine Triphosphatases↗
PubMed1996

Soluble N-ethylmaleimide-sensitive-factor attachment protein and N-ethylmaleimide-insensitive factors are required for Ca2+-stimulated exocytosis of insulin.

Ca2+ stimulates exocytosis in permeabilized insulin-secreting cells. To investigate the putative cytosolic components involved in the Ca2+ response, HIT-T15 cells (a pancreatic B-cell line) were permeabilized with streptolysin-O, a procedure that allows rapid exchange of soluble components including macromolecules. We found that in this cell preparation the secretory response to Ca2+ but not to guanosine 5'-[gamma-thio]triphosphate was lost as a function of time and could be restored by rat brain cytosol in a concentration-dependent manner. Reconstitutive activity of rat brain cytosol was found in a high-molecular-mass heat-labile partially N-ethylmaleimide(NEM)-sensitive fraction. The NEM-sensitive factor (NSF) and the soluble NSF attachment protein (alpha-SNAP) were found to be expressed in HIT-T15 cells and largely lost (about 30% remaining) from porated cells. Recombinant alpha-SNAP partially reconstituted the Ca2+ response when added to the permeabilized cells. Moreover, alpha-SNAP restored the effect of NEM-treated cytosol to the level observed for untreated cytosol. In contrast, NSF was ineffective when preincubated alone or with NEM-treated cytosol. Our results indicate that both alpha-SNAP and NEM-insensitive cytosolic factors are involved in Ca2+-mediated exocytosis from endocrine HIT-T15 cells.

Animals↗
PubMed1996

Does posterior sagittal anorectoplasty in patients with high imperforate anus provide superior fecal continence?

The posterior sagittal anorectoplasty (PSARP) has become the primary surgical procedure for patients with high imperforate anus. Very few careful long-term follow-up studies have established the superiority of the PSARP procedure over other surgical repair techniques. The authors' goal was to evaluate the operation and to identify the factors associated with improved continence. The medical records, operative reports, and radiographs of 53 patients (46 male, 7 female) who underwent PSARP for high imperforate anus at Children's Hospital and Medical Center (CHMC) between 1982 and 1990 were reviewed retrospectively. Subjective follow-up data were collected by telephone questionnaire, assessing habits indicative of stool continence, and a "fecal continence score" (FCS) was calculated for each patient. A prospective, 7-day diary assessing similar patterns of fecal continence was completed by each patient's family. The mean age of the patients studied was 8.0 years, and the mean follow-up period was 6.8 years. The telephone questionnaire was completed for 48 patients (94%). Toilet training for bowel continence was successful in 20 patients (42%) and occasionally successful in another 20 patients (42%), but 8 patients (16%) had no awareness of impending stool. Forty-five (94%) were physically active, but 16 (33%) reported social problems related to offending odor. The mean fecal continence score for all patients was 3.0 +/- 1.4 (5=excellent, completely continent), which was nearly identical to published scores for the other types of surgical repair. The FCS did not improve with age. The parents' responses to the telephone questionnaire matched the results obtained from the prospectively collected continence diary data. The authors' results for PSARP in patients with high imperforate anus do not differ substantially from those achieved by other repair techniques. Previously cited prognostic factors such as fistula anatomy and sacral anomalies did not appear to alter the functional results in the authors' series. Aggressive postoperative bowel management should be anticipated in all patients who have high imperforate anus and may benefit those who otherwise would achieve less satisfactory continence.

Adolescent↗
PubMed1996

Domains of alpha-SNAP required for the stimulation of exocytosis and for N-ethylmalemide-sensitive fusion protein (NSF) binding and activation.

The binding of alpha-SNAP to the membrane proteins syntaxin, SNAP-25, and synaptobrevin leads to the recruitment of the N-ethylmaleimide-sensitive fusion protein (NSF). ATP hydrolysis by NSF has been suggested to drive conformational changes in one or more of these membrane proteins that are essential for regulated exocytosis. Functional evidence for a role of alpha-SNAP in exocytosis in adrenal chromaffin cells comes from the ability of this protein to stimulate Ca(2+)-dependent exocytosis in digitonin-permeabilized cells. Here we examine the effect of a series of deletion mutants of alpha-SNAP on exocytosis, and on the ability of alpha-SNAP to interact with NSF, to define essential domains involved in protein-protein interactions in exocytosis. Deletion of extreme N- or C-terminal regions of alpha-SNAP produced proteins unable to bind to syntaxin or to stimulate exocytosis, suggesting that these domains participate in essential interactions. Deletion of C-terminal residues abolished the ability of alpha-SNAP to bind NSF. In contrast, deletion of up to 120 N-terminal residues did not prevent the binding of NSF to immobilized alpha-SNAP and such mutants were also able to stimulate the ATPase activity of NSF. These results suggest that the C-terminus, but not the N-terminus, of alpha-SNAP is crucial for interactions with NSF. The involvement of the C-terminus of alpha-SNAP, which contains a predicted coiled-coil domain, in the binding of both syntaxin and NSF would place the latter two proteins in proximity in a ternary complex whereupon the energy derived from ATP hydrolysis by NSF could induce a conformational change in syntaxin required for exocytosis to proceed.

Adenosine Triphosphatases↗
PubMed1996

Drug resistance in Nepali leprosy patients.

Although multidrug therapy (MDT) was introduced into Nepal in 1983, the MDT coverage only recently exceeded 67%. In view of the large number of patients who were still receiving dapsone monotherapy, it is relevant to investigate the current levels of dapsone and rifampin resistance. The study was undertaken at a leprosy referral hospital near Kathmandu. Over a 5 1/2-year period, 157 leprosy patients with a bacterial index (BI) > or = 2.0 were investigated for drug resistance according to the method of Rees. Among previously untreated cases, 6% of 88 isolates showed low-dose dapsone resistance; among previously treated patients with a presumed relapse, 47% of 34 isolates demonstrated dapsone resistance. In the remaining 35 cases there was no growth in control mice. Rifampin resistance was not confirmed in any case.

Adolescent↗
PubMed1995

Exposure of B-lineage lymphoid cells to low energy electromagnetic fields stimulates Lyn kinase.

Here, we present evidence that exposure of B-lineage lymphoid cells to low energy electromagnetic fields (EMF) stimulates the protein tyrosine kinases Lyn and Syk, results in tyrosine phosphorylation of multiple electrophoretically distinct substrates, and leads to downstream activation of protein kinase C (PKC). EMF exposure enhances protein tyrosine phosphorylation in Syk deficient but not in Lyn-deficient B-lineage lymphoid cells and stimulates Lyn kinase activity in wild-type as well as Syk-deficient B-lineage lymphoid cells. These results indicate that activation of Lyn kinase is sufficient and mandatory for EMF-induced tyrosine phosphorylation in B-lineage lymphoid cells. The PKC activity increases later than the Lyn activity and pretreatment with the PTK inhibitors genistein or herbimycin A abrogates the EMF-induced PKC signal. Thus, stimulation of Lyn is a proximal and mandatory step in EMF-induced activation of PKC in B-lineage lymphoid cells. Our observations prompt the hypothesis that a delicate growth regulatory balance might be altered in B-lineage lymphoid cells by EMF-induced activation of Lyn.

Amino Acid Sequence↗
PubMed1995

A role for soluble NSF attachment proteins (SNAPs) in regulated exocytosis in adrenal chromaffin cells.

Digitonin-permeabilized chromaffin cells secrete catecholamines by exocytosis in response to micromolar Ca2+ concentrations, but lose the ability to secrete in response to Ca2+ as the cells lose soluble proteins through the plasma membrane pores. Such secretory run-down can be retarded by cytosolic fractions, thus providing an assay for proteins potentially involved in the exocytotic process. We have used this assay to investigate the role of N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment proteins (SNAPs) in regulated exocytosis. Recombinant alpha- and gamma-SNAP stimulated Ca(2+)-dependent exocytosis, although recombinant NSF was ineffective, despite the fact that NSF and alpha-SNAP leak from the permeabilized cells with similar time courses. However, around one third of cellular NSF was found to be present in a non-cytosolic form and so it is possible that this is sufficient for exocytosis and that exogenous SNAPs stimulate the exocytotic mechanism by acting on the leakage-insensitive NSF. The stimulatory effect of alpha-SNAP displayed a biphasic dose-response curve and was maximal at 20 micrograms/ml. The effect of alpha-SNAP was Ca(2+)- and MgATP-dependent and was inhibited by N-ethylmaleimide and botulinum A neurotoxin, indicating a bona fide action on the exocytotic mechanism. Furthermore, Ca2+ concentrations which trigger catecholamine secretion acted to prevent the leakage of NSF and alpha-SNAP from permeabilized cells. These findings provide functional evidence for a role of SNAPs in regulated exocytosis in chromaffin cells.

Adrenal Medulla↗
PubMed1995

The durability and distribution of glass fibres in the rat following intra-peritoneal injection.

Intra-peritoneal (IP) injection is being recommended as a means of assessing potential carcinogenicity of MMF following inhalation. Little is known of the behaviour of fibres in the peritoneal cavity or its relevance to the lung. This study considered both the biopersistence and the distribution of dose following IP injection of fibres. Biopersistence of fibres in the peritoneal cavity has been compared with that observed previously in the lung. Marked differences were found, with long fibres (> 20 microns) being more durable in the peritoneal cavity than in the lung. Breakage could not account for this finding, whereas differences in dissolution could. The behaviour of fibres and powders and their distribution in the peritoneal cavity following injection of different masses is reported. Distribution of dose depended on injection mass, with masses of < 1.5 mg showing even uptake onto the surfaces of the peritoneal organs, and higher masses resulting in the development of nodules of injection material, free in the peritoneal cavity, or loosely bound to the peritoneum. With fine powder, some clearance was observed over the first 48 h after IP injection, but not with fibres. The findings on both durability and distribution of dose following IP injection have implications on the justification for the use of IP injections in assessment of potential carcinogenicity of fibres following inhalation.

Animals↗
PubMed1995

Deposition of inhaled asbestos and man-made mineral fibres in the respiratory tract.

This paper reviews publications dealing with the deposition of fibrous particles, including asbestos and man-made mineral fibres, in the respiratory tract of man and experimental animals, particularly of the rat. The effects of fibre diameter and length on total, thoracic and alveolar deposition are discussed. Total deposition in the respiratory tract of the rat increases quite steeply with aerodynamic diameter (Dae) from about 20% at a Dae of 1 micron to 100% at a Dae of 5 microns. Deposition in the alveolar region reaches a peak of about 10% at a Dae of about 2 microns, which corresponds to an actual fibre diameter of about 0.4 microns. For fibres with diameters greater than this, alveolar deposition falls rapidly. For example, long glass fibres with an actual diameter of 1.5 microns or short glass fibres with an actual diameter of 3 microns are essentially non-respirable in the rat. The fate of fibres deposited in different regions of the respiratory tract of the rat is also discussed and the factors which predispose fibres either to remain in alveolar macrophages or to be transferred to the interstitium and pulmonary lymphatics. Finally, the distributions in the lungs of fibres administered by inhalation and by intratracheal instillation are compared, and the advantages and drawbacks of each method of delivery discussed.

Administration, Inhalation↗