An unusual cause of an acutely locked knee.
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Acute Disease↗
Biomedical subjects
S Blake
Publications and source records attributed to S Blake.
Restriction fragment length polymorphisms and sequence analysis: an approach for genotyping infectious pancreatic necrosis virus reference strains and other aquabirnaviruses isolated from northwestern Spain.
Reference strains of infectious pancreatic necrosis virus resembling the 10 recognized serotypes and local isolates of aquabirnaviruses isolated in northwestern Spain from reservoirs (mollusks) and from asymptomatic and carrier cultured fish were genotyped by restriction fragment length polymorphism (RFLP) and nucleic acid sequence analyses. The RFLP analysis yielded seven genogroups, each of which was clearly correlated with a serotype. Sequence analysis of the three open reading frames provided quite similar results in terms of genogrouping. Based on the results of this study and in order to unify the two types of assays, we propose placing aquabirnaviruses into six genogroups, four of which can be subdivided into two genotypes based on a two-step restriction analysis. The genotyping corresponds with serotyping as follows: genogroup I includes two genotypes corresponding to serotypes A9 (genotype I.1) and A1 (genotype I.2); genogroup II corresponds to serotype A3; genogroup III includes genotypes III.1 (serotype A2) and III.2 (serotype B1); genogroups IV and V include two genotypes, each corresponding to serotypes A5, A6, A7, and A8 (genotypes IV.1, IV.2, V.1, and V.2, respectively);and genogroup VI corresponds to serotype A4. As expected, most local isolates belonged to genotype III.1 and genogroup II. However, a few local isolates corresponded to the American types of genogroup I. Finally, based on the results of this study and due to its simplicity, the two-step restriction analysis assay is proposed as a method for typing new isolates of aquabirnaviruses, and the results correspond to the results of conventional serotyping.
Animals↗
Iatrogenic copper deficiency following information and drugs obtained over the Internet.
We report the case of a 56-year-old woman with a 7-year history of metastatic cancer who presented with severe copper deficiency following self-treatment with the copper-chelating agent tetrathiomolybdate. This compound was used with the aim of inhibiting tumour angiogenesis and was obtained from the USA by placing an order on the internet. The patient exhibited severe neutropenia as her serum copper concentration fell from 19.8 micromol/L to 3.3 micromol/L and her caeruloplasmin concentration from 35 mg/dL to 4 mg/dL.
Copper↗
Characterization of aquabirnaviruses from flounder Pseudopleuronectes americanus and mummichog Fundulus heteroclitus in the Chesapeake Bay, Virginia, USA.
Viruses were isolated in cell culture from tissue homogenates of flounder Pseudopleuronectes americanus and mummichog Fundulus heteroclitus in the Chesapeake Bay, Virginia, USA. Neutralization and immunofluorescence tests with aquabirnavirus (West Buxton strain)-specific polyclonal antisera indicated that both viruses were aquabirnaviruses belonging to Serogroup A, the most common aquabirnavirus serogroup in the United States. This was confirmed by RT-PCR, with primers targeting the VP3 and VP2 gene of aquabirnaviruses. The VP2-specific RT-PCR cDNA amplification product was sequenced and deduced amino-acid sequences were compared with known sequences of the type strains of the 9 serotypes of aquabirnavirus Serogroup A. This demonstrated that the viruses from both flounder and mummichog belong to aquabirnavirus Genogroup 1. The flounder isolate exhibited deduced amino acid sequence similarities of 98.1% with the Jasper strain of serotype A9, and 97.7% with the West Buxton strain of serotype A1. The isolate from mummichog exhibited deduced amino acid sequence similarities of 99.1% with the West Buxton strain of Serotype A1 and 94.8% with the Jasper isolate of Serotype A9. Similarities of deduced amino acid sequences ranged from 79.9 to 86.9%, with representatives of the other 7 serotypes. This is the first report of an aquabirnavirus from mummichog F. heteroclitus and only the fifth report of an aquabirnavirus from a flounder species.
Amino Acid Sequence↗
Phylogenetic relationships of aquatic birnaviruses based on deduced amino acid sequences of genome segment A cDNA.
Aquatic birnaviruses, such as infectious pancreatic necrosis virus (IPNV), cause serious diseases in a variety of fish species used worldwide in aquaculture and have also been isolated from a variety of healthy fish and shellfish species. These viruses exhibit a high degree of antigenic heterogeneity and variation in biological properties such as pathogenicity, host range, and temperature of replication. To better understand genetic and biological diversity among these viruses, the nucleotide and deduced amino acid sequences were determined from cDNA of the large open reading frame (ORF) of genome segment A of the 9 type strains of Serogroup A and 4 other representative strains of Serotype A1, the predominant serotype in the United States. In addition, nucleotide and deduced amino acid sequences were determined for the VP2 coding region of a variety of isolates representing 5 of the 9 serotypes. VP2 is the major outer capsid protein of aquatic birnaviruses. RT-PCR was used to amplify a 2904 bp cDNA fragment including all but a few bp of the large ORF of genome segment A or a 1611 bp fragment representing the entire VP2 coding region. Nucleotide and deduced amino acid sequences were determined from the PCR products. Pairwise comparisons were made among our data and 2 other aquatic birnavirus sequences previously published. Several hypervariable regions were identified within the large ORF. The most divergent pair of viruses exhibited a similarity of 80.1% in the deduced amino acid sequence encoded by the large ORF. Genomic relationships revealed in a phylogenetic tree constructed from comparison of the deduced amino acid sequences of the large ORF demonstrated that these viruses were clustered into several genogroups. Phylogenetic comparison of the deduced amino acid sequences of the VP2 coding region of 28 aquatic birnavirus isolates, including the type strains of all 9 serotypes, demonstrated 6 genogroups, some of which were comprised of several genotypes. The most divergent pair of viruses exhibited a similarity of 81.2% in the deduced amino acid sequence from the VP2 coding region. In contrast to previous studies of much shorter genomic sequences within the C-terminus-pVP2/NS junction coding region, these genogroups based on the entire large ORF or the VP2 coding region generally correlated with geographical origin and serological classification. Isolates from the major Canadian serotypes were more closely related to the European isolates than to isolates from the United States.
Amino Acid Sequence↗
Azepanone-based inhibitors of human and rat cathepsin K.
The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.
Administration, Oral↗
Disease-modifying activity of SB 273005, an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis.
OBJECTIVE: To evaluate the effects of SB 273005, a potent, orally active nonpeptide antagonist of the integrin avbeta3 vitronectin receptor, on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS: Male Lewis rats with AIA were orally dosed either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 273005. Efficacy was determined by measurement of paw inflammation, assessment of bone mineral density using dual-energy x-ray absorptiometry (DEXA), magnetic resonance imaging (MRI), and histologic evaluation. RESULTS: SB 273005 is a potent antagonist of the closely related integrins, avbeta3 (Ki = 1.2 nM) and alphavbeta5 (Ki = 0.3 nM). When SB 273005 was administered prophylactically to AIA rats twice per day, it inhibited paw edema at doses of 10, 30, and 60 mg/kg, by 40%, 50%, and 52%, respectively. Therapeutic administration twice daily was also effective, and a reduction in paw edema was observed at 30 mg/kg and 60 mg/kg of the antagonist (by 36% and 48%, respectively). SB 273005 was also effective when administered once per day, both prophylactically and therapeutically. Significant improvement in joint integrity in treated rats was shown using DEXA and MRI analyses. These findings were confirmed histologically, and significant protection of bone, cartilage, and soft tissue was observed within the joint. CONCLUSION: Symptoms of AIA in rats were significantly reduced by either prophylactic or therapeutic treatment with the alphavbeta3 antagonist, SB 273005. Measurements of paw inflammation and of bone, cartilage, and soft tissue structure indicated that this compound exerts a protective effect on joint integrity and thus appears to have disease-modifying properties.
Administration, Oral↗
Evaluation of school-based HIV prevention education programs in New Jersey.
This paper presents results from a process evaluation conducted by the New Jersey Department of Education (NJDOE). Representative samples of middle and high school superintendents, principals, lead health teachers, and HIV teachers provided information assessing whether local district policy content was consistent with the state's policy code, the dynamics of local policy development, and school district staff perceptions and practices regarding HIV education policies. NJDOE also was interested in determining: if inservice training was accessible to teachers assigned to provide HIV education; the scope and impact of HIV inservice programs; and the training needs of staff assigned to teach the HIV curriculum. Finally, NJDOE was interested in determining: local curricula scope, sequence, and approach; the extent to which local curricula were skills-based; and local expectations for instructional outcomes. As a result of the evaluation, program staff identified areas needing remediation and planned for program improvement in new areas.
Adolescent↗
Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate.
Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis.
Animals↗
Restorative proctocolectomy in UK servicemen.
OBJECTIVE: To investigate the outcome of restorative proctocolectomy (RPC) in UK Servicemen and to determine the compatibility of this procedure with Service life. PATIENTS: All Servicemen undergoing restorative proctocolectomy for ulcerative colitis (UC) or familial adenomatous polyposis (FAP) up to December 31st 2000 were identified from Service records. Patients were reviewed by direct or telephone interview. Pouch function, military duties, medical category or reasons for discharge from the Service were recorded. RESULTS: Fifteen Servicemen (6 Royal Navy, 6 Army, 3 RAF), mean age 30 years, underwent RPC for UC (14) or FAP (1) with a median follow-up of 74 months. Eight remain in their Service, five of whom carry out full duties and three restricted duties. Of the seven who have left the Services only one was medically unfit to continue due to poor pouch function whilst six left voluntarily to pursue active civilian careers. Fourteen patients have acceptable pouch function; one pouch has been excised for intractable pouchitis. CONCLUSIONS: Restorative proctocolectomy is compatible with Service life and most individuals are capable of fulfilling active unrestricted military duties.
Adenomatous Polyposis Coli↗
Inhibitor of neurite outgrowth in humans.
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Animals↗
Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis.
OBJECTIVE: To evaluate the effects of SB 242235, a potent and selective inhibitor of p38 mitogen-activated protein (MAP) kinase, on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS: Male Lewis rats with AIA were orally treated either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 242235. Efficacy was determined by measurements of paw inflammation, dual-energy x-ray absorptiometry for bone-mineral density (BMD), magnetic resonance imaging (MRI), microcomputed tomography (CT), and histologic evaluation. Serum tumor necrosis factor alpha (TNFalpha) in normal (non-AIA) rats and serum interleukin-6 (IL-6) levels in rats with AIA were measured as markers of the antiinflammatory effects of the compound. RESULTS: SB 242235 inhibited lipopolysaccharide-stimulated serum levels of TNFalpha in normal rats, with a median effective dose of 3.99 mg/kg. When SB 242235 was administered to AIA rats prophylactically on days 0-20, it inhibited paw edema at 30 mg/kg and 10 mg/kg per day by 56% and 33%, respectively. Therapeutic administration on days 10-20 was also effective, and inhibition of paw edema was observed at 60, 30, and 10 mg/kg (73%, 51%, and 19%, respectively). Significant improvement in joint integrity was demonstrated by showing normalization of BMD and also by MRI and micro-CT analysis. Protection of bone, cartilage, and soft tissues was also shown histologically. Serum IL-6 levels were decreased in AIA rats treated with the 60 mg/kg dose of compound. CONCLUSION: Symptoms of AIA in rats were significantly reduced by both prophylactic and therapeutic treatment with the p38 MAP kinase inhibitor, SB 242235. Results from measurements of paw inflammation, assessment of BMD, MRI, and micro-CT indicate that this compound exerts a protective effect on joint integrity, and thus appears to have disease-modifying properties.
Absorptiometry, Photon↗
The Innovative Ward Project: promoting innovation in health service delivery.
An Innovative Ward Project was undertaken as part of the planning for redevelopment of the Princess Alexandra Hospital. Two inpatient units (one medical and one surgical) became pilot areas for developing, implementing and evaluating innovative approaches to service delivery. The project focused on the key areas related to structural environment, information technology and redesign of work practices. This paper provides an overview which includes the key elements utilised to foster innovation. The challenges of disseminating and adopting successful innovations beyond the Innovative Wards are discussed.
Communication↗
American Society for Bone and Mineral Research--22nd Annual Meeting.
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Journal Article↗
Isolation of infectious salmon anemia virus (ISAV) from Atlantic salmon in New Brunswick, Canada.
Infectious salmon anemia virus (ISAV) was isolated at a marine grow-out site in New Brunswick, Canada, from Atlantic salmon Salmo salar which experienced mortalities due to hemorrhagic kidney syndrome (HKS). Of 20 fish sampled in this study, 14 showed histologically various degrees of interstitial hemorrhaging, tubular epithelial degeneration and necrosis, and tubular casts in the posterior kidney, typical of HKS. Posterior kidney and spleen homogenates produced a cytopathic effect on chinook salmon embryo (CHSE-214) cells 10 to 14 d after inoculation. Pleomorphic virus particles in the size range 80 to 120 nm were seen by electron microscopy. The virus was confirmed as ISAV using reverse transcriptase-polymerase chain reaction (RT-PCR). This is a systematic diagnostic study of the isolation of ISAV on the North American continent and the first description of the growth of ISAV on the CHSE-214 cell line.
Anemia↗
Genomic relationships of the North American isolate of infectious salmon anemia virus (ISAV) to the Norwegian strain of ISAV.
Nucleotide and deduced amino acid sequences were determined for a 436 bp reverse transcriptase-polymerase chain reaction (RT-PCR) cDNA fragment from genome segment 8 and a 1151 bp RT-PCR cDNA fragment from genome segment 2 of the North American isolate of infectious salmon anemia virus (ISAV) and compared to the published sequences of Norwegian isolates of ISAV. The North American ISAV isolate exhibited 82.9% identity with the Sotra 92/93 ISAV isolate from Norway in the partial cDNA sequence of genome segment 2, which encodes a polymerase component protein (PB1). The North American ISAV exhibited 88 and 89% identity with 2 partial cDNA sequences of genome segment 8 (nonstructural, NS, gene) reported for the Glesvaer/2/90 isolate from Norway. The North American ISAV exhibited 96.6% similarity with the Sotra 92/93 ISAV isolate from Norway in the deduced amino acid sequences of the PB1 protein. The deduced amino acid sequence of the protein encoded in the partial cDNA fragment of open reading frame (ORF) 1 of genome segment 8 of the North American ISAV exhibited only 71.2 and 66.7% similarity with the 2 sequences of the Norwegian Glesvaer/2/90 isolate. However, the North American ISAV isolate exhibited 96.2 and 87.2% similarity with the 2 sequences of the Norwegian Glesvaer/2/90 isolate in the deduced amino acid sequences of the protein encoded in the partial cDNA of ORF 2. Comparison of these partial cDNA nucleotide and deduced amino acid sequences confirmed that the North American isolate is ISAV. However, the differences observed in these genomic sequences suggest that the North American isolate may represent a distinct genomic variant from the previously described Norwegian strains.
Amino Acid Sequence↗
Multiplex reverse transcriptase PCR assay for simultaneous detection of three fish viruses.
A multiplex reverse transcriptase (RT)-PCR assay was developed for the simultaneous detection of three different fish viruses: infectious pancreatic necrosis virus (IPNV), infectious hematopoietic necrosis virus (IHNV), and viral hemorrhagic septicemia virus (VHSV). The sensitivity levels of the multiplex RT-PCR assay were 100, 1, and 32 50% tissue culture infective doses/ml for IPNV, IHNV, and VHSV, respectively.
Animals↗
Investigation and modelling of the surface dose from linear accelerator produced 6 and 10 MV photon beams.
The radiation reaction from the surface dose to a patient's skin is clinically important as an indicator of tolerance to treatment and is frequently the most visible side-effect from external beam radiotherapy. To quantify surface dose, its build-up was investigated in a solid water phantom over a range of field sizes, source to skin distances, wedge angles and beam shaping conditions. These data were analysed and used to produce an empirical model of the effect of these factors which predicted surface dose to within 5% under test conditions. The effects of changing treatment techniques was investigated by comparing fixed to dynamic wedges, and multileaf collimator (MLC) with alloy blocks. It was found that the MLC reduced the surface dose relative to alloy blocks but that dynamic wedges made no change relative to open fields. Fixed wedges reduced the relative surface dose as a consequence of beam hardening. It is hoped that routine clinical use of the model to calculate skin dose will increase awareness of situations in which the skin sparing effect of modern linear accelerators may be compromised.
Equipment Design↗