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P Jacobs

Publications and source records attributed to P Jacobs.

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

Biochemical and immunological characterization of a recombinant precursor form of the house dust mite allergen Der p 1 produced by Drosophila cells.

BACKGROUND: The major house dust mite allergen Der p 1 elicits strong IgE antibody responses in patients suffering from mite allergy. OBJECTIVE: This study reports the expression and characterization of a recombinant precursor form of Der p 1 secreted as ProDer p 1 from insect cells. METHODS: The cDNA coding for ProDer p 1 was cloned downstream to the gp67 signal peptide, starting from commercial cDNA encoding Der p 1 and PCR-amplified ProDer p 1 genomic fragment. ProDer p 1, expressed in Drosophila cells and purified from culture medium, was compared to Der p 1 isolated from mite culture, in terms of glycosylation, enzymatic activity as well as IgG- and IgE-binding capacity. RESULTS: Sequence analysis of the genomic clone of ProDer p 1 revealed that, besides two introns in the mature Der p 1 coding sequence, two introns were also present in the propeptide coding sequence. ProDer p 1 was purifed to homogeneity by a combination of ion-exchange, hydroxyapatite and gel filtration chromatographies. The precursor form of Der p 1 could be processed in vitro into mature Der p 1 under acidic and reducing conditions. Carbohydrate analysis clearly indicated that ProDer p 1 expressed from insect cells was glycosylated and that glycan structures were located only in the prosequence. ProDer p 1 displayed a similar immunoreactivity towards IgE, monoclonal and polyclonal IgG antibodies compared to natural Der p 1. Specific activity measurements using synthetic substrates clearly indicated that, contrary to natural Der p 1, ProDer p 1 was totally enzymatically inactive. CONCLUSIONS: The expression of an enzymatically inactive and highly antigenic ProDer p 1 zymogen molecule could be a suitable strategy for the development of in vitro diagnosis test as well as for specific immunotherapy.

Allergens↗
PubMed2000

A cost-effectiveness analysis of the application of nitric oxide versus oxygen gas for near-term newborns with respiratory failure: results from a Canadian randomized clinical trial.

OBJECTIVE: To conduct a cost-effectiveness analysis of the use of inhaled nitric oxide (NO) vs. oxygen administered to near-term (gestational age > or =34 wks) newborns with severe respiratory illness that were referred for consideration of extracorporeal membrane oxygenation (ECMO). DESIGN: The cost-effectiveness analysis is based on outcome and utilization data from two multicentered randomized clinical trials conducted by the Canadian Inhaled Nitric Oxide Study group, one for patients with congenital diaphragmatic hernia (CDH) and one for patients without CDH. Data from the western Canadian ECMO center were used to establish costs. SETTING: Patients were cared for in Canadian regional neonatal intensive care units, including two ECMO centers. Air transport was used for transporting patients between centers. PATIENTS: Term and near-term newborns with severe respiratory illness who were receiving maximum conventional therapy and whose oxygenation index was >40. INTERVENTIONS: Patients randomly received NO or oxygen. If their conditions deteriorated, they qualified for ECMO. Not all that qualified for ECMO received it because of individual parent/ physician preferences. MEASUREMENTS AND MAIN RESULTS: The cost-effectiveness ratio was the ratio of net cost (including neonatal intensive care, ECMO, and transport) to net outcome (survival) for the two interventions. For non-CDH cases, the cost-effectiveness ratio was $36,613 (Canadian) per life saved; the confidence intervals were wide and the results were not statistically significant. For CDH patients, the death rate was lower for oxygen and the oxygen patients cost less; the results were not statistically significant. CONCLUSIONS: The small numbers of patients in the trials precluded significant results. Further, our results have a short-term time horizon (discharge to home or death). Thus, for non-CDH patients, the favorable ratio provides very qualified evidence in favor of NO.

Administration, Inhalation↗
PubMed2000

FRAXA and FRAXE: the results of a five year survey.

We report the results of a five year survey of FRAXA and FRAXE mutations among boys aged 5 to 18 with special educational needs (SEN) related to learning disability. We tested their mothers using the X chromosome not transmitted to the son as a control chromosome, and the X chromosome inherited by the son to provide information on stability of transmission. We tested 3738 boys and 2968 mothers and found 20 FRAXA and one FRAXE full mutations among the boys and none among the mothers. This gives an estimated prevalence of full mutations in males of 1 in 5530 for FRAXA and 1 in 23 423 for FRAXE. We found an excess of intermediate and premutation alleles for both FRAXA and FRAXE. For FRAXA this was significant at the 0.001 level but the excess for FRAXE was significant only at the 0.03 level. We conclude that the excess of intermediate and premutation sized alleles for FRAXA may well be a contributing factor to the boys' mental impairment, while that for FRAXE may be a chance finding. We studied approximately 3000 transmissions from mother to son and found five instabilities of FRAXA in the common or intermediate range and three instabilities of FRAXE in the intermediate range. Thus instabilities in trinucleotide repeat size for FRAXA and FRAXE are rare, especially among alleles in the common size range.

Adolescent↗
PubMed2000

Transthyretin isoleucine-122 mutation in African and American blacks.

The gene frequency of the transthyretin (TTR) mutation (Val122Ile) was studied in African and African-American populations. The African populations analyzed included the Zulu and Xhosa of South Africa, and Yorubas from the city of Ibadan, Nigeria. The African-American population included patients at the Veterans Affairs (VA) Medical Center, Indianapolis, and newborns from a local hospital in Indianapolis. The Val122Ile TTR mutation was identified in 1 of 55 Zulu, 0 of 34 Xhosa, 0 of 9 Nigerian subjects, 5 of 51 Veteran patients, and 3 of 103 newborns. Assuming the 2.91% prevalence in newborns to be the norm, there is a significant increased prevalence in the VA patient population.

Adult↗
PubMed2000

Lymphoma--histopathology in changing clinical perspective. Non-Hodgkin's Lymphoma Classification Project.

BACKGROUND: Lymphoma management has traditionally been dominated by nodal histopathology. Unfortunately, many different classifications coexisted and frequent revisions have often obscured clinical correlations. Some improvement in understanding histogenesis followed the introduction of immunophenotyping, while a number of new entities have been described in the last decade. In addition the whole question of lymphomagenesis is undergoing critical exploration. The use of cellular and molecular biological techniques is therefore shifting focus to the role of oncoproteins and the impact of mutation in the normally modulating suppressor genes. To accommodate these advances the International Lymphoma Study Group has proposed the Revised European-American Lymphoma Classification. While this is an undoubted advance, it has met with persisting concerns regarding applicability to patient management. STUDY SETTING: In determining the extent to which the latter reservation is valid, and at the same time directly testing the clinicopathological value of the new system, a group of acknowledged experts drawn from nine major academic centres worldwide analysed approximately 1,400 previously unreported cases, focusing on outcome. As part of that study 196 consecutive patients seen in Cape Town were separately examined. RESULTS: Findings here were similar to those of the overall experience, although distinct geographical differences emerged. Specifically in the follicular centre-cell lymphomas there was no difference in the 5-year failure-free survival rate, but these neoplasms accounted for 33% of lymphomas, which is similar to North America and London but contrasts with the 14% in the remaining six sites. Also, while mean survival for all types of peripheral T-cell lymphoma was 18% at 5 years, these accounted for 8% of lymphomas locally, as seen also in London and Hong Kong, but exceeding the 3-6% reported elsewhere. Local experience, as in the other eight centres, documented good diagnostic concordance between trained haematopathologists when this classification was used by them all. Furthermore, unusual subtypes were generally well accommodated within this revised system. It should be noted that while histopathological features retain predictive value, they should not be considered the predominant factor. It was concluded that for management decisions to be appropriate, renewed and correct weighting must be assigned to other prognostic variables that include clinical features and markers of tumour biology. SUMMARY: This more enlightened prerequisite is the central goal that underlies optimal treatment outcome, since it determines stratification to appropriate and peer-reviewed protocols. It follows that review of histopathology needs to precede management of all newly diagnosed cases, preferably only by accredited multidisciplinary clinics. The previous anachronism of basing therapy on opinions of non-specialist pathologists, without appropriate review, is unwise. Furthermore, treatment by lone practitioners, or even single-specialty groups that lack the discipline to analyse their findings critically and regularly report their updated results, can no longer be considered standard of practice and should be discouraged.

Adult↗
PubMed1999

P-glycoprotein inhibition by glibenclamide and related compounds.

Glibenclamide is well known to interact with the sulphonylurea receptor (SUR) and has been shown more recently to inhibit the cystic fibrosis transmembrane conductance regulator protein (CFTR), both proteins that are members of the ABC [adenosine 5'-triphosphate (ATP)-binding cassette] transporters. The effect of glibenclamide and two synthetic sulphonylcyanoguanidine derivatives (dubbed BM-208 and BM-223) was examined on P-glycoprotein, the major ABC transporter responsible for multidrug resistance (MDR) in cancer cells. To this end, we employed different cell lines that do or do not express P-glycoprotein, as confirmed by Western blotting: first, a tumour cell line (VBL600) selected from a human T-cell line (CEM) derived from an acute leukaemia; second, an epithelial cell line derived from a rat colonic adenocarcinoma (CC531(mdr+)) and finally, a non tumour epithelial cell line derived from the proximal tubule of the opossum kidney (OK). Glibenclamide and the two related derivatives inhibited P-glycoprotein because firstly, they acutely increased [3H]colchicine accumulation in P-glycoprotein-expressing cell lines only; secondly BM-223 reversed the MDR phenomenon, quite similarly to verapamil, by enhancing the cytotoxicity of colchicine, taxol and vinblastine and thirdly, BM-208 and BM-223 blocked the photoaffinity-labelling of P-glycoprotein by [3H]azidopine. Furthermore, glibenclamide is itself a substrate for P-glycoprotein, since the cellular accumulation of [3H]glibenclamide was low and substantially increased by addition of P-glycoprotein substrates (e. g., vinblastine and cyclosporine) only in the P-glycoprotein-expressing cell lines. We conclude that glibenclamide and two sulphonylcyanoguanidine derivatives inhibit P-glycoprotein and that sulphonylurea drugs would appear to be general inhibitors of ABC transporters, suggesting an interaction with some conserved motif.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

When there is no benchmark: designing a primary care-based chronic pain management program from the scientific basis up.

Managed care has been accused of ignoring the patient with pain. The challenge for a health maintenance organization (HMO) was not just how to deliver state-of-the-art care, but how to deliver it to the 40,000 members who experience chronic pain at a reasonable cost and with enduring outcomes. This article describes how one managed care organization set about improving the care of patients with chronic pain. The article includes the design process, the model implemented, and some suggestions for transfer of this technology to others who might want to explore developing a similar model.

Benchmarking↗
PubMed1999

Trace metal excretion in patients with homozygous hypercholesterolaemia.

In patients with familial hypercholesterolaemia regular therapeutic apheresis is acknowledged to have long-term benefit. A previously unrecognised complication of such intervention is the development of anaemia that reflects a sub-optimal dietary iron intake coupled with accelerated loss of this trace metal in the fluid discarded after each procedure. Additional contributions result from enhanced urinary excretion as a result of chelation to citrate used as an anticoagulant and frequent blood sampling. The underlying pathophysiologic process appears to be reduced deformability. We now document similar and significant losses of zinc, copper and chromium in these circumstances. In the case of the latter three elements, no associated clinical syndromes have thus far been identified, probably because deficiency states are less well-recognised than that due to iron loss and, additionally, because critical reductions are avoided by their replenishment during a normal food intake. These studies are, nevertheless, relevant since they are the basis for recommending prophylactic supplementation during this form of management.

Adolescent↗
PubMed1999

Differential neutralizing antibody responses to varicella-zoster virus glycoproteins B and E following naked DNA immunization.

The only available vaccine against varicella-zoster virus (VZV) consists of the VZV-Oka attenuated but persistent virus strain. Development of a safer, subunit vaccine is therefore desirable. In this prospect, nucleic acid vaccines, expressing truncated forms of VZV glycoproteins B (recgB) and E (recgE) from which the anchor and the cytoplasmic domains were deleted, were used to immunize mice. Vaccination with recgB encoding plasmid elicited a strong and specific humoral immune response. Total IgG and neutralizing titres were comparable to those previously obtained by vaccination with purified and adjuvanted native recgB. In contrast, mice immunization with recgE encoding plasmid only induced a very weak immune response whereas we previously showed that vaccination with adjuvanted native or denatured recgE protein led to high neutralizing titres. The weakness of the immune response induced by recgE-encoding plasmid depended neither on the deletion of the anchor domain in the gE gene nor on the animal model. Analysis of antibody isotypes produced by plasmid immunizations revealed a response slightly dominated by IgG2a. Taken together, the data indicate that a VZV subunit vaccine based on adjuvanted recombinant glycoprotein E is more promising than a nucleic acid-based vaccine strategy. As regards recgB, both vaccination approaches might be appropriate.

Animals↗
PubMed1999

In aplastic anemia progenitor cells have a reduced sensitivity to the effects of growth factors.

We have recently shown that in patients with aplastic anemia (AA) recovering following immunosuppressive therapy, the persistent reduction in the bone marrow clonogenic potential is unrelated to suppressive effects of the myeloid stroma and intrinsic to the hematopoietic progenitors. We examined the mechanisms of this defect by determining the response of the aplastic CD34+ clonogenic precursors to proliferative signals induced by hematopoietic growth factors and comparing their results with those of a control population. Light density bone marrow mononuclear cells were lymphocyte and monocyte depleted and enhanced for the CD34+ progenitors by immunomagnetic selection. Selected progenitors were then cultured in the mixed colony assay with incremental concentrations of combinations containing erythropoietin (Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and c-kit ligand. Bone marrow from aplastic patients had significantly fewer light density cells displaying the CD34 antigen (mean 0.65%, SD 0.35 vs. 1.62%, SD 1.4; p=0.002). Dose response studies on aplastic CD34+ cells demonstrated that at low concentrations of Epo, IL-3 and GM-CSF, clonogenic growth was significantly impaired but achieved normal values at concentrations giving plateau growth in control cultures. However, for all colony types, responses to effective concentrations of c-kit ligand corresponded with those of controls. These data suggest abnormalities at the receptor or signal transduction levels.

Adolescent↗
PubMed1999

Evaluation of a telepsychiatry pilot project.

We assessed a telepsychiatry pilot project in which a psychiatric hospital was linked with mental health clinics in five general hospitals. Information was collected through questionnaires administered to patients, service providers and psychiatric consultants, and by interviews. The technology was considered easy to use by participating health-care professionals and patients, and the quality of the sound and picture was adequate. Survey data suggested acceptance and satisfaction on the part of patients, service providers and psychiatric consultants. An economic analysis indicated that at 396 consultations per year the service cost the same as providing a travelling psychiatrist (C$610 per consultation); with more consultations, telepsychiatry was cheaper. Information gathered during the evaluation suggested that the use of videoconferencing for psychiatric consultations was a viable option for an integrated, community-based mental health service.

Canada↗
PubMed1999

An assessment framework for telemedicine applications.

Pressures for the adoption of telemedicine place increased demands on purchasers to assess applications of the technique. Assessment principles are helpful in defining an evaluation framework for use at the local level. We suggest an assessment approach that includes five specific elements: specification; performance measures; outcomes; summary measures; and operational and other considerations. The approach described here was developed to assist with the needs of individual health authorities and institutions within the health-care system of Alberta. Aspects of the approach are illustrated using a telepsychiatry example under the assumptions made. Conventional psychiatry (where the patient visited the psychiatrist) was most expensive for the patient. The alternatives, telepsychiatry and outreach psychiatry (where the psychiatrist travelled to the patient), cost about the same from the service provider's perspective (and from that of society as a whole); they were both much cheaper for the patient. At higher volumes, telepsychiatry would be cheaper than outreach.

Evaluation Studies as Topic↗
PubMed1999

Cost of care for individuals with cystic fibrosis: a regression approach to determining the impact of recombinant human DNase.

We estimated direct medical costs of care and important determinants of the costs in patients with cystic fibrosis (CF), including therapy with recombinant human DNase (rhDNase). Costs were estimated with resource use data from the Epidemiologic Study of Cystic Fibrosis. Ordinary least squares regression was used to determine the effect of clinical and demographic variables on individual cost of care. The estimated cost of caring for 303 patients in Alberta was $2,279,801 in 1996. The mean cost of care was $7524 (range $386-92,376)/patient. Regression results indicated that age and forced expiratory volume predicted had a negative association with costs. Being female, receiving rhDNase, and having Pseudomonas aeruginosa or Burkholderia cepacia were all associated with high costs. Our estimates indicated large interindividual variation in cost of care for patients with CF.

Adult↗
PubMed1999

Standard cost lists for healthcare in Canada. Issues in validity and inter-provincial consolidation.

A standard cost list is a listing of recommended costs for a selected group of services. Standard costs are used in economic evaluation studies to eliminate that proportion of cost differences between interventions that are due to cost differences between providers. In this article we provide a summary of cost lists for pharmaceutical economic evaluation purposes which have been developed in 2 provinces in Canada-Alberta and Manitoba. We then assess these 2 lists from 2 different viewpoints. First, we developed criteria for the internal and external validity of costs and, in light of these validity criteria, we assessed how the 2 standard cost lists compared with the 'ideal' measure of long run marginal costs. Second, we identified the criteria for the inter-provincial consolidation of standard cost measures (in order to develop a single, consolidated cost list); in light of these criteria, we assessed whether the degree to which the 2 separate lists could be consolidated. The lists achieved a considerable degree of external validity, but fared less well in terms of internal validity. However, these results depend on the 'ideal' measure of cost which is used. The lists, in the forms which were developed, are not easily consolidated into a single list. Further refined cost data would be needed in order to achieve consolidation.

Alberta↗