Biomedical subjects

S Leach

Publications and source records attributed to S Leach.

At least 19 recordsLinked to original sources

PubMed2007

Comparison of smallpox outbreak control strategies using a spatial metapopulation model.

To determine the potential benefits of regionally targeted mass vaccination as an adjunct to other smallpox control strategies we employed a spatial metapopulation patch model based on the administrative districts of Great Britain. We counted deaths due to smallpox and to vaccination to identify strategies that minimized total deaths. Results confirm that case isolation, and the tracing, vaccination and observation of case contacts can be optimal for control but only for optimistic assumptions concerning, for example, the basic reproduction number for smallpox (R0=3) and smaller numbers of index cases ( approximately 10). For a wider range of scenarios, including larger numbers of index cases and higher reproduction numbers, the addition of mass vaccination targeted only to infected districts provided an appreciable benefit (5-80% fewer deaths depending on where the outbreak started with a trigger value of 1-10 isolated symptomatic individuals within a district).

Disease Outbreaks↗

PubMed2006

Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations.

Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain-behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1(-/-) mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain-behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role.

Animals↗

PubMed2006

Real-time epidemic forecasting for pandemic influenza.

The ongoing worldwide spread of the H5N1 influenza virus in birds has increased concerns of a new human influenza pandemic and a number of surveillance initiatives are planned, or are in place, to monitor the impact of a pandemic in near real-time. Using epidemiological data collected during the early stages of an outbreak, we show how the timing of the maximum prevalence of the pandemic wave, along with its amplitude and duration, might be predicted by fitting a mass-action epidemic model to the surveillance data by standard regression analysis. This method is validated by applying the model to routine data collected in the United Kingdom during the different waves of the previous three pandemics. The success of the method in forecasting historical prevalence suggests that such outbreaks conform reasonably well to the theoretical model, a factor which may be exploited in a future pandemic to update ongoing planning and response.

Disease Outbreaks↗

PubMed2006

Possible ecology and epidemiology of medically important mosquito-borne arboviruses in Great Britain.

Nine different arboviruses are known to be transmitted by, or associated with, mosquitoes in Europe, and several (West Nile, Sindbis and Tahyna viruses) are reported to cause outbreaks of human disease. Although there have been no reported human cases in Great Britain (GB), there have been no published in-depth serological surveys for evidence of human infection. This paper investigates the ecological and entomological factors that could influence or restrict transmission of these viruses in GB, suggesting that in addition to West Nile virus, Sindbis and Tahyna viruses could exist in enzootic cycles, and that certain ecological factors could facilitate transmission to humans. However, the level of transmission is likely to be lower than in endemic foci elsewhere in Europe due to key ecological differences related to spatial and temporal dynamics of putative mosquito vectors and presence of key reservoir hosts. Knowledge of the potential GB-specific disease ecology can aid assessments of risk from mosquito-borne arboviruses.

Animals↗

PubMed2005

Potential transmission of West Nile virus in the British Isles: an ecological review of candidate mosquito bridge vectors.

West Nile virus (WNV) transmitted by mosquitoes (Diptera: Culicidae) infects various vertebrates, being pathogenic for birds, horses and humans. After its discovery in tropical Africa, sporadic outbreaks of WNV occurred during recent decades in Eurasia, but not the British Isles. WNV reached New York in 1999 and spread to California by 2003, causing widespread outbreaks of West Nile encephalitis across North America, transmitted by many species of mosquitoes, mainly Culex spp. The periodic reappearance of WNV in parts of continental Europe (from southern France to Romania) gives rise to concern over the possibility of WNV invading the British Isles. The British Isles have about 30 endemic mosquito species, several with seasonal abundance and other eco-behavioural characteristics predisposing them to serve as potential WNV bridge vectors from birds to humans. These include: the predominantly ornithophilic Culex pipiens L. and its anthropophilic biotype molestus Forskal; tree-hole adapted Anopheles plumbeus Stephens; saltmarsh-adapted Ochlerotatus caspius Pallas, Oc. detritus Haliday and Oc. dorsalis (Meigen); Coquillettidia richiardii Ficalbi, Culiseta annulata Schrank and Cs. morsitans (Theobald) from vegetated freshwater pools; Aedes cinereus Meigen, Oc. cantans Meigen and Oc. punctor Kirby from seasonal woodland pools. Those underlined have been found carrying WNV in other countries (12 species), including the rarer British species Aedes vexans (Meigen), Culex europaeus Ramos et al., Cx. modestus Ficalbi and Oc. sticticus (Meigen) as well as the Anopheles maculipennis Meigen complex (mainly An. atroparvus van Thiel and An. messeae Falleroni in Britain). Those implicated as key vectors of WNV in Europe are printed bold (four species). So far there is no proof of any arbovirus transmission by mosquitoes in the British Isles, although antibodies to Sindbis, Tahyna, Usutu and West Nile viruses have been detected in British birds. Neighbouring European countries have enzootic WNV and human infections transmitted by mosquito species that are present in the British Isles. However, except for localized urban infestations of Cx. pipiens biotype molestus that can be readily eliminated, there appear to be few situations in the British Isles where humans and livestock are exposed to sustained risks of exposure to potential WNV vectors. Monitoring of mosquitoes and arbovirus surveillance are required to guard the British Isles against WNV outbreaks and introduction of more anthropophilic mosquitoes such as Stegomyia albopicta (Skuse) and Ochlerotatus japonicus (Theobald) that have recently invaded Europe, since they transmit arboviruses elsewhere.

Animals↗

PubMed2005

Distribution of Ixodes ricinus in the British Isles: investigation of historical records.

Ixodes ricinus Linnaeus (Acari: Ixodidae) is the most abundant and widely distributed tick in the British Isles, and is a vector for a number of bacterial, viral and protozoal pathogens of both medical and veterinary importance. This report provides an update to the historical distribution data of I. ricinus, published by the Biological Records Centre (BRC), Monks Wood in The Provisional Atlas of the Ticks (Ixodidae) of the British Isles by K. P. Martyn (1988), and is supplemented with additional BRC records since 1988, additional data from published scientific literature and unpublished field studies, and enhanced with spatial and temporal information on tick stages collected and their host associations. Records have been mapped at 10 km resolution and enhanced to 5 km, 1 km and 0.1 km. Differentiation between records representing one-off collections from those representing populations of I. ricinus has been achieved through the classification of the records into either reported or established populations. Detailed seasonality and host associations of records are investigated, highlighting the value in obtaining additional detailed contemporary data to aid risk assessments and research within this field.

Animals↗

PubMed2004

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.

BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.

Adolescent↗

PubMed2002

Electronic poster presentations in BAPEN--a controlled evaluation.

INTRODUCTION: We sought to compare the quality of e-poster and traditional poster communications. METHODS: At the 2001 BAPEN congress, ten presenters were invited to supplement their poster by submitting its title and contents electronically. On projection, the submissions appeared as a poster. During chaired rounds, presenters 'talked to' the projection as if it were a traditional poster. They 'clicked' onto individual tables or figures to enlarge to full screen. A further 'click' returned the screen to poster format. Delegates attending two e-poster sessions, and a control group attending two simultaneous traditional poster rounds, responded to a questionnaire, on a scale 0--4, to statements which related: to the ability to (1) hear and (2) see well, (3) the posters'clarity and attractiveness, (4) whether the format of the session captured their interest and (5) encouraged discussion. Delegates also responded on how e-posters should be used in future meetings. Comparison was made using chi2 for trend. RESULTS: Questionnaires were returned from attendees at e-poster (27) and traditional (25) poster rounds. For all questions, the trend was in favour of e-posters with significant differences seen for 'seeing' (P= 0.009), 'interest capture' (P< 0.007) and 'encouragement of discussion' (P<0.05). Thirty-two vs one delegates thought that e-posters should be used in future, 28 vs 4 delegates thought that e-posters and traditional posters should be used together, but most(23 vs 8) thought that traditional posters should not be completely replaced. CONCLUSIONS: E-posters enable detailed search of a computer-based database of presentations, and viewing of the full content of all posters. Post-conference collaboration is enhanced by facilitating e-mail contact. E-posters should be used in tandem with traditional posters to improve the delivery of original communications.

Audiovisual Aids↗

PubMed2001

Transmission potential of smallpox in contemporary populations.

Despite eradication, smallpox still presents a risk to public health whilst laboratory stocks of virus remain. One factor crucial to any assessment of this risk is R0, the average number of secondary cases infected by each primary case. However, recently applied estimates have varied too widely (R0 from 1.5 to >20) to be of practical use, and often appear to disregard contingent factors such as socio-economic conditions and herd immunity. Here we use epidemic modelling to show a more consistent derivation of R0. In isolated pre-twentieth century populations with negligible herd immunity, the numbers of cases initially rose exponentially, with an R0 between 3.5 and 6. Before outbreak controls were applied, smallpox also demonstrated similar levels of transmission in 30 sporadic outbreaks in twentieth century Europe, taking into account pre-existing vaccination levels (about 50%) and the role of hospitals in doubling early transmission. Should smallpox recur, such estimates of transmission potential (R0 from 3.5 to 6) predict a reasonably rapid epidemic rise before the implementation of public health interventions, because little residual herd immunity exists now that vaccination has ceased.

Disease Outbreaks↗

PubMed2001

Molecular cloning of a third member of the potassium-dependent sodium-calcium exchanger gene family, NCKX3.

We describe here the identification and characterization of a novel member of the family of K(+)-dependent Na(+)/Ca(2+) exchangers, NCKX3 (gene SLC24A3). Human NCKX3 encodes a protein of 644 amino acids that displayed a high level of sequence identity to the other family members, rod NCKX1 and cone/neuronal NCKX2, in the hydrophobic regions surrounding the "alpha -repeat" sequences thought to form the ion-binding pocket for transport. Outside of these regions NCKX3 showed no significant identity to other known proteins. As anticipated from this sequence similarity, NCKX3 displayed K(+)-dependent Na(+)/Ca(2+) exchanger activity when assayed in heterologous expression systems, using digital imaging of fura-2 fluorescence, electrophysiology, or radioactive (45)Ca(2+) uptake. The N-terminal region of NCKX3, although not essential for expression, increased functional activity at least 10-fold and may represent a cleavable signal sequence. NCKX3 transcripts were most abundant in brain, with highest levels found in selected thalamic nuclei, in hippocampal CA1 neurons, and in layer IV of the cerebral cortex. Many other tissues also expressed NCKX3 at lower levels, especially aorta, uterus, and intestine, which are rich in smooth muscle. The discovery of NCKX3 thus expands the K(+)-dependent Na(+)/Ca(2+) exchanger family and suggests this class of transporter has a more widespread role in cellular Ca(2+) handling than previously appreciated.

Animals↗

PubMed2001

Neural activation during frequency-memory performance.

Lesion studies have demonstrated that frequency memory, or memory for the frequency of occurrence, is associated with prefrontal and not temporal lobe lesions. This study examined neural activation during performance on a frequency-memory-judgment task and a recognition-memory task, both using words. Relative to a control task, the authors observed peaks of activation during frequency-memory performance in the left ventrolateral prefrontal cortex (BA 45) and other areas typically associated with working memory (dorsolateral prefrontal cortex, posterior parietal cortex). Recognition performance was associated with activation in the same left ventrolateral prefrontal location as was observed with frequency memory. When comparing activation during frequency memory with activation during recognition memory, the authors found a suppression of activation in the hippocampus bilaterally during frequency memory. This study supports a neuroanatomical distinction between frequency and recognition memory.

Adult↗

PubMed2000

Reactions of e(-)(aq), CO(2)()(-), HO(), O(2)(*)(-) and O(2)((1)delta(g)) with a dendro[60]fullerene and C(60)[C(COOH)(2)](n) (n = 2-6).

Using pulse radiolysis and laser flash photolysis, we have investigated the reactions of the deleterious species, e(-)(aq), HO&z.rad;, O(2)(*)(-) and O(2)((1)Delta(g)) with 10 water-soluble cyclopropyl-fused C(60) derivatives including a mono-adduct dendro[60]fullerene (d) and C(60) derivatives based on C(60)[C(COOH)(2)](n=2-6), some of which are known to be neuroprotective in vivo. The rate constants for reactions of e(-)(aq) and HO&z.rad; lie in the range 0.5-3.3 x 10(10) M(-1) s(-1). The d and bis-adduct monoanion radicals display sharp absorption peaks around 1000 nm (epsilon = 7 000-11 500 M(-1) cm(-1)); the anions of the tris-, tetra-, and penta-adduct derivatives have broader, weaker absorptions. The monohydroxylated radicals have their most intense absorption maxima around 390-440 nm (epsilon = 1000-3000 M(-1) cm(-1)). The anion and hydroxylated radical absorption spectra display a blue-shift as the number of addends increases. The radical anions react with oxygen (k approximately 10(7)-10(9) M(-1) s(-1)). The reaction of O(2)(*)(-) with the C(60) derivatives does not occur via an electron transfer. The rate constants for singlet oxygen reaction with the dendrofullerene and eee-derivative in D(2)O at pH 7.4 are k approximately 7 x 10(7) and approximately 2 x 10(7) M(-1) s(-1) respectively, in contrast to approximately 1.2 x 10(5) M(-1) s(-1) for the reaction with C(60) in C(6)D(6). The large acceleration of the rates for electron reduction and singlet oxygen reactions in water is due to a solvophobic process.

Carbon↗

PubMed2000

Verbal working memory and solvent exposure: a positron emission tomography study.

Neuropsychological studies have documented frontal dysfunction in patients with a history of exposure to organic solvents. The deficits typically observed in these patients appear to be related to working memory (WM). This study used [15O] water positron emission tomography (PET) to examine the pattern of neural activation during verbal working memory in patients with a history of exposure to solvents. Six individuals with solvent exposure were compared with 6 age- and education-matched controls. On the 2 WM tasks examined with PET, with equivalent task performance, participants with solvent exposure demonstrated frontal peaks that were atypical for the tasks, whereas the posterior peaks were typical for the tasks. The results support frontal dysfunction and compensatory use within anterior regions of the WM system in patients with solvent exposure.

Brain↗

PubMed2000

Localized reversible frameshift mutation in the flhA gene confers phase variability to flagellin gene expression in Campylobacter coli.

Phase variation of flagellin gene expression in Campylobacter coli UA585 was correlated with high-frequency, reversible insertion and deletion frameshift mutations in a short homopolymeric tract of thymine residues located in the N-terminal coding region of the flhA gene. Mutation-based phase variation in flhA may generate functional diversity in the host and environment.

Bacterial Proteins↗

PubMed2000

Alternatively spliced isoforms of the rat eye sodium/calcium+potassium exchanger NCKX1.

We have investigated the structure, function, and expression of the rat eye sodium/calcium+potassium exchanger NCKX1. The sequence of independent rat NCKX1 clones and the analysis of rat eye mRNA by RT-PCR revealed a region of alternative splicing that comprised four exons and encoded a stretch of 113 amino acids near the beginning of the large cytosolic loop. In comparison with other NCKX1 molecules and the rat NCKX2 protein, rat NCKX1 was highly conserved within the hydrophobic regions but was quite divergent in the two large hydrophilic loops. The only exception was the region of the cytosolic loop encoded by the second alternatively spliced exon, which was approximately 60% identical. Similar to bovine, but different from human, rat NCKX1 possessed an acidic motif that was repeated 14 times in the cytoplasmic loop. Analysis of NCKX1 expression in different rat tissues by Northern blot revealed a very high level of expression of a 7-kb transcript in the eye but also lower levels of transcripts of various lengths in other tissues. The recombinant rat NCKX1 protein was tagged in the extracellular loop with the FLAG epitope and expressed in HEK-293 cells. Surface delivery and potassium-dependent sodium/calcium exchange activity were observed for each spliced variant.

Alternative Splicing↗

PubMed2000

Neural activation during performance of number-letter sequencing.

Recent advances in neuroimaging have enabled researchers to establish relatively specific areas of the brain that are involved in working memory. In this positron emission tomography study we examined the pattern of neural activation associated with performance on number-letter sequencing, a purported measure of working memory included in the new Wechsler scales for memory and intelligence. After controlling for basic audition, verbalization, and attention, areas of activation were observed in the orbital frontal lobe, dorsolateral prefrontal cortex, and posterior parietal cortex. This is highly consistent with reports from the literature on activation patterns associated with working memory. More activation peaks were observed in the right hemisphere, suggesting the participants utilized visualization of the verbal information. Consistent with task conceptualization, this study provides support for number-letter sequencing as a task involving working memory.

Adult↗

PubMed1999

A role for the hepatobiliary system in IgE-mediated intestinal inflammation in the rat.

BACKGROUND: For many years the central focus of research into gastrointestinal hypersensitivity reactions has been the mast cell population of the intestinal lamina propria. Since bile is known to deliver immunological mediators to the gastrointestinal tract, the possibility arises that extra-intestinal populations of mast cells may also contribute to IgE-mediated intestinal damage. OBJECTIVES: To characterize hepatic mast cells in the rat and to investigate the role of the hepatobiliary system in a model of IgE-mediated reactivity to dietary antigen. METHODS: Wistar rats were passively sensitized with monoclonal antidinitrophenyl (DNP) IgE antibodies, and were later challenged orogastrically with DNP-HSA. Additional animals were sensitized, then bile duct-cannulated prior to antigen challenge. At various time points, liver and intestinal samples were collected for histological examination, and bile was collected and assayed for histamine and TNFalpha. RESULTS: Hepatic mast cells display a mucosal mast cell-like phenotype, and are closely associated with the vessels of the portal triads. Orogastric antigen challenge led to a rapid and significant decline (P<0.0001) in detectable mast cells as a result of anaphylactic degranulation. The median number of granulated mast cells associated with each portal triad in liver sections declined from six per portal triad to one per portal triad post-antigen challenge. After 15 min, biliary histamine concentrations rose above background levels (P<0.01). TNFalpha was also detectable in the majority (4/6) of bile samples within 15 min of challenge. Histological examination of the gastrointestinal mucosa revealed disruption to the villous epithelium ranging from oedematous changes to gross destruction. Such damage was not seen in animals in which bile had been externally drained. CONCLUSION: The data indicate that biliary products are major contributors to the gastrointestinal damage arising from IgE-mediated hypersensitivity reactions in the rat, and such hypersensitivity reactions may involve a population of mast cells which reside in the liver.

Animals↗

PubMed1999

Concurrent paclitaxel and thoracic irradiation for locally advanced esophageal cancer.

Esophageal cancer is a major cause of morbidity and mortality worldwide. Although patients often present with apparently resectable disease, systemic spread frequently occurs before the development of symptoms and detection of tumor. The use of combined chemoradiation therapy, particularly before resection, appears to prolong survival and increase cure rates in certain histologic subtypes. Four randomized phase III trials compared preoperative chemoradiotherapy plus surgery with surgery alone. In trials including only patients with squamous histology, no improvement in survival was observed with preoperative chemoradiation therapy; however, in a trial including only patients with adenocarcinoma histology, improved median and overall survival were observed. Paclitaxel has been evaluated as a single agent in a phase II trial in previously untreated patients with locally advanced unresectable or metastatic esophageal cancer; the overall response rate was 32% and median survival was 13.2 months. Paclitaxel-based combinations also have been evaluated in esophageal cancer; particularly encouraging preliminary results have been achieved with paclitaxel/cisplatin/5-fluorouracil. Because paclitaxel is a potent radiosensitizer, it also has been evaluated in combination with radiation therapy for esophageal and other thoracic cancers, alone and in combination with other chemotherapeutic agents. Preliminary results suggest that neoadjuvant therapy with paclitaxel-based combinations (including 5-fluorouracil and cisplatin) and radiation is highly active, with variable toxicity. A goal of future trials is to assess paclitaxel-based combined modality therapy in combination with other new chemotherapeutic agents.

Antineoplastic Agents, Phytogenic↗