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PubMed1990

Characterization of a myosin-like antigen from Onchocerca volvulus.

Recombinant cDNAs expressing an immunodominant antigen (Onchoag-1) of Onchocerca volvulus were identified by immunoscreening a cDNA expression library. The Onchoag-1 cDNAs are derived from an 8-kb mRNA that codes for a protein with an apparent molecular mass of 200 kDa. Indirect immunofluorescence using antisera against a recombinant fusion protein showed that Onchoag-1 is located in the muscle tissues of adult O. volvulus. The 2-kb sequence of one of the cDNAs contains a single open translation reading frame that encodes a protein with sequence similarities to Caenorhabditis elegans myosin heavy chain. Analysis of the 3' region of Onchoag-1 chromosomal gene reveals that it is frequently interrupted by short introns that follow the GT/AG rule at their splice sites. Studies on this myofibrillar antigen should contribute to our understanding of muscle function in O. volvulus as well as provide useful insight to the genesis of the immunopathological damage that is often associated with allergic reactions (the Mazzotti reactions) in onchocerciasis patients, following the administration of a chemotherapeutic agent such as diethylcarbamazine.

Amino Acid Sequence↗
PubMed2005

Analysis of anabolic steroids in the horse: development of a generic ELISA for the screening of 17alpha-alkyl anabolic steroid metabolites.

Due to the potential for misuse of a wide range of anabolic steroids in horse racing, a screening test to detect multiple compounds, via a common class of metabolites, would be a valuable forensic tool. An enzyme-linked immunosorbent assay (ELISA) has been developed to detect 17alpha-alkyl anabolic steroid metabolites in equine urine. 16beta-Hydroxymestanolone (16beta,17beta-dihydroxy-17alpha-methyl-5alpha-androstan-3-one) was synthesised in six steps from commercially available epiandrosterone (3beta-hydroxy-5alpha-androstan-17-one). Polyclonal antibodies were raised in sheep, employing mestanolone (17beta-hydroxy-17alpha-methyl-5alpha-androstan-3-one) or 16beta-hydroxymestanolone conjugated to human serum albumin, via a 3-carboxymethyloxime linker, as antigens. Antibody cross-reactivities were determined by assessing the ability of a library of 54 representative steroids to competitively bind the antibodies. Antibodies raised against 16beta-hydroxymestanolone showed excellent cross-reactivities for all of the 16beta,17beta-dihydroxy-17alpha-methyl steroids analysed and an ELISA has been developed to detect these steroid metabolites. Using this 16beta-hydroxymestanolone assay, urine samples from horses administered with stanozolol (17alpha-methyl-pyrazolo[4',3':2,3]-5alpha-androstan-17beta-ol), were analysed raw, following beta-glucuronidase hydrolysis, and following solid-phase extraction (SPE) procedures. The suppressed absorbances observed were consistent with detection of the metabolite 16beta-hydroxystanozolol. Positive screening results were confirmed by comparison with standard LCMS analyses. Antibodies raised against mestanolone were also used to develop an ELISA and this was used to detect metabolites retaining the parent D-ring structure following methandriol (17alpha-methylandrost-5-ene-3beta,17beta-diol) administration. The ELISA methods developed have application as primary screening tools for detection of new and known anabolic steroid metabolites.

Anabolic Agents↗
PubMed2004

Infusion techniques for peripheral arterial thrombolysis.

BACKGROUND: Thrombolytic therapy is a useful tool in the management of acute peripheral arterial ischaemia. Fibrinolytic drugs are used to disperse blood clot to clear arterial occlusion. A variety of techniques are used to deliver these agents. OBJECTIVES: To determine the optimal technique for infusion of fibrinolytic drugs in peripheral arterial ischaemia. SEARCH STRATEGY: The Cochrane Library (issue 3, 2003) and the Specialised Trials Register of the Cochrane Review Group on Peripheral Vascular Diseases (July 2003) were searched. Proceedings from meetings of British, European and North American Vascular Surgical and Radiological Societies, plus reference lists of identified studies were also searched for relevant trials. Major pharmaceutical firms and trialists were asked about unpublished trials. SELECTION CRITERIA: Two reviewers independently selected randomised controlled trials comparing infusion techniques of fibrinolytic agents in the treatment of acute peripheral arterial ischaemia. Trials with poor quality methodology were excluded. DATA COLLECTION AND ANALYSIS: Data from included trials were collated and analysed for the following outcomes: limb salvage, amputation, death, vessel patency, time to achieve thrombolysis, and reduction in the need for surgical intervention. Complication rates were compared for: major haemorrhage, cerebrovascular accident and distal embolization. MAIN RESULTS: Intra-arterial delivery of thrombolytic agents appeared to be more effective than intravenous administration. Thrombolysis was more effective when the angiographic catheter was placed within the thrombus. Although 'high dose' and 'forced infusion' techniques achieved vessel patency in less time than 'low dose infusion', there were more bleeding complications, and no increase in patency rates or improvement in limb salvage at 30 days. REVIEWER'S CONCLUSIONS: Implications for practice Thrombolysis should be reserved for patients with limb threatening ischaemia, due to the high risk of haemorrhage or death. Greater benefit is seen when the thrombolytic agent is delivered into the thrombus. Systemic intravenous thrombolysis is less effective than intra-arterial thrombolysis and is associated with an increase in bleeding complications. 'High dose' and 'forced infusion' techniques, or adjunctive agents such as platelet glycoprotein IIb/IIIa inhibitors may speed up thrombolysis, but these are not accompanied by lower amputation rates or a decreased need for adjunctive endovascular or surgical procedures. 'Low dose continuous infusion', following initial lacing of the thrombus with a high dose of the thrombolytic agent, is the least labour intensive technique. Implications for research Only large multicentre trials with carefully controlled inclusion criteria will be sufficiently powerful to demonstrate genuine benefit for a particular thrombolytic regime.

Fibrinolytic Agents↗
PubMed2006

Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug.

BACKGROUND: Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS: In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS: The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 micromole/kg) which produced peak serum concentration of approximately 36 microM and had a half-life of approximately 40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS: The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development.

Animals↗
PubMed2007

Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists.

Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.

Administration, Oral↗
PubMed2003

Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats.

Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRH-stimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonad-intact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [d-Ala(6), des-Gly(10)]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.

Anilides↗
PubMedDate not supplied

Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of transformed cell lines, but generally spares most normal cells. Transduction by an adenoviral vector expressing human TRAIL cDNA (Ad.TRAIL-GFP) resulted in both direct tumor cell killing as well as a potent bystander effect through presentation of TRAIL by transduced normal cells. Administration of Ad.TRAIL-GFP significantly prolonged survival of mice harboring either intracerebral glioblastomas or breast carcinoma-induced peritoneal carcinomatosis. Additionally, TRAIL induced prolonged transgene expression in normal tissue, presumably as a result of diminished immune-mediated destruction of vector-transduced cells. Taken together, these data suggest that vector-mediated transduction of TRAIL may represent an effective strategy for cancer gene therapy.

Adenoviruses, Human↗
PubMed2006

Vaccines for preventing influenza in the elderly.

BACKGROUND: Influenza vaccination of elderly individuals is recommended worldwide and has been targeted toward the elderly and those at serious risk of complications. OBJECTIVES: Our aim was to review the evidence of efficacy, effectiveness and safety of influenza vaccines in individuals aged 65 years or older. SEARCH STRATEGY: We searched the following databases on The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness (Issue 1, 2006); MEDLINE (January 1966 to March Week 3 2006); EMBASE (Dialog 1974 to 1979; SilverPlatter 1980 to December 2005); Biological Abstracts (SilverPlatter 1969 to December 2004); and Science Citation Index (Web of Science 1974 to December 2004). SELECTION CRITERIA: We considered randomised, quasi-randomised, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered. DATA COLLECTION AND ANALYSIS: We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths. MAIN RESULTS: Sixty-four studies were included in the efficacy / effectiveness assessment, resulting in 96 data sets. In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against ILI was 23% (6% to 36%) and non-significant against influenza (RR 1.04: 95% CI 0.43 to 2.51). We found no correlation between vaccine coverage and ILI attack rate. Well matched vaccines prevented pneumonia (VE 46%; 30% to 58%), hospital admission (VE 45%; 16% to 64%) and deaths from influenza or pneumonia (VE 42%, 17% to 59%). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19; 95% CI 0.02 to 2.01), ILI (RR 1.05: 95% CI 0.58 to 1.89), or pneumonia (RR 0.88; 95% CI 0.64 to 1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%; 12% to 38%) and all-cause mortality (VE 42%; 24% to 55%). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%; 21% to 33%), respiratory diseases (VE* 22%; 15% to 28%) and cardiac disease (VE* 24%; 18% to 30%); and for all-cause mortality (VE* 47%; 39% to 54%). The public health safety profiles of the vaccines appear to be acceptable. AUTHORS' CONCLUSIONS: In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest. The apparent high effectiveness of the vaccines in preventing death from all causes may reflect a baseline imbalance in health status and other systematic differences in the two groups of participants.

Aged↗
PubMed2006

Coccidioidomycosis in pregnancy: case report and review of the literature.

BACKGROUND: Coccidioidomycosis is an uncommon fungal infection during pregnancy. We report a case and review the literature on coccidioidomycosis in pregnancy. METHODS: We searched MEDLINE (1966-2005), PubMed (1950-2005), Embase (1974-2005), the Cochrane Library, and the Index-Catalogue of the Library of the Surgeon-General's Office United States Army (1880-1961) for cases of coccidioidomycosis occurring during pregnancy. We describe a woman with disseminated coccidioidomycosis during the last trimester of pregnancy with fungemia, respiratory failure, a miliary pattern on chest radiograph, and skin and bony involvement. RESULTS: We identified 80 additional cases of coccidioidomycosis occurring with pregnancy in the literature. The mean age of patients was 26 years (range 16-38 years). Disseminated disease was strongly associated with the trimester of pregnancy; 40% of the cases diagnosed before pregnancy, 50% of the cases diagnosed in the first trimester, 62% of the cases diagnosed in the second trimester, and 96% of the cases diagnosed in the third trimester had dissemination (P<.001). In addition, African American women had a 13-fold increased risk of dissemination compared with white women (P=.007). CONCLUSIONS: Mortality rates have improved over time in association with the timely administration of antifungal therapy. Disseminated coccidioidomycosis may occur during pregnancy, especially during the third trimester. Improved maternal and fetal survival is associated with early disease recognition and administration of amphotericin B.

Adolescent↗
PubMed2006

[From the Cochrane Library: Improvement of photodamaged skin with retinoid creams and not with other local treatments].

A Cochrane systematic review of 30 randomised clinical trials assessed the effects of current treatments for adults with mild-to-severe changes in facial and forearm skin that occurred as a result of prolonged exposure to the sun ('photodamage'). Topical tretinoin > or = 0.02% improved the appearance of mild-to-severe photodamage. Tazarotene 0.01-0.1% and isotretinoin 0.1% provided benefit to patients with moderate photodamage. The treatment duration was 4-11 months. Adverse effects were pain and redness. Both the efficacy and adverse effects were dose-dependent. Other treatments, such as polysaccharides, hydroxy acids, surgical procedures and laser, cannot be recommended.

Administration, Cutaneous↗
PubMed1999

Excess capacity: markets regulation, and values.

OBJECTIVE: To examine the conceptual bases for the conflicting views of excess capacity in healthcare markets and their application in the context of today's turbulent environment. STUDY SETTING: The policy and research literature of the past three decades. STUDY DESIGN: The theoretical perspectives of alternative economic schools of thought are used to support different policy positions with regard to excess capacity. Changes in these policy positions over time are linked to changes in the economic and political environment of the period. The social values implied by this history are articulated. DATA COLLECTION: Standard library search procedures are used to identify relevant literature. PRINCIPAL FINDINGS: Alternative policy views of excess capacity in healthcare markets rely on differing theoretical foundations. Changes in the context in which policy decisions are made over time affect the dominant theoretical framework and, therefore, the dominant policy view of excess capacity. CONCLUSIONS: In the 1990s, multiple perspectives of optimal capacity still exist. However, our evolving history suggests a set of persistent values that should guide future policy in this area.

Attitude to Health↗
PubMed2006

[Sublingual immunotherapy--coming of age?].

BACKGROUND: Immunotherapy is the only therapeutic modality in allergic patients with long lasting effects on the reactivity of the immune system to specific allergen exposure. Classical, subcutaneous, immunotherapy is associated with ubiquitous local and rare but potentially life-threatening systemic side effects. Sublingual immunotherapy is a relatively new modality of treatment, utilizing daily gradually increasing concentrations of allergen that are placed sublingually for a few minutes and swallowed afterwards. AIMS: To summarize "state of the art" concepts on sublingual immunotherapy, its mechanisms of action as well as safety and efficacy in the treatment of allergic disease. METHODS: A Medline search was performed through the PubMed service of the National Library of Medicine, for the period 1985 to December 2004, using "sublingual" and "imm unotherapy" in the title or abstract. The latest Cochrane Library meta-analysis on the subject was extracted as well as the original publications on which the analysis is based. RESULTS: Sublingual immunotherapy is a safe treatment in patients of all ages with asthma and other allergic diseases. The modality is more effective than placebo in the treatment of allergic rhinitis in adults. Our local experience supports a remarkable safety profile and efficacy. CONCLUSIONS: Sublingual immunotherapy is a promising treatment for allergic patients. Further study is needed but it seems reasonable to assume that an increasing number of patients will benefit from this modality in the near future.

Administration, Sublingual↗
PubMed2002

Nitric oxide donors for the treatment of preterm labour.

BACKGROUND: A number of tocolytics have been advocated for the treatment of threatened preterm labour in order to delay delivery. The rationale is that a delay in delivery may be associated with improved neonatal morbidity or mortality. Nitric oxide donors, such as nitroglycerin, have been used to relax the uterus. This review addresses their efficacy, side effects and influence on neonatal outcome. OBJECTIVES: To determine whether nitric oxide donors administered in threatened preterm labour are associated with a delay in delivery, adverse side effects or improved neonatal outcome. SEARCH STRATEGY: A comprehensive search of the Cochrane Pregnancy and Childbirth Group trials register (March 2002) and the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) was undertaken. SELECTION CRITERIA: Randomised controlled trials of nitric oxide donors administered for tocolysis. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were done independently by two reviewers. MAIN RESULTS: Five randomised controlled trials (466 women) were included. Nitroglycerine was the NO donor used in all these trials. Nitric oxide donors did not delay delivery nor improve neonatal outcome when compared with placebo, no treatment or alternative tocolytics such as ritodrine, albuterol and magnesium sulphate. There was, however, a reduction in number of deliveries less than 37 weeks when compared with alternative tocolytics but the numbers of deliveries before 32 and 34 weeks were not influenced. Side effects (other than headache) were reduced in women who received nitric oxide donors rather than other tocolytics. However, women were significantly more likely to experience headache when NO donors had been used. REVIEWER'S CONCLUSIONS: There is currently insufficient evidence to support the routine administration of nitric oxide donors in the treatment of threatened preterm labour.

Female↗
PubMed2006

A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus.

A humanized monoclonal antibody (mAb) has been developed and its potential to protect from or cure a Venezuelan equine encephalomyelitis virus (VEEV) infection was evaluated. The VEEV-neutralizing, protective murine mAb 3B4C-4 was humanized using combinatorial antibody libraries and phage-display technology. Humanized VEEV-binding Fabs were evaluated for virus-neutralizing capacity, then selected Fabs were converted to whole immunoglobulin (Ig) G1, and stable cell lines were generated. The humanized mAb Hy4-26C, designated Hy4 IgG, had virus-neutralizing capacity similar to that of 3B4C-4. Passive antibody protection studies with purified Hy4 IgG were performed in adult Swiss Webster mice. As little as 100 ng Hy4 IgG protected 90 % of mice challenged with 100 intraperitoneal (i.p.) mean morbidity (MD(50)) doses of virulent VEEV (Trinidad donkey) 24 h after antibody transfer; also, 500 mug Hy4 IgG protected 80 % of mice inoculated with 100 intranasal MD(50) doses of VEEV. Moreover, 10 mug passive Hy4 IgG protected 70 % of mice from a VEEV challenge dose as great as 10(7) i.p. MD(50). Hy4 IgG also protected mice from challenge with another epizootic VEEV variety, 1C (P676). Importantly, therapeutic administration of the humanized mAb to mice already infected with VEEV cured 90 % of mice treated with Hy4 IgG within 1 h of VEEV inoculation and 75 % of mice treated 24 h after virus infection.

Animals↗
PubMed2006

A potent human anti-eotaxin1 antibody, CAT-213: isolation by phage display and in vitro and in vivo efficacy.

The CC chemokine, eotaxin1 (CCL11) is an important regulator of eosinophil function. A marked accumulation of eosinophils in tissues has been correlated with the up-regulation of eotaxin1 expression in several diseases. The potential therapeutic value of neutralizing the effects of eotaxin1 in inflammatory conditions (including asthma) is under investigation. A human single-chain fragment variable antibody that neutralizes human eotaxin1 (CAT-212) was produced using antibody phage display and converted to whole antibody IgG4 format (CAT-213). A novel approach to lead optimization in which the length of the variable heavy chain complementarity-determining region 3 was reduced by one amino acid resulted in an increase in potency of >1000-fold compared with the parent anti-eotaxin1 antibody. The optimized antibody binds eotaxin1 with high affinity (80.4 pM) and specificity. CAT-213 and CAT-212 do not bind or neutralize a range of other human proteins including human monocyte chemoattractant protein-1, a structurally similar chemokine. CAT-213 neutralizes the ability of eotaxin1 to cause an increase in intracellular calcium signaling (with an IC(50) value of 2.86 nM), migration of CCR3-expressing L1.2 cells (with an IC(50) value of 0.48 nM), and inhibition of the eotaxin1-evoked shape change of human eosinophils in vitro (with an IC(50) of 0.71 nM). Local administration of CAT-213 to mice (1-100 microg kg(-1)) attenuates dermal eosinophilia induced by human eotaxin1, achieving >90% inhibition of eosinophil influx. CAT-213 may therefore be of therapeutic value in inhibiting diseases in which eotaxin1 and eosinophils play a major role, for example, severe asthma.

Algorithms↗
PubMed2002

Public health, GIS, and the internet.

Internet access and use of georeferenced public health information for GIS application will be an important and exciting development for the nation's Department of Health and Human Services and other health agencies in this new millennium. Technological progress toward public health geospatial data integration, analysis, and visualization of space-time events using the Web portends eventual robust use of GIS by public health and other sectors of the economy. Increasing Web resources from distributed spatial data portals and global geospatial libraries, and a growing suite of Web integration tools, will provide new opportunities to advance disease surveillance, control, and prevention, and insure public access and community empowerment in public health decision making. Emerging supercomputing, data mining, compression, and transmission technologies will play increasingly critical roles in national emergency, catastrophic planning and response, and risk management. Web-enabled public health GIS will be guided by Federal Geographic Data Committee spatial metadata, OpenGIS Web interoperability, and GML/XML geospatial Web content standards. Public health will become a responsive and integral part of the National Spatial Data Infrastructure.

Geographic Information Systems↗
PubMed2002

Phage-displayed Bet mim 1, a mimotope of the major birch pollen allergen Bet v 1, induces B cell responses to the natural antigen using bystander T cell help.

BACKGROUND AND OBJECTIVE: In previous studies we have generated mimotopes of Bet v 1, the major birch pollen allergen, by biopannings of phage-display random peptide libraries. In the present study, we analysed the humoral and cellular immune response to Bet v 1-mimotopes. METHODS: The mimotope CFPYCYPSESA, designated Bet mim 1, was used for intraperitoneal immunizations of BALB/c mice in phage-displayed form. For examination of the humoral immune response, enzyme-linked immunosorbent assay (ELISA) experiments were applied. Stimulation capacities were investigated in cultured mouse splenocytes and in humoral Bet v 1-specific T cell clones. RESULTS: We demonstrated that the Bet mim 1-induced murine antibody response against Bet v 1 was predominated by the IgG1 isotype. In these mice only the phage-displayed mimotopes, but neither the allergen nor the synthetic Bet mim 1-mimotopes were able to stimulate proliferation of cultured splenocytes. Using Bet v 1-specific T cell clones of allergic patients, phage-displayed and synthetic mimotopes were unable to stimulate T cell proliferation. Moreover, tolerance induction to Bet v 1 in mice by intranasal administration of Bet mim 1-phages or Bet mim 1-peptide failed. CONCLUSION: Taking these results together, our data indicate that Bet mim 1 mimics a Bet v 1-epitope on the B cell but not on the T cell level. We suggest that the phage itself is responsible for the recruitment of T cells providing bystander help in the formation of a mimotope-specific humoral response.

Allergens↗
PubMed2002

Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia.

Caspase family genes play a critical role in the initiation and execution of programmed cell death. Programmed cell death is an important contributor to neuronal loss following cerebral ischemia. We have performed a series of experiments to investigate the role of a specific caspase, caspase-2, in the development of delayed neuronal death following transient global ischemia in the rat. A rat ischemic brain cDNA library was screened, and two splice-variants of caspase-2 mRNA were identified, caspase-2S and caspase-2L, which were highly homologous with the sequences of human and mouse caspase-2S and caspase-2L genes, respectively. RT-PCR demonstrated an increase in expression of both caspase-2S and caspase-2L mRNA at 8, 24 and 72 h of reperfusion after global ischemia. The ratio of the two PCR fragments did not change significantly throughout the time course of reperfusion. Western blot with monoclonal antibody specific to the pro-apoptotic caspase-2L splice variant revealed an increase in procaspase-2 (51 kDa) protein from 4 to 72 h following ischemia compared with sham-operated controls. Furthermore, an approximately 30-kDa cleavage product appeared at 8 h and increased with increasing duration of reperfusion. Thus, caspase-2L is both translated and activated following transient global ischemia. Finally, intraventricular administration of the caspase-2-like inhibitor (VDVAD-FMK) 30 min before induction of ischemia decreased the number of CA1 neurons staining positively for DNA damage (Klenow-labeling assay) and increased the number of healthy-appearing CA1 neurons (cresyl violet) compared with vehicle-treated controls. Taken together, the data suggest that caspase-2 induction and activation are important mediators of delayed neuronal death following transient global ischemia.

Alternative Splicing↗