Biomedical subjects
S Baker
Publications and source records attributed to S Baker.
The genome sequence of Schizosaccharomyces pombe.
We have sequenced and annotated the genome of fission yeast (Schizosaccharomyces pombe), which contains the smallest number of protein-coding genes yet recorded for a eukaryote: 4,824. The centromeres are between 35 and 110 kilobases (kb) and contain related repeats including a highly conserved 1.8-kb element. Regions upstream of genes are longer than in budding yeast (Saccharomyces cerevisiae), possibly reflecting more-extended control regions. Some 43% of the genes contain introns, of which there are 4,730. Fifty genes have significant similarity with human disease genes; half of these are cancer related. We identify highly conserved genes important for eukaryotic cell organization including those required for the cytoskeleton, compartmentation, cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. These genes may have originated with the appearance of eukaryotic life. Few similarly conserved genes that are important for multicellular organization were identified, suggesting that the transition from prokaryotes to eukaryotes required more new genes than did the transition from unicellular to multicellular organization.
Role of subintimal angioplasty in the treatment of chronic lower limb ischaemia.
OBJECTIVES: To determine the clinical outcome of subintimal angioplasty (SA) and to assess impact on surgical workload. DESIGN: Retrospective review of a single radiologist's case series. MATERIALS: One hundred and twenty two patients with critical limb ischaemia and 26 with claudication. METHODS: One hundred and fifty eight limbs treated by SA. MAIN OUTCOME MEASURES: Technical success and complications; cumulative patency, limb salvage and survival; affect of SA on vascular workload. RESULTS: The technical success rate was 85%. There were 26 procedural complications (16%) but no patient required emergency surgery; 30-day mortality was 3%. Primary and secondary 12-month patency rates were 27 and 33%. Limb salvage rate was 88% at 12 months. SA initially reduced the number of patients needing arterial surgery, although this then increased due to late failure of SA and an increase in de novo bypass. CONCLUSIONS: SA carries a low risk of major complications and high immediate technical success. Poor long-term patency suggests that SA is not as durable as bypass surgery. However, failed SA did not compromise subsequent surgery, which only became necessary in a proportion of patients. Our data suggests that there is little to be lost by using SA as first-line treatment for patients with limb-threatening ischaemia who are poor operative risks or who have no autologous vein available.
Aero-allergy in South African olympic athletes.
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Unexpected formation of an epoxide-derived multisubstrate adduct inhibitor on the active site of GAR transformylase.
Multisubstrate adduct inhibitors (MAI) of glycinamide ribonucleotide transformylase (GAR Tfase), which incorporate key features of the folate cofactor and the beta-GAR substrate, typically exhibit K(i)'s in the picomolar range. However, these compounds have reduced bioavailability due to the incorporation of a negatively charged phosphate moiety that prevents effective cellular uptake. Thus, a folate analogue that is capable of adduct formation with the substrate on the enzyme active site could lead to a potent GAR Tfase inhibitor that takes advantage of the cellular folate transport systems. We synthesized a dibromide folate analogue, 10-bromo-10-bromomethyl-5,8,10-trideazafolic acid, that was an intermediate designed to assemble with the substrate beta-GAR on the enzyme active site. We have now determined the crystal structure of the Escherichia coli GAR Tfase/MAI complex at 1.6 A resolution to ascertain the nature and mechanism of its time-dependent inhibition. The high-resolution crystal structure clearly revealed the existence of a covalent adduct between the substrate beta-GAR and the folate analogue (K(i) = 20 microM). However, the electron density map surprisingly indicated a C10 hydroxyl in the adduct rather than a bromide and suggested that the multisubstrate adduct is not formed directly from the dibromide but proceeds via an epoxide. Subsequently, we demonstrated the in situ conversion of the dibromide to the epoxide. Moreover, synthesis of the authentic epoxide confirmed that its inhibitory, time-dependent, and cytotoxic properties are comparable to those of the dibromide. Further, inhibition was strongest when the dibromide or epoxide is preincubated with both enzyme and substrate, indicating that inhibition occurs via the enzyme-dependent formation of the multisubstrate adduct. Thus, the crystal structure revealed the successful formation of an enzyme-assembled multisubstrate adduct and highlighted a potential application for epoxides, and perhaps aziridines, in the design of efficacious GAR Tfase inhibitors.
Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18.
Salmonella enterica serovar Typhi (S. typhi) is the aetiological agent of typhoid fever, a serious invasive bacterial disease of humans with an annual global burden of approximately 16 million cases, leading to 600,000 fatalities. Many S. enterica serovars actively invade the mucosal surface of the intestine but are normally contained in healthy individuals by the local immune defence mechanisms. However, S. typhi has evolved the ability to spread to the deeper tissues of humans, including liver, spleen and bone marrow. Here we have sequenced the 4,809,037-base pair (bp) genome of a S. typhi (CT18) that is resistant to multiple drugs, revealing the presence of hundreds of insertions and deletions compared with the Escherichia coli genome, ranging in size from single genes to large islands. Notably, the genome sequence identifies over two hundred pseudogenes, several corresponding to genes that are known to contribute to virulence in Salmonella typhimurium. This genetic degradation may contribute to the human-restricted host range for S. typhi. CT18 harbours a 218,150-bp multiple-drug-resistance incH1 plasmid (pHCM1), and a 106,516-bp cryptic plasmid (pHCM2), which shows recent common ancestry with a virulence plasmid of Yersinia pestis.
Interception, retention and translocation under greenhouse conditions of radiocaesium and radiostrontium from a simulated accidental source.
The behaviour of radioactive aerosols released from a severely damaged nuclear reactor and deposited on cereals was simulated under controlled conditions. 137Cs- and 90Sr-labelled aerosols were generated by volatilisation at high temperature of an artificially spiked pellet of depleted UO2. After cooling and maturation the aerosols were allowed to deposit on spring wheat (Triticum aestivum L. var. Arbon) cultures grown on lysimeters under greenhouse conditions. At the time of contamination the wheat plants were at different stages of development, from early vegetative growth (two leaves) until nearly mature (end of flowering). The estimated interception coefficient (micro) amounted to 13.1 m2 kg(-1); such a high value may be explained by the experimental conditions that created an over-saturated atmosphere during the contamination process and wet leaf surfaces. The first simulated rain, applied 6 days after the contamination, removed four times more 137Cs (54%+/-12 of the intercepted radionuclides) than 90Sr (15%+/-20) from the aerial parts. At harvest approximately 2% of the Sr and less than 1% of the Cs initially intercepted by the aerial parts is recovered for plants contaminated during the early development stages. A significantly higher proportion of the intercepted activity is still present for plants contaminated in the late development stages. The translocation to grains (TLF) increases when deposit occurs closer to the mature stage of the plant. The initial decrease of TLF values that we observed for strontium contamination in the earliest development stages is most probably due to the contribution of root uptake. Ploughing and re-sowing after the first rain, applied as a countermeasure reduced the 137Cs content in leaves and stems at harvest approximately 3 times but had no effect on the 90Sr content in vegetative organs. It reduced the 137Cs-contamination level in edible parts (grain) by a factor of 2 compared to the unploughed control, but doubled the 90Sr content.
Genome sequence of Yersinia pestis, the causative agent of plague.
The Gram-negative bacterium Yersinia pestis is the causative agent of the systemic invasive infectious disease classically referred to as plague, and has been responsible for three human pandemics: the Justinian plague (sixth to eighth centuries), the Black Death (fourteenth to nineteenth centuries) and modern plague (nineteenth century to the present day). The recent identification of strains resistant to multiple drugs and the potential use of Y. pestis as an agent of biological warfare mean that plague still poses a threat to human health. Here we report the complete genome sequence of Y. pestis strain CO92, consisting of a 4.65-megabase (Mb) chromosome and three plasmids of 96.2 kilobases (kb), 70.3 kb and 9.6 kb. The genome is unusually rich in insertion sequences and displays anomalies in GC base-composition bias, indicating frequent intragenomic recombination. Many genes seem to have been acquired from other bacteria and viruses (including adhesins, secretion systems and insecticidal toxins). The genome contains around 150 pseudogenes, many of which are remnants of a redundant enteropathogenic lifestyle. The evidence of ongoing genome fluidity, expansion and decay suggests Y. pestis is a pathogen that has undergone large-scale genetic flux and provides a unique insight into the ways in which new and highly virulent pathogens evolve.
Symmetry, sexual dimorphism in facial proportions and male facial attractiveness.
Facial symmetry has been proposed as a marker of developmental stability that may be important in human mate choice. Several studies have demonstrated positive relationships between facial symmetry and attractiveness. It was recently proposed that symmetry is not a primary cue to facial attractiveness, as symmetrical faces remain attractive even when presented as half faces (with no cues to symmetry). Facial sexual dimorphisms ('masculinity') have been suggested as a possible cue that may covary with symmetry in men following data on trait size/symmetry relationships in other species. Here, we use real and computer graphic male faces in order to demonstrate that (i) symmetric faces are more attractive, but not reliably more masculine than less symmetric faces and (ii) that symmetric faces possess characteristics that are attractive independent of symmetry, but that these characteristics remain at present undefined.
Long-term resource variation and group size: a large-sample field test of the Resource Dispersion Hypothesis.
BACKGROUND: The Resource Dispersion Hypothesis (RDH) proposes a mechanism for the passive formation of social groups where resources are dispersed, even in the absence of any benefits of group living per se. Despite supportive modelling, it lacks empirical testing. The RDH predicts that, rather than Territory Size (TS) increasing monotonically with Group Size (GS) to account for increasing metabolic needs, TS is constrained by the dispersion of resource patches, whereas GS is independently limited by their richness. We conducted multiple-year tests of these predictions using data from the long-term study of badgers Meles meles in Wytham Woods, England. The study has long failed to identify direct benefits from group living and, consequently, alternative explanations for their large group sizes have been sought. RESULTS: TS was not consistently related to resource dispersion, nor was GS consistently related to resource richness. Results differed according to data groupings and whether territories were mapped using minimum convex polygons or traditional methods. Habitats differed significantly in resource availability, but there was also evidence that food resources may be spatially aggregated within habitat types as well as between them. CONCLUSIONS: This is, we believe, the largest ever test of the RDH and builds on the long-term project that initiated part of the thinking behind the hypothesis. Support for predictions were mixed and depended on year and the method used to map territory borders. We suggest that within-habitat patchiness, as well as model assumptions, should be further investigated for improved tests of the RDH in the future.
Addison's disease: after 40 years much remains the same.
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Free fluid on abdominal computed tomography without solid organ injury after blunt abdominal injury does not mandate celiotomy.
BACKGROUND: Mandatory celiotomy has been proposed for all patients with unexplained free fluid on abdominal computed tomography (CT) scanning after blunt abdominal injury. This recommendation has been based upon retrospective data and concerns over the potential morbidity from the late diagnosis of blunt intestinal injury. This study examined the rate of intestinal injury in patients with free fluid on abdominal CT after blunt abdominal trauma. METHODS: This study was a multicenter prospective series of all patients with blunt abdominal trauma admitted to four level I trauma centers over 22 months. Data were collected concurrently at the time of patient enrollment and included demographics, injury severity score, findings on CT scan, and presence or absence of blunt intestinal injury. This database was specifically queried for those patients who had free fluid without solid organ injury. RESULTS: In all, 2,299 patients were evaluated. Free fluid was present in 265. Of these, 90 patients had isolated free fluid with only 7 having a blunt intestinal injury. Conversely, 91% of patients with free fluid did not. All patients with free fluid were observed for a mean of 8 days (95% confidence interval 6.1 to 10.4, range 1 to 131). There were no missed injuries. CONCLUSIONS: Free fluid on abdominal CT scan does not mandate celiotomy. Serial observation with the possible use of other adjunctive tests is recommended.
Antibodies to tissue transglutaminase: comparison of ELISA and immunoprecipitation assay in the presence and in the absence of calcium ions.
Endomysial antibodies are characteristic of coeliac disease and tissue transglutaminase (tTG) has been identified as a major component of the endomysial antigen. tTG autoantibodies were measured in sera from patients with coeliac disease using ELISA based on guinea pig tTG and immunoprecipitation assay (IPA) based on 35S-labelled human tTG produced in an in vitro transcription/translation system. In addition, the effect of calcium ions on the interaction between tTG autoantibodies in the two assays was studied. Under standard (i.e. Ca2+-free) conditions, 36/39 (92%) coeliac sera were positive for IgA tTG antibodies by ELISA and 34/39 (87%) sera were positive by IPA. Comparison of ELISA and IPA results showed three sera positive by ELISA but negative by IPA and one serum which was positive by IPA but negative by ELISA. Bland and Altman analysis of the correlation between the ELISA and IPA showed that the results for 37 out of 39 samples were in the agreement. The results by ELISA carried out without and with Ca2+ were in good agreement (r=0.99; n=39). IPA using Ca2+ containing buffer detected fewer samples compared to IPA using standard assay buffer however the results of the two assays also showed a good agreement (r=0.93; n=39). Our studies confirm that antibodies to tTG are good markers of coeliac disease and indicate that the autoantibody binding sites on tTG are formed in a way which is essentially independent of Ca2+.
Black populations, human immunodeficiency virus/acquired immune deficiency syndrome, and research: implications for nurses.
Knowledge that is generated from research is critical toward understanding the prevention, impact, and treatment of human immunodeficiency virus (HIV) disease and acquired immune deficiency syndrome (AIDS). During the past several decades, the Black community has been disproportionately affected by the HIV/AIDS epidemic. Therefore, engaging their participation in HIV/AIDS research is necessary to understand the disease further and to develop strategies for nursing interventions. Many factors hinder Blacks from participating in HIV/AIDS research. This review provides information for nurses about problems related to recruitment and recommendations for recruiting Black participants for HIV/AIDS research.
Salmonella enterica serovar Typhi possesses a unique repertoire of fimbrial gene sequences.
Salmonella enterica serotype Typhi differs from nontyphoidal Salmonella serotypes by its strict host adaptation to humans and higher primates. Since fimbriae have been implicated in host adaptation, we investigated whether the serotype Typhi genome contains fimbrial operons which are unique to this pathogen or restricted to typhoidal Salmonella serotypes. This study established for the first time the total number of fimbrial operons present in an individual Salmonella serotype. The serotype Typhi CT18 genome, which has been sequenced by the Typhi Sequencing Group at the Sanger Centre, contained a type IV fimbrial operon, an orthologue of the agf operon, and 12 putative fimbrial operons of the chaperone-usher assembly class. In addition to sef, fim, saf, and tcf, which had been described previously in serotype Typhi, we identified eight new putative chaperone-usher-dependent fimbrial operons, which were termed bcf, sta, stb, ste, std, stc, stg, and sth. Hybridization analysis performed with 16 strains of Salmonella reference collection C and 22 strains of Salmonella reference collection B showed that all eight putative fimbrial operons of serotype Typhi were also present in a number of nontyphoidal Salmonella serotypes. Thus, a simple correlation between host range and the presence of a single fimbrial operon seems at present unlikely. However, the serotype Typhi genome differed from that of all other Salmonella serotypes investigated in that it contained a unique combination of putative fimbrial operons.
Reliability of nurses' neurological assessments in the cardiothoracic surgical intensive care unit.
BACKGROUND: Alterations in mental status are common among patients in the cardiothoracic surgical intensive care unit. Changes in mental status can be caused by metabolic factors, medications, or brain injury. In this setting, reliable, serial neurological evaluations are critical for assessing the effectiveness of treatment and the need for additional studies. OBJECTIVES: To estimate the reliability of the Rancho Los Amigos Cognitive Scale and the newly developed Neurologic Intensive Care Evaluation as measures of cognitive function in the cardiothoracic surgical intensive care unit. METHODS: Nurses used 1 of the 2 scales as part of routine neurological assessments of patients in the cardiothoracic surgical intensive care unit. For each test, scores of different observers were correlated and a reliability estimate formed. RESULTS: Interrater reliability was high for both evaluations (Rancho scale, 0.91; Neurologic Intensive Care Evaluation, 0.94). Correlations between the scores of different pairs of observers were also high (mean rho values, 0.84 for the Rancho scale and 0.77 for the Neurologic Intensive Care Evaluation). CONCLUSIONS: Both scales are reliable indicators of the neurological state of patients in the cardiothoracic surgical intensive care unit. These scales measure different, although limited, aspects of cognitive function. Each test was simple to administer and did not take more time than the standard nursing neurological examination. Most of the variability in scoring was related to the different degrees of stimulation used by examiners when assessing patients, not to differences in the interpretation of patients' responses.
Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study.
BACKGROUND: Patients with systemic lupus erythematosus (SLE) who experience persistent multiorgan dysfunction, despite standard doses of intravenous cyclophosphamide, represent a subset of patients at high risk of early death. We investigated the safety and efficacy of immune suppression and autologous haemopoietic stem-cell infusion to treat such patients. METHODS: From 1996, we selected patients with persistent SLE despite use of cyclophosphamide. Patients underwent dose-intense immune suppression and autologous haemopoietic stem-cell (CD34) infusion. Peripheral blood lymphocytes were analysed by flow cytometry, ELISA, and T-cell-receptor spectratyping before and after transplantation. We mobilised autologous haemopoietic stem cells with 2.0 g/m2 cyclophosphamide and 10 microg/kg granulocyte colony stimulating factor daily, enriched with CD34-positive selection, and reinfused after immunosuppression with 200 mg/kg cyclophosphamide, 1 g methylprednisolone, and 90 mg/kg equine antithymocyte globulin. RESULTS: Nine patients underwent stem-cell mobilisation but two were excluded before transplantation because of infection. The remaining seven received high-dose chemotherapy and stem-cell infusion. Median time to an absolute neutrophil count higher than 0.5x10(9)/L and nontransfused platelet count higher than 20x10(9)/L was 9 days (range 8-11) and 11 days (10-13), respectively. At a median follow-up of 25 months (12-40), all patients were free from signs of active lupus. Renal, cardiac, pulmonary, and serological markers, and T cell phenotype and repertoire had normalised. INTERPRETATION: Patients remained free from active lupus and improved continuously after transplantation, with no immunosuppressive medication or small residual doses of prednisone. T-cell repertoire diversity and responsiveness was restored. Durability of remission remains to be established.
A novel kinase, AATYK induces and promotes neuronal differentiation in a human neuroblastoma (SH-SY5Y) cell line.
Apoptosis Associated Tyrosine Kinase (AATYK), a novel protein recently isolated from differentiating 32D mouse myeloid cells, contains a putative tyrosine kinase domain and several binding motifs for src homology 2 (SH-2) and src homology 3 (SH-3) domain containing proteins. We observed that AATYK is expressed in different regions of the brain. Although it might play a role in normal nervous system development by modulating apoptosis, little is known regarding its function in the brain or its intracellular localization and kinase activity. Recognizing its homology with Insulin like growth factor-I (IGF-I) receptor (IGF-IR) and the critical role of IGF-I in neuronal survival, we hypothesized that AATYK plays an important role in neuronal differentiation/apoptosis. To test this hypothesis, we transfected the human adrenergic neuroblastoma (NB):SH-SY5Y cells with AATYK cDNA under a tetracycline-repressible promoter and established stable cell lines that readily express AATYK on removal of tetracycline. AATYK immunoprecipitated from these cell lysates is an active kinase. Indirect immunofluorescent staining of the clones revealed AATYK to be localized in the cytoplasm. By itself, AATYK overexpression for short duration (2-3 days) did not induce differentiation in the stable SH-SY5Y clones. On the other hand, overexpression for longer periods (7-8 days) per se, significantly (P<0.05-0.001) increased the percent of differentiated cells as well as the neurite length. AATYK-induced differentiation was in the same range as the differentiation induced by agents like all-trans retinoic acid (RA), 12-O-Tetradecanoyl phorbol 13-acetate (TPA) and IGF-I. In addition, AATYK significantly promoted the neuronal differentiation induced by these agents. Our results demonstrate for the first time that AATYK is an active, non-receptor, cytosolic kinase which induces neuronal differentiation and also promotes differentiation induced by other agents in the SH-SY5Y cells.