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L Smith

Publications and source records attributed to L Smith.

At least 19 recordsLinked to original sources
PubMed2006

Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening.

BACKGROUND: The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at-risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high-risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds. METHODS: 277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population. RESULTS: Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative. CONCLUSION: In high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.

Adult↗
PubMed2006

Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability.

Certain chromosome rearrangements display a significant delay in chromosome replication timing (DRT) that is associated with a subsequent delay in mitotic chromosome condensation (DMC). DRT/DMC chromosomes are common in tumor cells in vitro and in vivo and occur frequently in cells exposed to ionizing radiation. A hallmark for these chromosomes is the delayed phosphorylation of serine 10 of histone H3 during mitosis. The chromosome passenger complex, consisting of multiple proteins including Aurora B kinase and INCENP is thought to be responsible for H3 phosphorylation, chromosome condensation and the subsequent segregation of chromosomes. In this report, we show that chromosomes with DRT/DMC contain phosphorylated Chk1, consistent with activation of the S-M phase checkpoint. Furthermore, we show that INCENP is recruited to the DRT/DMC chromosomes during all phases of mitosis. In contrast, Aurora B kinase is absent on DRT/DMC chromosomes when these chromosomes lack serine 10 phosphorylation of H3. We also show that mitotic arrest deficient 2 (Mad2), a member of the spindle assembly checkpoint, is present on DRT/DMC chromosomes at a time when the normally condensed chromosomes show no Mad2 staining, indicating that DRT/DMC activates the spindle assembly checkpoint. Finally, cells with DRT/DMC chromosomes have centrosome amplification, abnormal spindle assembly, endoreduplication and significant chromosome instability.

Aurora Kinase B↗
PubMed2006

Commercial sex venues: a closer look at their impact on the syphilis and HIV epidemics among men who have sex with men.

OBJECTIVE: To provide insight into the role of commercial sex venues in the spread of syphilis and HIV among men who have sex with men (MSM). STUDY: A cross sectional study of 1351 MSM who were diagnosed with early syphilis who did and did not encounter sexual partners at commercial sex venues. RESULTS: Overall, 26% MSM diagnosed with syphilis had sexual encounters at commercial sex venues. Of these, 74% were HIV positive, 94% reported anonymous sex, and 66% did not use a condom. Compared to those who did not have a sexual encounter at these venues, they were twice as likely to be HIV positive (OR = 1.91, 95% CI 1.36 to 2.68), six times more likely to have anonymous sex (OR = 6.18, 95% CI 3.37 to 11.32), twice as likely not to use condom (OR = 2.02, 95% CI 1.71 to 2.38), and twice as likely to use non-injecting drugs (OR = 1.65, 95% CI 1.21 to 2.37). CONCLUSIONS: MSM diagnosed with syphilis who frequent commercial sex venues are engaging in high risk behaviours for syphilis and HIV transmission and acquisition. Thus commercial sex venues are one of the focal points of syphilis and HIV transmission and acquisition.

Adult↗
PubMed2006

Economic evaluation of alternative management methods of first-trimester miscarriage based on results from the MIST trial.

OBJECTIVES: To compare the cost-effectiveness of alternative management methods of first-trimester miscarriage. DESIGN: Economic evaluation conducted alongside a large randomised controlled trial (the MIST trial). SETTING: Early pregnancy assessment units of seven participating hospitals in southern England. SAMPLE: A total of 1200 women with a confirmed pregnancy of less than 13 weeks of gestation with a diagnosis of incomplete miscarriage or missed miscarriage. METHODS: Random allocation to expectant management, medical management or surgical management. Collection of health service and broader resource use data, unit costs for each resource item and clinical outcomes. MAIN OUTCOME MEASURES: Costs (pounds, 2001-02 prices) to the health service, social services, women, carers and wider society during the first 8 weeks postrandomisation. Cost-effectiveness estimates, expressed in terms of incremental cost per gynaecological infection prevented; cost-effectiveness acceptability curves presented at alternative willingness-to-pay thresholds for preventing gynaecological infection. RESULTS: There was no significant difference in the incidence of gynaecological infection between groups. The net societal cost per woman was estimated at 1086.20 pounds in the expectant group, 1410.40 pounds in the medical group and 1585.30 pounds in the surgical group. Expectant management had a 97.8% probability of being the most cost-effective management method at a willingness-to-pay threshold of 10,000 pounds for preventing one gynaecological infection, while medical management had a 2.2% probability of being the most cost-effective management method. Expectant management retained the highest probability of being the most cost-effective management method at all willingness-to-pay thresholds of less than 70,000 pounds for preventing one gynaecological infection. CONCLUSIONS: Expectant and medical management of first-trimester miscarriage possess significant economic advantages over traditional surgical management.

Abortion, Spontaneous↗
PubMed2006

Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial).

OBJECTIVE: To ascertain whether a clinically important difference exists in the incidence of gynaecological infection between surgical management and expectant or medical management of miscarriage. DESIGN: Randomised controlled trial comparing medical and expectant management with surgical management of first trimester miscarriage. SETTING: Early pregnancy assessment units of seven hospitals in the United Kingdom. PARTICIPANTS: Women of less than 13 weeks' gestation, with a diagnosis of early fetal demise or incomplete miscarriage. INTERVENTIONS: Expectant management (no specific intervention); medical management (vaginal dose of misoprostol preceded, for women with early fetal demise, by oral mifepristone 24-48 hours earlier); surgical management (surgical evacuation). MAIN OUTCOME MEASURES: Confirmed gynaecological infection at 14 days and eight weeks; need for unplanned admission or surgical intervention. RESULTS: 1200 women were recruited: 399 to expectant management, 398 to medical management, and 403 to surgical management. No differences were found in the incidence of confirmed infection within 14 days between the expectant group (3%) and the surgical group (3%) (risk difference 0.2%, 95% confidence interval - 2.2% to 2.7%) or between the medical group (2%) and the surgical group (0.7%, - 1.6% to 3.1%). Compared with the surgical group, the number of unplanned hospital admissions was significantly higher in both the expectant group (risk difference - 41%, - 47% to - 36%) and the medical group (- 10%, - 15% to - 6%). Similarly, when compared with the surgical group, the number of women who had an unplanned surgical curettage was significantly higher in the expectant group (risk difference - 39%, - 44% to - 34%) and the medical group (- 30%, - 35% to - 25%). CONCLUSIONS: The incidence of gynaecological infection after surgical, expectant, and medical management of first trimester miscarriage is low (2-3%), and no evidence exists of a difference by the method of management. However, significantly more unplanned admissions and unplanned surgical curettage occurred after expectant management and medical management than after surgical management. TRIAL REGISTRATION NATIONAL RESEARCH REGISTER: N0467011677/N0467073587.

Abortion, Spontaneous↗
PubMed2006

A questionnaire study to assess long-term outcome in patients with abnormal esophageal manometry.

Patients with unexplained chest pain or dysphagia are often referred for esophageal manometric studies to further investigate their symptoms. Four main manometric abnormalities have been described: achalasia, diffuse esophageal spasm, "nutcracker" (hypercontracting) esophagus, and hypocontracting esophagus. With the exception of achalasia, treatments are of limited benefit and the natural history of these conditions is largely unknown. We sent questionnaires to patients who were investigated at least three years before our study began. They repeated a DeMeester symptom questionnaire that they had completed at the time of their initial study. Questionnaires were sent to 137 patients with diffuse esophageal spasm, "nutcracker" (hypercontracting) esophagus, or hypocontracting esophagus. We also sent questionnaires to 57 patients with dysphagia or chest pain who had had normal esophageal manometry and pH studies. These patients acted as symptomatic controls. Responses were compared using the Wilcoxon signed ranks test. Seventy-two (53%) patients with diffuse esophageal spasm, "nutcracker" esophagus, or hypocontracting esophagus replied. An additional 8 (6%) patients died. Symptom scores in all three conditions had improved significantly over time (p < or = 0.01 for each condition, Wilcoxon signed ranks test). Patients with dysphagia or chest pain but normal esophageal studies had not improved. The significance of diffuse esophageal spasm, "nutcracker" esophagus, and hypocontracting esophagus found at esophageal manometry remains uncertain. Although treatment is often ineffective, these conditions typically run a benign course. Patients can be reassured that their symptoms are likely to improve with time.

Adult↗
PubMed2006

MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome.

Dysfunction of the ubiquitin-proteasome system occurs in the substantia nigra (SN) in Parkinson's disease (PD). However, it is unknown whether this is a primary cause or a secondary consequence of other components of the pathogenic process. We have investigated in nonhuman primates whether initiating cell death through mitochondrial complex I inhibition using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) altered proteasomal activity or the proteasomal components in the SN. Chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolase (PGPH) activating of 20S proteasome were decreased in SN homogenates of MPTP-treated marmosets compared to naïve animals. Western blotting revealed a marked decrease in the expression of 20S-alpha subunits, but no change in 20S-beta subunits in the SN of MPTP-treated marmoset compared to naïve animals. There was a marked decrease in the expression of the proteasome activator 700 (PA700) and proteasome activator 28 (PA28) regulatory complexes. The 20S-alpha4 subunit immunoreactivity was decreased in the nucleus of colocalized tyrosine hydroxylase (TH)-positive cells of MPTP-treated animals compared to naïve animals but no difference in the intensity of 20S-beta1i subunit staining. Immunoreactivity for PA700-Rpt5 and PA28-alpha subunits within surviving TH-positive cells of MPTP-treated marmoset was reduced compared to naïve controls. Overall, the changes in proteasomal function and structure occurring follow MPTP-induced destruction of the SN in common marmosets were very similar to those found in PD. This suggests that altered proteasomal function in PD could be a consequence of other pathogenic processes occurring in SN as opposed to initiating cell death as previously suggested.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

A retrospective analysis of ezetimibe treatment in renal transplant recipients.

A retrospective review was conducted to determine the safety and efficacy of ezetimibe as a treatment option for renal transplant recipients. We evaluated the medical records of 34 adult renal transplant recipients receiving ezetimibe as monotherapy or combination therapy. Fasting lipid profiles were obtained at baseline and at 1-6 months post-ezetimibe initiation. Twenty patients received cyclosporine, 12 patients received tacrolimus, 1 patient received either sirolimus or no calcineurin therapy at the time of ezetimibe initiation. Monotherapy was started in 8 patients, who had all previously failed statins, and combination therapy was utilized in 26 patients. Monotherapy or combination therapy resulted in a mean reduction in total cholesterol of 23.3%, triglycerides 40.2%, low-density lipoproteins 16.8% and high-density lipoproteins 4.8% after 3.1 months of therapy. Ezetimibe as combination or monotherapy is a safe and effective treatment option for dyslipidemia in renal transplant recipients without changes in calcineurin inhibitor levels or renal function.

Adult↗
PubMed2005

DLG5 variants do not influence susceptibility to inflammatory bowel disease in the Scottish population.

INTRODUCTION: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G-->A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection. AIMS: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population. PATIENTS AND METHODS: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system. RESULTS: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15. CONCLUSIONS: The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.

Adult↗
PubMed2005

Enzyme-linked immunospot assay responses to early secretory antigenic target 6, culture filtrate protein 10, and purified protein derivative among children with tuberculosis: implications for diagnosis and monitoring of therapy.

BACKGROUND: The ability to detect tuberculosis-specific lymphocytes by enzyme-linked immunospot (ELISPOT) assay may have important implications for the diagnosis and monitoring of tuberculosis in children, for which routine methods lack sensitivity. We conducted a study to determine the presence and time course of ELISPOT responses in children with tuberculosis. METHODS: Blood samples were obtained from children with a clinical diagnosis of tuberculosis, and interferon-gamma ELISPOT assays were performed using purified protein derivative (PPD), early secretory antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP10) as stimulants. A subset of children were retested after 1, 3, and 6 months of therapy. RESULTS: Detectable responses to ESAT-6 or CFP10 were found in 49 of 70 children with clinical tuberculosis but were more frequently found in those with culture-proven disease (P = .05). The number of subjects with responses to PPD increased after 1 month of therapy (P = .0004) and decreased at 3 and 6 months. CONCLUSION: Tuberculosis-specific ELISPOT testing is a promising tool that should be evaluated as a potential diagnostic test for childhood tuberculosis. We caution against the use of an early decrease in response as a marker of successful antituberculous chemotherapy.

Antigens, Bacterial↗
PubMed2005

Release of TNF-alpha and IL-1beta from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin.

BACKGROUND: Formulations of amphotericin include a deoxycholate suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (L-Amph). Fever is most frequent with d-Amph, intermediate with Ablc, and lowest with L-Amph. OBJECTIVE: To determine if the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1) from brain endothelium corresponds to the incidence of amphotericin fever. RESULTS: Release of TNF-alpha and IL-1beta after L-Amph treatment was similar to negative controls while after d-Amph treatment release was similar to lipopolysaccharide. Ablc treatment produced intermediate pyrogen release.NF-kappaB expression, a transcriptional regulator for TNF-alpha and IL-1beta genes, corresponded to this secretion pattern. TNF-alpha release was elevated 2 hours (p = 0.0021) after treatment while significant elevations in IL-1beta required 6 hours (p = 0.0009). CONCLUSION: Results from this in vitro study suggest that amphotericin fever may be directly mediated by brain endothelium. These experiments also suggest that amphotericin fever is initially mediated by TNF-alpha.

Amphotericin B↗
PubMed2005

Effects of three months of low molecular weight heparin (dalteparin) treatment after bypass surgery for lower limb ischemia--a randomised placebo-controlled double blind multicentre trial.

OBJECTIVES: To test the hypothesis that long-term postoperative dalteparin (Fragmin), Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment. DESIGN: Prospective randomised double blind multicenter study. MATERIALS AND METHODS: Using a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000 IU dalteparin or placebo injections once daily for 3 months. All patients received 75 mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months. RESULTS: At 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups. CONCLUSIONS: In patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia.

Aged↗
PubMed2005

Development of a holistic admission assessment: an integrated care pathway for the hospice setting.

This article describes the development of a holistic admission assessment for all inpatients admitted to a 66-bedded hospice, structured in the form of an integrated care pathway (ICP). The need for an improved assessment process was identified by clinical staff, who recognized that the existing assessment was not truly holistic and was dependent on the skills of the assessors. The assessment also lacked appropriate goals and actions. The recently published National Institute for Clinical Excellence (NICE) guidance on Improving Supportive and Palliative Care for Adults with Cancer, has also highlighted key areas for the improvement of patient assessment in specialist palliative care (NICE, 2004). Implementation of the ICP has resulted in a systematic and timely holistic assessment process for patients. The ICP addresses effectively the NICE recommendations for the assessment of specialist palliative care patients.

Critical Pathways↗
PubMed2004

MedPost: a part-of-speech tagger for bioMedical text.

SUMMARY: We present a part-of-speech tagger that achieves over 97% accuracy on MEDLINE citations. AVAILABILITY: Software, documentation and a corpus of 5700 manually tagged sentences are available at ftp://ftp.ncbi.nlm.nih.gov/pub/lsmith/MedPost/medpost.tar.gz

Abstracting and Indexing↗
PubMed2004

Identification of related gene/protein names based on an HMM of name variations.

Gene and protein names follow few, if any, true naming conventions and are subject to great variation in different occurrences of the same name. This gives rise to two important problems in natural language processing. First, can one locate the names of genes or proteins in free text, and second, can one determine when two names denote the same gene or protein? The first of these problems is a special case of the problem of named entity recognition, while the second is a special case of the problem of automatic term recognition (ATR). We study the second problem, that of gene or protein name variation. Here we describe a system which, given a query gene or protein name, identifies related gene or protein names in a large list. The system is based on a dynamic programming algorithm for sequence alignment in which the mutation matrix is allowed to vary under the control of a fully trainable hidden Markov model.

Algorithms↗
PubMed2004

Retrieving definitional content for ontology development.

Ontology construction requires an understanding of the meaning and usage of its encoded concepts. While definitions found in dictionaries or glossaries may be adequate for many concepts, the actual usage in expert writing could be a better source of information for many others. The goal of this paper is to describe an automated procedure for finding definitional content in expert writing. The approach uses machine learning on phrasal features to learn when sentences in a book contain definitional content, as determined by their similarity to glossary definitions provided in the same book. The end result is not a concise definition of a given concept, but for each sentence, a predicted probability that it contains information relevant to a definition. The approach is evaluated automatically for terms with explicit definitions, and manually for terms with no available definition.

Bayes Theorem↗