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1.  Transhemispheric Cortical Plasticity Following Contralateral C7 Nerve Transfer: A Rat Functional Magnetic Resonance Imaging Survival Study 
The Journal of hand surgery  2013;38(3):478-487.
PMCID: PMC4174583  PMID: 23428188
Brachial plexus; cortical plasticity; C7 nerve transfer; functional magnetic resonance imaging
2.  Risk factors for iatrogenic retinal breaks induced by separation of posterior hyaloid face during 23-gauge pars plana vitrectomy 
Eye  2013;27(5):652-656.
To describe the incidence and features of intraoperative retinal breaks caused by induction of posterior hyaloid face (PHF) separation during 23-gauge pars plana vitrectomy (PPV).
A prospective, consecutive, single surgeon, observational study of patients undergoing 23-gauge transconjunctival sutureless vitrectomy for macular pathology or floaters, was carried out between 2009 and 2011 at Calderdale Royal Hospital, UK. PHF separations were categorised as either suction induced or requiring membrane blue (DORC Limited) with suction (adherent). The outcome measure was dichotomised into retinal break or tear and no retinal break or tear. Forced entry and parsimonious multiple logistic regression analyses were conducted, using statistical software, to test for significance of association of the set of recorded factors and covariates with the dichotomised outcome measure.
Data were collected and analysed from 137 patients. The incidence of iatrogenic retinal breaks associated with PHF separation during 23-gauge PPV was 18.2%. Under both forced entry and parsimonious multiple logistic regression models, the odds of a retinal break or tear reduce by about 3–4% for each increasing year of age. Findings also showed some substantive association in the forced entry model, with the odds of a retinal break or tear for adherent cases being around 3.8 times those for suction-only cases.
Mechanical detachment of the PHF represents an important risk factor in the formation of retinal breaks. Particular care should be taken to examine intraoperatively for iatrogenic breaks in order to prevent missed breaks and subsequent rhegmatogenous retinal detachments.
PMCID: PMC3650290  PMID: 23449510
23-gauge; sutureless; vitrectomy; iatrogenic; retinal; breaks
3.  A cross-sectional study of Mycoplasma genitalium infection and correlates in women undergoing population-based screening or clinic-based testing for Chlamydia infection in London 
BMJ Open  2014;4(2):e003947.
To determine Mycoplasma genitalium infection and correlates among young women undergoing population-based screening or clinic-based testing for Chlamydia infection.
Cross-sectional study.
National Chlamydia Screening Programme (NCSP) and two London sexually transmitted infection (STI) clinics.
2441 women aged 15–64 years who participated in the NCSP and 2172 women who attended two London STI clinics over a 4-month period in 2009.
Outcome measures
(1) M genitalium prevalence in defined populations (%). (2) Age-adjusted ORs (aORs) for correlates of M genitalium infection.
The overall frequency of M genitalium and Chlamydia trachomatis was 3% and 5.4%, respectively. Co-infection was relatively uncommon (0.5% of all women); however 9% of women with C trachomatis also had M genitalium infection. M genitalium was more frequently detected in swab than urine samples (3.9 vs 1.3%, p<0.001) with a significantly higher mean bacterial load (p ≤ 0.001). Among NCSP participants, M genitalium was significantly more likely to be diagnosed in women of black/black British ethnicity (aOR 2.3, 95% CI 1.2 to 4.5, p=0.01). M genitalium and C trachomatis and were both significantly associated with multiple sexual partners in the past year (aOR 2.4, 95% CI 1.3 to 4.4, p=0.01 and aOR 2.0, 95% CI 1.4 to 2.8, p<0.01). Among STI clinic attendees, M genitalium was more common in women who were less than 25 years in age.
M genitalium is a relatively common infection among young women in London. It is significantly more likely to be detected in vulvovaginal swabs than in urine samples. Co-infection with Chlamydia is uncommon. The clinical effectiveness of testing and treatment strategies for M genitalium needs further investigation.
PMCID: PMC3918997  PMID: 24503298
Epidemiology; Genitourinary Medicine; Microbiology
4.  The Multifaceted Effects of Omega-3 Polyunsaturated Fatty Acids on the Hallmarks of Cancer 
Journal of Lipids  2013;2013:261247.
Omega-3 polyunsaturated fatty acids, in particular eicosapentaenoic acid, and docosahexaenoic acid have been shown to have multiple beneficial antitumour actions that affect the essential alterations that dictate malignant growth. In this review we explore the putative mechanisms of action of omega-3 polyunsaturated fatty acid in cancer protection in relation to self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion, and how these will hopefully translate from bench to bedside.
PMCID: PMC3671553  PMID: 23762563
5.  Cortical plasticity induced by different degrees of peripheral nerve injuries: a rat functional magnetic resonance imaging study under 9.4 Tesla 
Major peripheral nerve injuries not only result in local deficits but may also cause distal atrophy of target muscles or permanent loss of sensation. Likewise, these injuries have been shown to instigate long-lasting central cortical reorganization.
Cortical plasticity changes induced after various types of major peripheral nerve injury using an electrical stimulation technique to the rat upper extremity and functional magnetic resonance imaging (fMRI) were examined. Studies were completed out immediately after injury (acute stage) and at two weeks (subacute stage) to evaluate time affect on plasticity.
After right-side median nerve transection, cortical representation of activation of the right-side ulnar nerve expanded intra-hemispherically into the cortical region that had been occupied by the median nerve representation After unilateral transection of both median and ulnar nerves, cortical representation of activation of the radial nerve on the same side of the body also demonstrated intra-hemispheric expansion. However, simultaneous electrical stimulation of the contralateral uninjured median and ulnar nerves resulted in a representation that had expanded both intra- and inter-hemispherically into the cortical region previously occupied by the two transected nerve representations.
After major peripheral nerve injury, an adjacent nerve, with similar function to the injured nerve, may become significantly over-activated in the cortex when stimulated. This results in intra-hemispheric cortical expansion as the only component of cortical plasticity. When all nerves responsible for a certain function are injured, the same nerves on the contralateral side of the body are affected and become significantly over-activated during a task. Both intra- and inter-hemispheric cortical expansion exist, while the latter dominates cortical plasticity.
PMCID: PMC3659007  PMID: 23659705
Functional magnetic resonance imaging (fMRI); Cortical plasticity; Peripheral nervous system (PNS); Central nervous system; Nerve injury; BOLD
6.  A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer 
British Journal of Cancer  2012;106(5):839-845.
Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy.
Eligible patients (3–6 per cohort) had extensive-stage SCLC, measurable disease, ⩽1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1–3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m−2, days 1–3). The primary endpoint was to determine the maximum tolerated dose of obatoclax.
Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts.
Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin–etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.
PMCID: PMC3305978  PMID: 22333598
small cell lung cancer; apoptosis; Bcl-2 gene family; CNS symptoms
7.  Contrasting Effects of Physical Wear on Elution of Two Antibiotics from Orthopedic Cement 
The use of antibiotics as a supplement to bone cement for the purposes of providing a local release of antibiotics is common practice in arthroplasty surgery and the kinetics of elution of the antibiotics in such systems have been investigated previously. However, in these previous studies no account was taken of the potential effects that wear may have on the elution kinetics of the antibiotic. Here, we have modified an existing wear testing rig to allow the simultaneous study of the elution kinetics of bone cement samples containing antibiotics being subjected to immersion only and immersion and conjoint wear. The results show contrasting effects with two commonly used antibiotics. Bone cement containing daptomycin showed no substantial change in antibiotic elution due to wear, while cement containing gentamicin (the most commonly used antibiotic in this application) in contrast demonstrated a substantial reduction in the rate of antibiotic elution when wear was applied. Scanning electron microscopy revealed a possible explanation for these diverse results, due to wear-induced “sealing” of the surface in conjunction with the crystal morphology of the antibiotic.
PMCID: PMC3294895  PMID: 22155831
8.  Endovascular Treatment of a Giant Aneurysm of the Maxillary Artery 
Aneurysms of the maxillary artery are rare and the majority of the literature refers to false aneurysms. We report the first case of what we believe to be a spontaneous true maxillary artery aneurysm and its endovascular management.
PMCID: PMC3420425  PMID: 22937466
9.  IDSieve: Protein Identification Using Peptide pI Filtering of MS/MS Data for Improved Confidence in Identifications 
The main challenge of tandem mass spectrometry based proteomic analysis is to correctly match the tandem mass spectra produced to the correct peptides. However, the large number of protein sequences in a database increases the chances of a false positive identification for any given peptide match. Here we present an automated algorithm called IDSieve that utilizes target-decoy database search strategy in combination with pI filtering to allow greater confidence for peptide identifications. IDSieve considers the SEQUEST parameters Xcorr and äCn to assign statistical confidence (false discovery rates) to the peptide matches. The distribution of predicted pI values for peptide spectrum matches (PSMs) is considered separately for each immobilized pH gradient isoelectric focusing fraction, and matches with pI values within 1.5 times inter-quartile range (within pI range) are analyzed independently of matches outside the pI ranges. We tested the performance of IDSieve and Peptide/Protein Prophet on the SEQUEST outputs from 60 immobilized pH gradient isoelectric focusing fractions derived from mouse intestinal epithelial cell protein extracts. Our results demonstrated that IDSieve produced 1355 more peptide spectrum matches (or 330 more peptides) than Peptide Prophet using comparable false positive rate cutoffs. Therefore, combining pI filtering with the appropriate statistical significance measurements allows for a higher number of protein identifications without adversely affecting the false positive rate. We further tested the performance of pI filtering using ID Sieve when samples were prefractionated using either pH range 3.5–4.5 or 3–10, and either 24cm or 7cm IPG strips.
PMCID: PMC3186675
10.  Does the UK government's teenage pregnancy strategy deal with the correct risk factors? Findings from a secondary analysis of data from a randomised trial of sex education and their implications for policy 
Much of the UK government's 1999 report on teenage pregnancy was by necessity based on rather old or non‐longitudinal research.
To examine the associations between risk factors identified in the report and pregnancy at or before age 16 years among young women and partners of young men using the more recent data.
Socioeconomic disadvantage, being born to a teenage mother, expectation of being a teenage parent, low educational expectations and various other behaviours are potential risk factors for teenage pregnancy, as suggested by unadjusted analyses. Those who cited school as providing information on sex had a reduced risk of pregnancy at or before age 16 years, as did girls reporting easy communication with parent or guardian at baseline. Various measures of low sexual health knowledge were not associated, in either adjusted or unadjusted analyses, with increased risk of pregnancy at or before age 16 years among boys or girls.
A focus on many of the risk factors identified in the 1999 report is supported herein. It is suggested that knowledge may not be an important determinant, but that relationships with parents and school, as well as expectations for the future, may have important influences on teenage pregnancy. The analysis also provides new insights into risk factors for pregnancies among the partners of young men.
PMCID: PMC2465587  PMID: 17183010
11.  Public involvement in modernising genitourinary medicine clinics: using general public and patient opinion to influence models of service delivery 
Sexually Transmitted Infections  2006;82(6):484-488.
To determine which of the options available to modernise genitourinary medicine (GUM) clinics in the UK are most acceptable to patients and potential patients; to assess whether the views of a general population sample differ from those of clinic attenders. .
A questionnaire was used to explore the acceptability of different ways of delivering sexual healthcare including the potential trade‐off between convenience/range of services with cost/staffing constraints. Potential differences in responses by age, sex, ethnicity and current attendance at a GUM clinic were evaluated using multivariate analysis.
542 respondents in the community and 202 clinic attenders provided responses. Delivery of sexual healthcare by specialist nurses and general practitioners was acceptable to 81% and 72% of interviewees, respectively, assuming common protocols were adhered to. The proportion of individuals who would accept a consultation with a nurse increased to 91% if the waiting time for an appointment could be reduced as a result. Men were less likely to accept a consultation with a nurse (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.35 to 0.79), and Asian (OR 0.38, 95% CI 0.23 to 0.64) and other black (OR 0.41, 95% CI 0.2 to 0.87) ethnic groups were less likely to accept a consultation with a general practitioner. 44% of patients preferred walk‐in clinics even if waiting times for an appointment were reduced to 48 h.
Delivery of sexual healthcare by nurses and general practitioners was generally found to be acceptable, although this varies by patient sex and ethnicity. Some differences exist between the preferences of a general population sample compared with clinic attenders, but overall there is a high level of concordance. Walk‐in clinics remain a popular choice even when appointment waiting times are short.
PMCID: PMC2563868  PMID: 16757514
12.  Risk factors associated with pelvic inflammatory disease 
Sexually Transmitted Infections  2006;82(6):452-457.
To investigate factors associated with pelvic inflammatory disease (PID).
A case–control study was used to investigate demographic and behavioural factors, and causative agents associated with PID.
A total of 381 participants were recruited: 140 patients, and 105 and 136 controls in tubal ligation and general practice groups, respectively. When compared with a PID‐free tubal ligation control group, increased risk of PID was associated with: age <25 years; age at first sexual intercourse <20 years; non‐white ethnicity; not having had children; a self‐reported history of a sexually transmitted disease; and exposure to Chlamydia trachomatis. When compared with a general practice control group, increased risk was associated with: age <25 years; age at first sexual intercourse <15 years; lower socioeconomic status; being single; adverse pregnancy outcome; a self‐reported history of a sexually transmitted disease; and exposure to C trachomatis. Of the cases, 64% were not associated with any of the infectious agents measured in this study (idiopathic).
A high proportion of cases were idiopathic. PID control strategies, which currently focus on chlamydial screening, have to be reviewed so that they can prevent all cases of PID. Behavioural change is a key factor in the primary prevention of PID, and potential modifiable risk factors were associated with PID.
PMCID: PMC2563866  PMID: 16901918
13.  Developing critical mass and growing our own academics 
Archives of Disease in Childhood  2006;91(12):1027-1029.
Academic paediatrics is an exciting and rewarding career path but is not immune to the problems of recruitment and retention currently affecting most branches of medicine. The Modernising Medical Careers initiative, with its explicit academic training path, offers an unparalleled opportunity to develop novel schemes that promote recruitment and retention. Coordinated action is required to define, publicise and support the new academic training programmes and to attract the best trainees into them.
PMCID: PMC2082978  PMID: 17119077
14.  Behavioural predictors of subsequent hepatitis C diagnosis in a UK clinic sample of HIV positive men who have sex with men 
Sexually Transmitted Infections  2006;82(4):298-300.
To explore the associations between self reported high risk sexual behaviours and subsequent diagnosis with hepatitis C virus (HCV) infection.
The Sex, Health and Anti‐Retrovirals Project (SHARP) was a cross sectional study of sexual behaviour in HIV positive, men who have sex with men (MSM) attending a London outpatient clinic. From July 1999 to August 2000 participants completed a computer assisted self interview questionnaire (CASI) on recent sexual behaviour, recreational drug use, and detailed reporting of the last two sexual episodes involving different partners. Results were combined with routine clinic data and subsequent testing for HCV up to 21 April 2005. A new HCV diagnosis was defined as anti‐HCV antibody seroconversion or positive HCV RNA following a previous negative. Incident rate ratios (IRR) were calculated using Poisson regression in Stata (version 9). Men contributed time at risk from interview until either their diagnosis or their last negative test result.
Of the 422 men who completed questionnaires, 308 (73%) had sufficient clinical and HCV testing data available for analysis. Incident HCV infection was identified in 11 men. Unprotected anal intercourse, more than 30 sex partners in the past year, higher numbers of new anal sex partners, rimming (oro‐anal sex), fisting, use of sex toys, and intranasal recreational drug use were associated with HCV. In multivariate analysis only fisting remained associated with HCV (adjusted IRR 6.27, p = 0.005).
In this study of HIV positive MSM, fisting is strongly associated with HCV infection. Where individuals report high risk sexual behaviours, clinicians should offer appropriate testing for HCV infection.
PMCID: PMC2564713  PMID: 16877578
hepatitis C virus infection; sexual behaviour; MSM; HIV positive
15.  One stop shop versus collaborative integration: what is the best way of delivering sexual health services? 
Sexually Transmitted Infections  2006;82(3):202-206.
To examine various models of integrated and/or one stop shop (OSS) sexual health services (including general practice, mainstream specialist services, and designated young people's services) and explore their relative strengths and weaknesses.
Literature review and interviews with key informants involved in developing the National Strategy for Sexual Health and HIV (n = 11).
The paper focuses on five broad perspectives (logistics, public health, users, staff, and cost). Contraceptive and genitourinary medicine issues are closely related. However, there is no agreement about what is meant by having “integrated” services, about which services should be integrated, or where integration should happen. There are concerns that OSSs will result in over‐centralisation, to the disadvantage of stand alone and satellite services. OSS models are potentially more user focused, but the stigma that surrounds sexual health services may create an access barrier. From staff perspectives, the advantages are greater career opportunities and increased responsibility, while the disadvantages are concern that OSSs will result in loss of expertise and professional status. Cost effectiveness data are contradictory.
Although there is a policy commitment to look at how integrated services can be better developed, more evidence is required on the impact and appropriateness of this approach.
PMCID: PMC2564738  PMID: 16731668
integration; one stop shop; sexual health; contraception; sexually transmitted diseases
16.  Influence of family type and parenting behaviours on teenage sexual behaviour and conceptions 
Longitudinal data were used to explore relations between teenage pregnancy, sexual behaviour, and family type. The study examined whether students from lone parent and/or teenage mother initiated families more commonly report sex, lack of contraception at first sex, and/or conceptions by age 15/16, and whether such associations can be explained by low parental strictness, difficult parent‐child communication, and/or low parental input into sex education. Up to date longitudinal UK research on family influences on conceptions is lacking, as is longitudinal research on family influences on sexual behaviour. No previous studies have comprehensively examined effects of parenting behaviours. Unlike previous research, this study tested theories suggesting that parenting deficits among lone parent and teenage initiated families increase risk of teenage pregnancy among their children.
Secondary analysis of data from a trial of sex education.
Girls and boys from lone parent families or having mothers who were teenagers when they were born were more likely to report sex but not lack of contraception at first sex by age 15/16. Girls and boys with mothers having them as teenagers, and boys but not girls from lone parent families, were more likely to report being involved in conceptions by age 15/16. Only the association between teenage mother family and girls' conceptions was reduced by adjusting for a parenting behaviour measure.
Students from lone parent families or having mothers who were teenagers when they were born are more likely to report early sexual debut and conceptions by age 15/16, but this is not generally explained by parenting style.
PMCID: PMC2563952  PMID: 16698980
teenage; pregnancy; conception; adolescence; family; parenting; sexual; behaviour; contraception
17.  Sexual behaviour, condom use, and disclosure of HIV status in HIV infected heterosexual individuals attending an inner London HIV clinic 
Sexually Transmitted Infections  2006;82(2):117-120.
The National Strategy for Sexual Health and HIV for England (2001) emphasised the role of HIV services in reducing secondary transmission of HIV through prevention work with HIV infected people.
To determine the sexual behaviour, condom use, and disclosure of HIV status of HIV infected heterosexuals attending an inner London HIV clinic.
Cross sectional questionnaire study of heterosexual HIV infected individuals attending an HIV outpatient clinic.
We collected demographic data for all respondents and sexual behaviour data for those sexually active over the past year using a self administered questionnaire. Viral load and CD4 count for responders and age, sex, ethnicity, viral load, and CD4 count for non‐responders were obtained from the clinic database.
The response rate was 47.3% (n = 142). 100 participants reported being sexually active in the past year, of whom 73% used condoms when they last had vaginal sex. Knowledge of partner's HIV status was the only variable significantly associated with the participant disclosing their HIV status to their partner (p<0.001). In those who had disclosed their status, only knowledge of partner's HIV status was significantly associated with condom use (p = 0.03).
Issues relating to non‐disclosure and partner notification in HIV infected heterosexuals will need to be better understood to improve sexual health in this group and to reduce onward transmission of HIV.
PMCID: PMC2564680  PMID: 16581734
heterosexual transmission; sexual behaviour; HIV; UK
18.  Change of refractive state and eye size in children of birth weight less than 1701 g 
To determine the refractive status and ocular dimensions of a cohort of children at age 10–12 years with birth weight below 1701 g, and also the relation between the neonatal ophthalmic findings and subsequent refractive state.
293 low birthweight children who had been examined in the neonatal period were assessed at 10–12 years of age. The examination consisted of autorefraction, keratometry, and A‐scan. Results of right eyes were compared with published normative data.
293 of the birth cohort of 572 children consented to participate. The average mean spherical equivalent (MSE) in the low birthweight cohort was +0.691 dioptre, significantly higher than the control data (+0.30D, p = 0.02). The average change in MSE over the 10–12 year period was −1.00 dioptre (n = 256), but only 62.1% of cases showed a shift in refractive error of the appropriate magnitude and direction. The presence of any retinopathy of prematurity (ROP) increases the risk of developing anisometropia sixfold.
Low birth weight and ROP both significantly impact the refractive state in the long term. At age 10–12 years children born preterm have an increased prevalence of all refractive errors. In low birthweight children refractive state is relatively stable over the first decade of life with a shift towards myopia of 1 dioptre.
PMCID: PMC1857007  PMID: 16547327
refractive error; retinopathy of prematurity; myopia; low birth weight
19.  Anoxic-epileptic seizures: observational study of epileptic seizures induced by syncopes 
Archives of Disease in Childhood  2005;90(12):1283-1287.
Aims: To describe a large series of children with anoxic-epileptic seizures (AES)—that is, epileptic seizures induced by syncopes.
Methods: Retrospective case-note review in a tertiary paediatric neurology unit. For all 27 children seen with a definite diagnosis of AES between 1972 and 2002, a review of clinical histories, videotapes, and EEG/ECG studies was undertaken. Main outcome measures were: age of onset, frequency and type of syncopes; age of onset and frequency of AES; type and duration of induced epileptic seizures; effect of treatment of syncopal and epileptic components.
Results: Median age of onset of syncopes was 8 months (range 0.2–120), frequency 2 in total to 40/day, median total ∼200. Syncopes were predominantly reflex asystolic (RAS), prolonged expiratory apnoea (cyanotic breath-holding spells), or of mixed or uncertain origin; there was one each of ear piercing and hair grooming vasovagal syncope and one of compulsive Valsalva. Median age of onset of AES was 17 months (range 7–120), frequency from total 1 to 3/day, median total 3. The epileptic component was almost always bilateral clonic; three had additional epilepsy, one each with complex partial seizures, myoclonic absences, and febrile seizures plus. Median duration of epileptic component was 5 minutes (range 0.5–40, mean 11). Cardiac pacing prevented RAS in two patients: most other anti-syncope therapies were ineffective. Diazepam terminated the epileptic component in 6/8. Valproate or carbamazepine abolished AES in 5/7 without influencing syncope frequency.
Conclusions: Although uncommon compared with simple syncopes, syncope triggered epileptic seizures (AES) are an important treatable basis of status epilepticus.
PMCID: PMC1720208  PMID: 16159903
21.  HER2 amplification status in breast cancer: a comparison between immunohistochemical staining and fluorescence in situ hybridisation using manual and automated quantitative image analysis scoring techniques 
Journal of Clinical Pathology  2005;58(7):710-714.
Aims: To compare the results of breast cancer sections with HercepTest™ immunohistochemistry (IHC) scores ranging from 0 to 3+ with fluorescence in situ hybridisation (FISH) for HER2 amplification. The HER2 digital scoring application of the Micrometastasis Detection System (MDS™) was used, together with manual scoring of FISH and HercepTest, to determine whether this system provides an accurate alternative.
Methods: Paraffin wax embedded sections were stained using HercepTest and analysed by eye and automated quantitative image analysis. FISH was performed using the PathVysion™ fluorescent probe and scored by eye and automated quantitative image analysis using MDS.
Results: Of 114 cases, 26% were amplified by FISH, whereas only 18% scored 3+; 32% of IHC 2+ cases were amplified by FISH, and one showed borderline amplification. Six percent of IHC negative cases (0 or 1+) were amplified by FISH, and one showed borderline amplification. Of IHC 3+ cases, 10% were non-amplified by FISH. Classification discrepancies were seen in 18% of HercepTest cases scored by eye and using the MDS system. MDS was consistent with visual FISH scoring and correctly differentiated most ambiguous visual IHC scores.
Conclusions: FISH provides a more accurate and consistent scoring system for determining HER2 amplification than HercepTest. The MDS system provides a reliable, consistent alternative to visual IHC and FISH scoring. IHC is still a valuable technique to aid in identification of isolated or heterogeneous tumour populations for subsequent FISH analysis, and a combined FISH and HercepTest approach to all breast cancer cases may be the most efficient strategy.
PMCID: PMC1770709  PMID: 15976337
FISH; HER2; breast cancer; Herceptin; immunohistochemistry
22.  The effect of dislike of school on risk of teenage pregnancy: testing of hypotheses using longitudinal data from a randomised trial of sex education 
Study objective: To examine whether attitude to school is associated with subsequent risk of teenage pregnancy. To test two hypotheses that attitude to school is linked to pregnancy via pathways involving young people having "alternative" expectations or deficits in sexual health knowledge and confidence.
Design: Analysis of longitudinal data arising from a trial of sex education. Examination of associations between attitude to school and protected first sex, unprotected first sex, unprotected and protected last sex, and pregnancy, both crude and adjusting in turn for expectation of parenting by age 20, lack of expectation of education/training at age 20, and sexual health knowledge and confidence.
Setting: Schools in central and southern England.
Participants: Girls of median age 13.7 years at baseline, 14.7 years at follow up 1, and 16.0 years at follow up 2.
Main results: In unadjusted analysis, attitude to school was significantly associated with protected and unprotected first sex by follow up 1, protected first sex between follow up 1 and 2, unprotected last sex, and pregnancy. Dislike of school was more strongly associated with increased risk of these outcomes than was ambivalence to school. These associations remained after adjusting for socioeconomic status and for expectation of parenting, lack of expectation of education/training, and various indicators of knowledge and confidence about sexual health.
Conclusions: Dislike of school is associated with subsequent increased risk of teenage pregnancy but the mechanism underlying any possible causal link is unlikely to involve "alternative" expectations or deficits in sexual health knowledge or confidence.
PMCID: PMC1733029  PMID: 15709083
23.  Visual function in low birthweight children 
The British Journal of Ophthalmology  2004;88(9):1149-1153.
Aim: To determine the visual functions, at age 10–12 years, of a geographically based cohort of children of birth weight less than 1701 g. The results were compared to a group of children born at full term.
Methods: 572 low birthweight (LBW) “low birthweight cohort” children who had been examined in the neonatal period were invited for review at 10–12 years of age. 169 11 year old schoolchildren born at full term were also recruited, “school cohort.” Visual acuity (at distance and near), contrast sensitivity, colour vision, and visual fields were measured.
Results: 293 of the original 572 participants consented to a further examination. Compared to the school cohort of children born at term the low birthweight cohort showed significantly lower near and distance acuities and contrast sensitivity (p<0.001 for all uniocular and binocular measures). Retinopathy of prematurity (ROP) was a very poor predictor of outcome and multivariate analysis did not identify any key neonatal factors as predictors of long term visual outcome.
Conclusions: Low birthweight children have a small but statistically significant deficit in both visual acuity and contrast sensitivity. Low birth weight and ROP both impact on long term visual functions.
PMCID: PMC1772308  PMID: 15317706
visual function; low birthweight children
24.  Gratification disorder ("infantile masturbation"): a review 
Archives of Disease in Childhood  2004;89(3):225-226.
Background: Little has been published on gratification disorder ("infantile masturbation") in early childhood.
Aims: To expand on the profile of patients diagnosed with this condition.
Methods: Retrospective case note review; Fraser of Allander Neurosciences Unit paediatric neurology outpatient department 1972–2002.
Results: Thirty one patients were diagnosed (11 males and 20 females). Twenty one were referred for evaluation of possible epileptic seizures or epilepsy. The median age at first symptoms was 10.5 months (range 3 months to 5 years 5 months). The median age at diagnosis was 24.5 months (range 5 months to 8 years). The median frequency of events was seven times per week, and the median length 2.5 minutes. Events occurred in any situation in 10 children, and in a car seat in 11. Types of behaviour manifested were dystonic posturing in 19, grunting in 10, rocking in 9, eidetic imagery in 7, and sweating in 6. Two children had been previously diagnosed as having definite epilepsy. In nine cases home video was invaluable in allowing confident diagnosis.
Conclusion: Gratification disorder, otherwise called infantile masturbation, is an important consideration in the differential diagnosis of epilepsy and other paroxysmal events in early childhood. Home video recording of events often prevents unnecessary investigations and treatments.
PMCID: PMC1719833  PMID: 14977696
25.  P44-M Calculation of the Isoelectric Point of Tryptic Peptides Based on Adjacent Amino Acid Effects 
Current algorithms for the calculation of peptide or protein pI, based solely on the charge associated with individual amino acids, can calculate pI values to within ±0.2pI units. Here we present a new pI calculation algorithm that takes into account the effect of adjacent amino acids on the pI value. The algorithm takes into account the effect of adjacent amino acids ±3 residues away from a charged aspartic or glutamic acid, as well as effects on the C-terminus, and applies a correction factor to the pK values of the charged amino acids. Large pK shifts are observed for the short-range interactions of aspartic and glutamic acid with the N-terminus and with internal histidine, lysine, or arginine residues. Conversely, interactions of aspartic and glutamic acid with hydrophobic, slightly polar, or other aspartic and glutamic acid residues are negligible. This results in a much narrower distribution of peptides across individual IPG-IEF fractions. The correction factors are derived from a 5000-peptide training set using a genetic optimization approach. The unique advantage of the genetic algorithms is that the pK optimization problem is independent of the evaluation function employed. This in turn allows the optimization function to determine the next set of solutions that can then be re-evaluated. This cycle continues until a set convergence criterion is reached. The accuracy of the new pI values obtained with this method approaches the error associated with the manufacture of the IPG strip (±0.05 pI units). The approach is demonstrated for cytosolic cell extracts derived from the breast cancer cell line DU4475, and from membrane preparations from human lung tissue samples.
PMCID: PMC2291873

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