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1.  “It can't be very important because it comes and goes”—patients' accounts of intermittent symptoms preceding a pancreatic cancer diagnosis: a qualitative study 
BMJ Open  2014;4(2):e004215.
This article explores how people with pancreatic cancer interpreted prediagnostic signs and symptoms, and what triggered them to seek medical help for symptoms that occurred intermittently.
Thematic analysis of prediagnostic symptom descriptions drawn from a qualitative interview study of people with experiences of pancreatic cancer.
40 people affected by pancreatic cancer (32 patients and 8 relatives of people who had died). Age at interview ranged from 35 to 84 years; 55% were men; and 57.5% of patients had been offered potentially curative surgery.
Respondents interviewed at home were recruited from different parts of the UK during 2009/2010.
Analysis of the interviews suggested that intermittent symptoms were not uncommon in the months, or even years, before diagnosis but that the fact that the symptom did not persist was often taken by the patient as a reassuring indicator that it could not be ‘very important’. Such symptoms were rarely acted upon until a pattern became apparent, the frequency of symptom episodes increased, there was a change in the nature of the intermittent symptoms or additional symptom(s) appeared. These findings build on social science theories of consultation behaviour.
Our study—the largest reported collection of qualitative interviews with people with pancreatic cancer—reports for the first time that symptoms of an intermittent nature may precede a pancreatic cancer diagnosis. Patients (and potentially their doctors as well) may be falsely reassured by symptoms that come and go. Pancreatic cancer might be identified at a stage where curative treatment is more likely if there were greater awareness that intermittent gastrointestinal symptoms can have a serious cause, and if patients with intermittent pancreatitis-like symptoms were investigated more readily.
PMCID: PMC3932002  PMID: 24549161
Qualitative Research; Primary Care; Social Medicine
2.  Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene 
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues. The hepatocerebral form (mtDNA depletion in liver and brain) has been associated with mutations in the POLG, PEO1 (Twinkle), DGUOK and MPV17 genes, the latter encoding a mitochondrial inner membrane protein of unknown function. The aims of this study were to clarify further the clinical, biochemical, cellular and molecular genetic features associated with MDS due to MPV17 gene mutations. We identified 12 pathogenic mutations in the MPV17 gene, of which 11 are novel, in 17 patients from 12 families. All patients manifested liver disease. Poor feeding, hypoglycaemia, raised serum lactate, hypotonia and faltering growth were common presenting features. mtDNA depletion in liver was demonstrated in all seven cases where liver tissue was available. Mosaic mtDNA depletion was found in primary fibroblasts by PicoGreen staining. These results confirm that MPV17 mutations are an important cause of hepatocerebral mtDNA depletion syndrome, and provide the first demonstration of mosaic mtDNA depletion in human MPV17 mutant fibroblast cultures. We found that a severe clinical phenotype was associated with profound tissue-specific mtDNA depletion in liver, and, in some cases, mosaic mtDNA depletion in fibroblasts.
PMCID: PMC3895632  PMID: 23714749
MPV17; mitochondrial DNA depletion; hepatocerebral disease; neonatal liver disease
3.  Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model 
Brain  2013;136(10):3106-3118.
Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the ‘diagnostic odyssey’ for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. All cases had been tested for spinocerebellar ataxia 1–3, 6, 7 and Friedrich’s ataxia and had multiple other biochemical, genetic and invasive tests. In those cases where we identified the genetic mutation, we determined the time to diagnosis. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. The highest detection rate was in those with an adolescent onset and a family history (75%). The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. In the cases where we made an eventual diagnosis, the delay was 3–35 years (mean 18.1 years). Alignment and coverage metrics indicated that the capture and sequencing was highly efficient and the consumable cost was ∼£400 (€460 or US$620). Our pathogenicity interpretation pathway predicted 13 different mutations in eight different genes: PRKCG, TTBK2, SETX, SPTBN2, SACS, MRE11, KCNC3 and DARS2 of which nine were novel including one causing a newly described recessive ataxia syndrome. Genetic testing using targeted capture followed by next-generation sequencing was efficient, cost-effective, and enabled a molecular diagnosis in many refractory cases. A specific challenge of next-generation sequencing data is pathogenicity interpretation, but functional analysis confirmed the pathogenicity of novel variants showing that the pipeline was robust. Our results have broad implications for clinical neurology practice and the approach to diagnostic testing.
PMCID: PMC3784284  PMID: 24030952
ataxia; genetics; autosomal dominant cerebellar ataxia; autosomal recessive cerebellar ataxia; diagnosis
4.  Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics 
Brain  2012;135(11):3392-3403.
Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.
PMCID: PMC3501970  PMID: 23107649
mitochondrial DNA; mtDNA maintenance; mtDNA depletion; multiple mitochondrial DNA deletions; RRM2B
5.  The Role of Phytonutrients in Skin Health 
Nutrients  2010;2(8):903-928.
Photodamage is known to occur in skin with exposure to sunlight, specifically ultraviolet (UV) radiation. Such damage includes inflammation, oxidative stress, breakdown of the extracellular matrix, and development of cancer in the skin. Sun exposure is considered to be one of the most important risk factors for both nonmelanoma and melanoma skin cancers. Many phytonutrients have shown promise as photoprotectants in clinical, animal and cell culture studies. In part, the actions of these phytonutrients are thought to be through their actions as antioxidants. In regard to skin health, phytonutrients of interest include vitamin E, certain flavonoids, and the carotenoids, β-carotene, lycopene and lutein.
PMCID: PMC3257702  PMID: 22254062
photodamage; vitamin E; flavonoids; carotenoids
6.  Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X‐chromosome inactivation 
Journal of Medical Genetics  2006;44(2):148-152.
Rett syndrome (RTT) is an X‐linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X‐chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing.
Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele‐specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated.
Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations.
XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.
PMCID: PMC2598067  PMID: 16905679
7.  NTNG1 Mutations are a Rare Cause of Rett Syndrome 
A translocation that disrupted the Netrin G1 gene (NTNG1) was recently reported in a patient with the early seizure variant of Rett syndrome (RTT). The netrin G1 protein (NTNG1) has an important role in the developing central nervous system, particularly in axonal guidance, signalling and NMDA receptor function and was a good candidate gene for RTT. We recruited 115 patients with RTT (females: 25 classic and 84 atypical; 6 males) but no mutation in the MECP2 gene. For those 52 patients with epileptic seizure onset in the first six months of life, CDKL5 mutations were also excluded. We aimed to determine whether mutations in NTNG1 accounted for a significant subset of patients with RTT, particularly those with the early onset seizure variant and other atypical presentations. We sequenced the nine coding exons of NTNG1 and identified four sequence variants, none of which were likely to be pathogenic. Mutations in the NTNG1 gene appear to be a rare cause of RTT but NTNG1 function demands further investigation in relation to the central nervous system pathophysiology of the disorder.
PMCID: PMC2577736  PMID: 16502428
Rett syndrome; Netrin G1; Autism; NMDA receptor
8.  The BRIDG Project: A Technical Report 
The Biomedical Research Integrated Domain Group (BRIDG) project is a collaborative initiative between the National Cancer Institute (NCI), the Clinical Data Interchange Standards Consortium (CDISC), the Regulated Clinical Research Information Management Technical Committee (RCRIM TC) of Health Level 7 (HL7), and the Food and Drug Administration (FDA) to develop a model of the shared understanding of the semantics of clinical research.
The BRIDG project is based on open-source collaborative principles and an implementation-independent, use-case driven approach to model development. In the BRIDG model, declarative and procedural knowledge are represented using the Unified Modeling Language (UML) class, activity and state diagrams.
The BRIDG model currently contains harmonized semantics from four project use cases: the caXchange project and the patient study calendar project from caBIG™; the standard data tabular model (SDTM) from CDISC; and the regulated products submission model (RPS) from HL7. Scalable harmonization processes have been developed to expand the model with content from additional use cases.
The first official release of the BRIDG model was published in June 2007. Use of the BRIDG model by the NCI has supported the rapid development of semantic interoperability across applications within the caBIG™ program.
The BRIDG project has brought together different standards communities to clarify the semantics of clinical research across pharmaceutical, regulatory, and research organizations. Currently, the NCI uses the BRIDG model to support interoperable application development in the caBIG™, and CDISC and HL7 are using the BRIDG model to support standards development.
PMCID: PMC2274793  PMID: 18096907
9.  How the internet affects patients' experience of cancer: a qualitative study 
BMJ : British Medical Journal  2004;328(7439):564.
Objective To explore how men and women with cancer talk about using the internet.
Design Qualitative study using semistructured interviews collected by maximum variation sampling.
Setting Respondents recruited throughout the United Kingdom during 2001-2.
Participants 175 men and women aged 19-83 years, with one of five cancers (prostate, testicular, breast, cervical, or bowel) diagnosed since 1992 and selected to include different stages of treatment and follow up.
Results Internet use, either directly or via friend or family, was widespread and reported by patients at all stages of cancer care, from early investigations to follow up after treatment. Patients used the internet to find second opinions, seek support and experiential information from other patients, interpret symptoms, seek information about tests and treatments, help interpret consultations, identify questions for doctors, make anonymous private inquiries, and raise awareness of the cancer. Patients also used it to check their doctors' advice covertly and to develop an expertise in their cancer. This expertise, reflecting familiarity with computer technology and medical terms, enabled patients to present a new type of “social fitness.”
Conclusion Cancer patients used the internet for a wide range of information and support needs, many of which are unlikely to be met through conventional health care. Serious illness often undermines people's self image as a competent member of society. Cancer patients may use the internet to acquire expertise to display competence in the face of serious illness.
PMCID: PMC381051  PMID: 15001506
11.  Recruitment of UK-trained doctors into general practice: findings from national cohort studies. 
BACKGROUND: In recent years there have been difficulties with recruitment in the United Kingdom (UK) to principalships in general practice. AIM: To compare recruitment trends in cohorts defined by year of qualification and to report attitudes of young doctors about the attractiveness of a career in general practice. DESIGN OF STUDY: Cohort studies. SETTING: UK medical qualifiers in the years 1974, 1977, 1983, 1988, 1993, and 1996. METHOD: Postal questionnaire surveys conductedfrom 1975 to 1999. RESULTS: Five years after qualification, 23.8% of 1993 qualifiers were in UK general practice, compared with 25.9% and 32.8% of 1988 and 1983 qualifiers respectively. Six per cent of responders in the 1993 cohort were general practitioner (GP) principals, compared with 10% of the 1988 cohort and 20% of the 1983 cohort. Ten years after qualification, 37.7% of 1988 qualifiers and 42.7% of 1983 qualifiers were in UK general practice. Older GPs had lower job satisfaction than their contemporaries in hospital practice, while younger GPs were more satisfied than younger hospital doctors with the time available for leisure. Although young doctors are less inclined to enter general practice nowadays, over haf of the 1996 qualifiers, when surveyed in 1999, actually regarded general practice as a more attractive career than hospital practice. CONCLUSION: Patterns of entry into and commitment to UK general practice are changing. Fewer young doctors are choosing and entering general practice and early commitment to full-time principalships is falling. The 1996 cohort, however, took an encouragingly positive view of the attractiveness of careers in general practice.
PMCID: PMC1314291  PMID: 12014533
14.  Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes 
Journal of Clinical Investigation  1999;104(9):R33-R39.
The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic β cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human β-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25–53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation.
PMCID: PMC481047  PMID: 10545530
15.  GP recruitment and retention: a qualitative analysis of doctors' comments about training for and working in general practice. 
BACKGROUND AND AIMS: General practice in the UK is experiencing difficulty with medical staff recruitment and retention, with reduced numbers choosing careers in general practice or entering principalships, and increases in less-than-full-time working, career breaks, early retirement and locum employment. Information is scarce about the reasons for these changes and factors that could increase recruitment and retention. The UK Medical Careers Research Group (UKMCRG) regularly surveys cohorts of UK medical graduates to determine their career choices and progression. We also invite written comments from respondents about their careers and the factors that influence them. Most respondents report high levels of job satisfaction. A noteworthy minority, however, make critical comments about general practice. Although their views may not represent those of all general practitioners (GPs), they nonetheless indicate a range of concerns that deserve to be understood. This paper reports on respondents' comments about general practice. ANALYSIS OF DOCTORS' COMMENTS: Training Greater exposure to general practice at undergraduate level could help to promote general practice careers and better inform career decisions. Postgraduate general practice training in hospital-based posts was seen as poor quality, irrelevant and run as if it were of secondary importance to service commitments. In contrast, general practice-based postgraduate training was widely praised for good formal teaching that met educational needs. The quality of vocational training was dependent upon the skills and enthusiasm of individual trainers. Recruitment problems Perceived deterrents to choosing general practice were its portrayal, by some hospital-based teachers, as a second class career compared to hospital medicine, and a perception of low morale amongst current GPs. The choice of a career in general practice was commonly made for lifestyle reasons rather than professional aspirations. Some GPs had encountered difficulties in obtaining posts in general practice suited to their needs, while others perceived discrimination. Newly qualified GPs often sought work as non-principals because they felt too inexperienced for partnership or because their domestic situation prevented them from settling in a particular area. Changes to general practice The 1990 National Health Service (NHS) reforms were largely viewed unfavourably, partly because they had led to a substantial increase in GPs' workloads that was compounded by growing public expectations, and partly because the two-tier system of fund-holding was considered unfair. Fund-holding and, more recently, GP commissioning threatened the GP's role as patient advocate by shifting the responsibility for rationing of health care from government to GPs. Some concerns were also expressed about the introduction of primary care groups (PCGs) and trusts (PCTs). Together, increased workload and the continual process of change had, for some, resulted in work-related stress, low morale, reduced job satisfaction and quality of life. These problems had been partially alleviated by the formation of GP co-operatives. Retention difficulties Loss of GPs' time from the NHS workforce occurs in four ways: reduced working hours, temporary career breaks, leaving the NHS to work elsewhere and early retirement. Child rearing and a desire to pursue interests outside medicine were cited as reasons for seeking shorter working hours or career breaks. A desire to reduce pressure of work was a common reason for seeking shorter working hours, taking career breaks, early retirement or leaving NHS general practice. Other reasons for leaving NHS general practice, temporarily or permanently, were difficulty in finding a GP post suited to individual needs and a desire to work abroad. CONCLUSIONS: A cultural change amongst medical educationalists is needed to promote general practice as a career choice that is equally attractive as hospital practice. The introduction of Pre-Registration House Officer (PRHO) placements in general practice and improved flexibility of GP vocational training schemes, together with plans to improve the quality of Senior House Officer (SHO) training in the future, are welcome developments and should address some of the concerns about poor quality GP training raised by our respondents. The reluctance of newly qualified GPs to enter principalships, and the increasing demand from experienced GPs for less-than-full-time work, indicates a need for a greater variety of contractual arrangements to reflect doctors' desires for more flexible patterns of working in general practice.
PMCID: PMC2560447  PMID: 12049026
16.  Prospective study of POLG mutations presenting in children with intractable epilepsy: Prevalence and clinical features 
Epilepsia  2013;54(6):1002-1011.
To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma.
Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon–intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records.
Key Findings
We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged.
Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2-weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.
PMCID: PMC3757309  PMID: 23448099
Metabolic diseases; Mitochondrial diseases; Genetic epilepsies; Children

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