Most upper and lower gastrointestinal endoscopies in Great Britain and Ireland are performed by surgeons, physicians or radiologists. Since the introduction of the 'nurse endoscopist' by the British Society of Gastroenterology Working Party, few centres in the UK have adopted this policy. We have reviewed the anxiety about nurse practitioner endoscopists among patients and physicians. Finally, the role and future of the nurse practitioner endoscopist in the UK is discussed.
The genes of cellular cooperation that evolved with multicellularity about a billion years ago are the same genes that malfunction to cause cancer. We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient “toolkit” of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress of the neoplasm in the host organism differs distinctively from normal Darwinian evolution. Comparative genomics and the phylogeny of basal metazoans, opisthokonta and basal multicellular eukaryotes should help identify the relevant genes and yield the order in which they evolved. This order will be a rough guide to the reverse order in which cancer develops, as mutations disrupt the genes of cellular cooperation. Our proposal is consistent with current understanding of cancer and explains the paradoxical rapidity with which cancer acquires a suite of mutually-supportive complex abilities. Finally we make several predictions and suggest ways to test this model.
cancer; genetics; evolution; metazoan
The mechanical stiffness of individual cells is important in tissue homeostasis, cell growth, division, and motility, and the epithelial-mesenchymal transition in the initiation of cancer. In this work, a normal squamous cell line (EPC2) and metaplastic (CP-A) as well as dysplastic (CP-D) Barrett’s Esophagus columnar cell lines are studied as a model of pre-neoplastic progression in the human esophagus. We used the combination of an atomic force microscope (AFM) with a scanning confocal fluorescence lifetime imaging microscope (FLIM) to study the mechanical properties of single adherent cells. 64 force indentation curves were taken over the nucleus of each cell in an 8×8 grid pattern. Analyzing the force indentation curves, indentation depth dependent Young’s moduli were found for all cell lines. Stiffness tomograms demonstrate distinct differences between the mechanical properties of the studied cell lines. Comparing the stiffness for indentation forces of 1 nN, most probable Young’s moduli were calculated to 4.7 kPa for EPC2 (n=18 cells), 3.1 kPa for CP-A (n=10), and 2.6 kPa for CP-D (n=19). We also tested the influence of nuclei and nucleoli staining organic dyes on the mechanical properties of the cells. For stained EPC2 cells (n=5), significant stiffening was found (9.9 kPa), while CP-A cells (n=5) showed no clear trend (2.9 kPa) and a slight softening was observed (2.1 kPa) in the case of CP-D cells (n=16). Some force-indentation curves show non-monotonic discontinuities with segments of negative slope, resembling a sawtooth pattern. We found the incidence of these ‘breakthrough events’ to be highest in the dysplastic CP-D cells, intermediate in the metaplastic CP-A cells, and lowest in the normal EPC2 cells. This observation suggests that the microscopic explanation for the increased compliance of cancerous and pre-cancerous cells may lie in their susceptibility to ‘crumble and yield’ rather than their ability to ‘bend and flex’.
Cell mechanics; cancer cells; atomic force microscopy (AFM); fluorescence lifetime imaging microscopy (FLIM); nanoindentation
Genes store heritable information, but actual gene expression often depends on many so-called epigenetic factors, both physical and chemical, external to DNA. Epigenetic changes can be both reversible and heritable. The genome is associated with a physical object (DNA) with a specific location, whereas the epigenome is a global, systemic, entity. Furthermore, genomic information is tied to specific coded molecular sequences stored in DNA. Although epigenomic information can be associated with certain non-DNA molecular sequences, it is mostly not. Therefore, there does not seem to be a stored ‘epigenetic programme’ in the information-theoretic sense. Instead, epigenomic control is—to a large extent—an emergent self-organizing phenomenon, and the real-time operation of the epigenetic ‘project’ lies in the realm of nonlinear bifurcations, interlocking feedback loops, distributed networks, top-down causation and other concepts familiar from the complex systems theory. Lying at the heart of vital eukaryotic processes are chromatin structure, organization and dynamics. Epigenetics provides striking examples of how bottom-up genetic and top-down epigenetic causation intermingle. The fundamental question then arises of how causal efficacy should be attributed to biological information. A proposal is made to implement explicit downward causation by coupling information directly to the dynamics of chromatin, thus permitting the coevolution of dynamical laws and states, and opening up a new sector of dynamical systems theory that promises to display rich self-organizing and self-complexifying behaviour.
epigenetics; emergence; causality
Alzheimer’s disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.
AD; APOE; microarray; gene expression; human brain
Active Crohn's disease can be treated using liquid diet therapy (LDT), but non‐adherence may limit success, necessitating corticosteroid therapy. Whole‐protein polymeric formula (PF) seems to be much more palatable than amino acid‐based elemental formula (EF) and thus may significantly improve adherence to LDT.
To compare adherence to LDT using PF versus EF.
Success in completing a 6‐week course of LDT, need for nasogastric tube administration of formula and use of LDT for relapses were compared between children presenting with active disease and treated with EF (n = 53) and children given PF (n = 45).
Remission rates were similar (EF 64%, 95% CI 51 to 77 vs PF 51%, 95% CI 37 to 66; p>0.15). 72% (95% CI 60 to 84) given EF completed the initial course of LDT compared with 58% (95% CI 44 to 72) given PF (p = 0.15). Of those failing to complete the initial course, 13% on EF and 16% on PF gave up by choice (non‐adherence), the remainder stopping due to treatment failure. Nasogastric administration was more frequent with EF (55%, 95% CI 42 to 68) compared to PF (31%, 95% CI 17 to 45) (p = 0.02). Among those treated successfully at first presentation, LDT was used for 28% of relapses in the EF group (95% CI 12 to 44) and 39% in the PF group (95% CI 19 to 59) (p>0.2) over the next year.
PF did not effect adherence to LDT but was associated with significantly reduced need for nasogastric tube administration of formula.
liquid diet therapy; elemental formula; polymeric formula; crohn's disease; corticosteroids
To determine whether the energy density of isocaloric nocturnal enteral feeds (NEF) influences daily nutrient intake in children.
In a 6 week, randomised, crossover trial, the impact on spontaneous nutrient intake of manipulating the energy density of two isocaloric overnight feeds (1.0 kcal/ml and 1.5 kcal/ml) was compared in a group of 32 children aged 1–10 years (or 8–25 kg body weight) on long term, overnight enteral feeding at home. Total daily oral energy, protein, fat and carbohydrate intake were assessed using 3 day food diaries. Anthropometric data were also recorded during the study.
Spontaneous intakes of energy, protein, fat and carbohydrate from food were 20–30% greater when receiving the lower nutrient density feed (1 kcal/ml). This was due to a gender effect; males consumed twice as much protein from food than females and had slightly higher (but not significant) energy and fat intakes when on the larger volume feed. All children increased in weight, height and mid‐upper arm circumference in the 6 week period.
Children appear to tolerate and grow equally well, irrespective of the nutrient density and volume of NEF taken. However, it appears that children will consume a more energy and nutrient dense oral diet when given their NEF as a higher volume/lower nutrient density feed. This is particularly so for boys, while for girls the volume of NEF or feed concentration appeared to have no impact on quantity of oral diet taken. However, further blinded studies with larger subject numbers would be useful to support these findings.
appetite; children; energy density; enteral nutrition; tube feeding
The optimal dose of protein substitute has not been determined in children with phenylketonuria (PKU).
To determine if a lower dose of protein substitute could achieve the same or better degree of blood phenylalanine control when compared to the dosage recommended by the UK MRC.1
In a six week randomised, crossover study, two doses of protein substitute (Protocol A: 2 g/kg/day of protein equivalent; Protocol B: 1.2 g/kg/day protein equivalent) were compared in 25 children with well controlled PKU aged 2–10 years (median 6 years). Each dose of protein substitute was taken for 14 days, with a 14 day washout period in between. Twice daily blood samples (fasting pre‐breakfast and evening, at standard times) for plasma phenylalanine were taken on day 8–14 of each protocol. The median usual dose of protein substitute was 2.2 g/kg/day (range 1.5–3.1 g/kg/day).
When compared with control values, median plasma phenylalanine on the low dose of protein substitute increased at pre‐breakfast by 301 μmol/l (95% CI 215 to 386) and in the evening by 337 μmol/l (95% CI 248 to 431). On the high dose of protein substitute, plasma phenylalanine concentrations remained unchanged when compared to control values. However, wide variability was seen between subjects.
A higher dosage of protein substitute appeared to contribute to lower blood phenylalanine concentrations in PKU, but it did have a variable and individual impact and may have been influenced by the carbohydrate (+/− fat) content of the protein substitute.
phenylketonuria; phenylalanine; protein substitute; energy intake
To identify the clinical and biochemical risk factors associated with outcome of paracetamol induced significant hepatotoxicity in children.
Retrospective case notes review of those with paracetamol overdose admitted from 1992 to 2002. Patients were analysed in two groups: group I recovered after conservative treatment and group II developed progressive liver dysfunction and were listed for liver transplantation.
Of 51 patients (6 males, 45 females, aged 0.8–16.1 years), 6 (aged <7 years) received cumulative multiple doses, and 45 a single large overdose (median 345 mg/kg, range 91–645). The median (range) interval to hospital at presentation post‐ingestion was 24 hours (4–65) and 44 hours (24–96) respectively in groups I and II. Patients received standard supportive treatment including N‐acetylcysteine. All children in group I survived. In group II, 6/11 underwent orthotopic liver transplantation (OLT) and 2/6 survived; 5/11 died awaiting OLT. Cerebral oedema was the main cause of death. Children who presented late to hospital for treatment and those with progressive hepatotoxicity with prothrombin time >100 seconds, hypoglycaemia, serum creatinine >200 μmol/l, acidosis (pH <7.3), and who developed encephalopathy grade III, had a poor prognosis or died. Although hepatic transaminase levels were markedly raised in both groups, there was no correlation with necessity for liver transplantation or death.
Accidental or incidental paracetamol overdose in children may be associated with toxic liver damage leading to fulminant liver failure. Delayed presentation and/or delay in treatment, and hepatic encephalopathy ⩾grade III were significant risk factors, implying poor prognosis and need for OLT. Prompt identification of high risk patients, referral to a specialised unit for management, and consideration for liver transplantation is essential.
paracetamol; fulminant liver failure; orthotopic liver transplantation; hepatotoxicity
A randomised open label study of the combined use of paracetamol and ibuprofen to rapidly reduce fever is reported. The advantage of using both medications is less than half a degree centigrade in the first hour, and insufficient to warrant routine use.
acetaminophen; preschool; fever; ibuprofen
Background: In paediatric clinical practice treatment is often adjusted in relation to body size, for example the calculation of pharmacological and dialysis dosages. In addition to use of body weight, for some purposes total body water (TBW) and surface area are estimated from anthropometry using equations developed several decades previously. Whether such equations remain valid in contemporary populations is not known.
Methods: Total body water was measured using deuterium dilution in 672 subjects (265 infants aged <1 year; 407 children and adolescents aged 1–19 years) during the period 1990–2003. TBW was predicted (a) using published equations, and (b) directly from data on age, sex, weight, and height.
Results: Previously published equations, based on data obtained before 1970, significantly overestimated TBW, with average biases ranging from 4% to 11%. For all equations, the overestimation of TBW was greatest in infancy. New equations were generated. The best equation, incorporating log weight, log height, age, and sex, had a standard error of the estimate of 7.8%.
Conclusions: Secular trends in the nutritional status of infants and children are altering the relation between age or weight and TBW. Equations developed in previous decades significantly overestimate TBW in all age groups, especially infancy; however, the relation between TBW and weight may continue to change. This scenario is predicted to apply more generally to many aspects of paediatric clinical practice in which dosages are calculated on the basis of anthropometric data collected in previous decades.
Methods: An experienced neurology ward sister was trained in the differential diagnosis of headache disorders. Over six months, patients with non-acute headache disorders and role players trained to present with benign or sinister headaches were seen by both the nurse and a consultant neurologist. Both reached independent diagnoses of various headache disorders.
Results: Consultants diagnosed 239 patients with tension-type headache (47%), migraine (39%), or other headache disorders (14%). The nurse agreed with the consultant in 92% of cases of tension-type headache, 91% of migraine, and 61% of other diagnoses. Where the nurse did not agree with the diagnosis, most would have been referred for a consultant opinion. Both the nurse and the doctors misdiagnosed the same three of 13 role players. The investigation rate of the consultants varied between 18% and 59%. Only one clinically relevant abnormality was found on head scans and this was strongly suspected clinically.
Conclusions: A headache nurse specialist can be trained to diagnose tension-type headache and migraine. A nationwide nurse led diagnostic headache service could lead to substantial reduction in neurology waiting times.
Background: Published formulae, frequently used to predict the volume of transfused red cells required to achieve a desired rise in haemoglobin (Hb) or haematocrit (Hct), do not appear to have been validated in clinical practice.
Aims: To examine the relation between transfusion volume and the resulting rise in Hb and Hct in critically ill children.
Methods: Phase 1: Sample of 50% of children admitted during 1997; 237 of these 495 patients received at least one packed red cell transfusion; 82 children were transfused without confounding factors that could influence the Hb/Hct response to transfusion and were analysed further. Actual rise in Hb concentration or haematocrit was compared to that expected from use of existing formulae. A new formula was developed. Phase 2: In 50 children receiving a packed red cell transfusion during 2001, actual rise in Hb concentration was compared to expected rise in Hb with use of the new formula.
Results: Phase 1: Existing formulae performed poorly; median ratio of actual/predicted rise in Hb or Hct ranged from 0.61 to 0.85. Using the regression coefficients new formulae were developed for both Hb and Hct. These formulae were applicable across all age and diagnostic groups. Phase 2: Median ratio of actual/predicted rise in Hb improved to 0.95 with use of the new formula.
Conclusions: Existing formulae underestimate the volume of packed red cells required to achieve a target Hb or Hct. Adoption of the new formulae could reduce the number of transfusion episodes in PICU, cutting costs and reducing risk.
Aims: To assess the rates of violence in nursery rhymes compared to pre-watershed television viewing.
Methods: Data regarding television viewing habits, and the amount of violence on British television, were obtained from Ofcom. A compilation of nursery rhymes was examined for episodes of violence by three of the researchers. Each nursery rhyme was analysed by number and type of episode. They were then recited to the fourth researcher whose reactions were scrutinised.
Results: There were 1045 violent scenes on pre-watershed television over two weeks, of which 61% showed the act and the result; 51% of programmes contained violence. The 25 nursery rhymes had 20 episodes of violence, with 41% of rhymes being violent in some way; 30% mentioned the act and the result, with 50% only the act. Episodes of law breaking and animal abuse were also identified. Television has 4.8 violent scenes per hour and nursery rhymes have 52.2 violent scenes per hour. Analysis of the reactions of the fourth researcher were inconclusive.
Conclusions: Although we do not advocate exposure for anyone to violent scenes or stimuli, childhood violence is not a new phenomenon. Whether visual violence and imagined violence have the same effect is likely to depend on the age of the child and the effectiveness of the storyteller. Re-interpretation of the ancient problem of childhood and youth violence through modern eyes is difficult, and laying the blame solely on television viewing is simplistic and may divert attention from vastly more complex societal problems.
Objectives: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers.
Methods: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02–20.16) years.
Results: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective.
Conclusions: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment.
Objectives: To evaluate the effect of peripheral blood stem cell transplantation on functional capacity, and to determine the role of a mixed type, moderate intensity exercise programme in the recovery of patients after intensive cancer treatment.
Methods: Peak aerobic capacity and muscular strength (upper body, lower body, and handgrip strength) measures were assessed before (PI) and after (PII) transplant and after a 12 week intervention period (PIII). After PII, 12 patients aged 16–64 years were allotted in equal numbers to a control group or exercise intervention group.
Results: Mean peak aerobic capacity and muscular strength were reduced after the transplant, with significant (p<0.05) decreases for upper body strength. No change was found in aerobic capacity and muscular strength between PII and PIII for the control group. In contrast, participation in the exercise programme led to significant improvements in peak aerobic capacity (p<0.05) and upper and lower body strength (p<0.01). In addition, values recorded after the three month intervention period were significantly higher than before treatment for peak aerobic capacity (litres/min (p<0.05) and ml/kg/min (p<0.01)) and lower body strength (p<0.01).
Conclusion: Intensive treatment for cancer can adversely affect aerobic capacity and muscular strength. A mixed type, moderate intensity exercise programme can help patients to regain fitness and strength within three months. No exercise can exacerbate physical losses resulting from treatment.
Treatment-resistant cluster headache can be successfully alleviated with deep brain stimulation (DBS) of the posterior hypothalamus . Magnetoencephalography (MEG) is a non-invasive functional imaging technique with both high temporal and high spatial resolution. However, it is not known whether the inherent electromagnetic (EM) noise produced by high frequency DBS is compatible with MEG.
Materials and methods:
We used MEG to record brain activity in an asymptomatic cluster headache patient with a DBS implanted in the right posterior hypothalamus while he made small movements during periods of no stimulation, 7 Hz stimulation and 180 Hz stimulation.
We were able to measure brain activity successfully both during low and high frequency stimulation. Analysis of the MEG recordings showed similar activation in motor areas in during the patient’s movements as expected. We also observed similar activations in cortical and subcortical areas that have previously been reported to be associated with pain when the patient’s stimulator was turned on or off [2,3].
These results show that MEG can be used to measure brain activity regardless of the presence of high frequency deep brain stimulation.
Aims: To determine the reliability of a panel of blood tests in screening for ulcerative colitis and Crohn's disease.
Methods: The subjects were 153 children referred to a paediatric gastroenterology department with possible inflammatory bowel disease (IBD). Of these, 103 were found to have IBD (Crohn's disease 60, ulcerative colitis 37, indeterminate colitis 6). The 50 without IBD formed the controls. Blood tests evaluated included haemoglobin, platelet count, ESR, CRP, and albumin. Receiver operating characteristic curves were used where possible to determine optimal threshold values. Binary logistic regression analysis was used to investigate the five screening tests in combination, and a stepwise method was used to find the best test combination.
Results: The optimal screening strategy used a combination of haemoglobin and platelet count and "1 of 2 abnormal" as the criterion for positivity. This was associated with a sensitivity of 90.8% (95% CI 83.3 to 95.7%), a specificity of 80.0% (95% CI 65.7 to 89.8%), and positive and negative predictive values of 94.4% and 75.9% respectively.
Conclusions: Haemoglobin and platelet count provide a useful screening test combination for patients with suspected IBD. These tests are not completely reliable however. If clinical suspicion is high further investigations are required.
Aims: To investigate anecdotal evidence that the name "Shufflebottom" originates from the dominantly inherited characteristic of bottom shuffling.
Methods: A questionnaire based retrospective study to determine the incidence of bottom shuffling and age of first walking among those named "Shufflebottom" and a control population, of those named "Walker".
Results: There was no statistically significant difference in incidence of bottom shuffling or age at first walking, between the two groups. The incidence of bottom shuffling (21.4%) was generally higher than has been described previously and Walkers were more likely to walk later than Shufflebottoms.
Conclusion: Shufflebottoms are no more likely to bottom shuffle than other children. The origin of the surname as representing this physical characteristic cannot be confirmed.
Aims: To determine the likelihood of finding an antivaccination site on the world wide web and to characterise their explicit claims and rhetorical appeals.
Methods: Using "vaccination" and "immunisation", examining the first 10 sites displayed on seven leading search engines. Detailed examination of content of 100 antivaccination sites found on Google.
Results: 43% of websites were antivaccination (all of the first 10 on Google). Main rhetorical appeals involve themes of the scientific veracity of antivaccination argument; rapport with parents seeking to protect their children from harm; and alleged collusion between doctors, the pharmaceutical industry, and government to deny vaccine harm.
Conclusions: There is a high probability that parents will encounter elaborate antivaccination material on the world wide web. Factual refutational strategies alone are unlikely to counter the highly rhetorical appeals that shape these sites.