Showing papers by "Leicester Royal Infirmary published in 2006"

Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment I

Abstract: Immunohistochemistry is no longer a technique used only for research but is employed increasingly for diagnosis and for the assessment of therapeutic biomarkers. The latter, in particular, often require a semiquantitative evaluation of the extent of their presence. There are many factors that can affect this that relate to the method: fixation of tissue, duration and type of antigen retrieval, antibody specificity, antibody dilution and detection systems. Other complexities relate to assessment. Different scoring systems are used for either the same or different antigens. Cut-off levels for assessing whether a tissue is 'positive' or 'negative' can vary for the same antigen. Whilst there are quality assurance schemes for the methodology that have improved standards of staining, there are no similar schemes that relate to interpretation, although errors here can create as many problems. There have been improvements in automated analysis but availability is limited and it is still predominantly a research tool. In order for quantification of immunohistochemistry to be a reliable and reputable tool, there must be easy to use, reproducible, standardized protocols for assessment which are international. Improvements in automated analysis with wider applicability could lead to standardization.

Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia.

Abstract: Diffusion tensor magnetic resonance imaging (DT-MRI) has previously been used to investigate white matter tracts in schizophrenia, with inconsistent results The aim of the study was to use a novel method for tract-specific measurements of fronto-temporal fasciculi in early-onset schizophrenia We hypothesized that by making tract-specific measurements, clear diffusion abnormalities would be revealed in specific fasciculi in schizophrenia Measurements of diffusion anisotropy and mean diffusivity were localized within fronto-temporal fasciculi by forming 3-D reconstructions of the cingulum, uncinate, superior longitudinal, and inferior fronto-occipital fasciculi using diffusion tensor tractography We were limited in our ability to test our hypothesis by the important and surprising finding that age affected DT-MRI-based measures in schizophrenia patients in a different way from comparison subjects, most notably in the left superior longitudinal fasciculus The youngest schizophrenia patients that we studied had lower diffusion anisotropy than age-matched comparison subjects, but this difference diminished with increasing age The main conclusion of this study was that direct comparisons of absolute DT-MRI-based measures between individuals with schizophrenia and comparison subjects may be problematic and misleading because of underlying age-related differences in brain maturation between groups

The obstetric and gynaecological management of women with inherited bleeding disorders--review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors' Organization.

Abstract: The gynaecological and obstetric management of women with inherited coagulation disorders requires close collaboration between obstetrician/gynaecologists and haematologists. Ideally these women should be managed in a joint disciplinary clinic where expertise and facilities are available to provide comprehensive assessment of the bleeding disorder and a combined plan of management. The haematologist should arrange and interpret laboratory tests and make provision for appropriate replacement therapy. These guidelines have been provided for healthcare professionals for information and guidance and it is also intended that they are readily available for women with bleeding disorders.

United Kingdom Collaborative Randomized Trial of Neonatal Extracorporeal Membrane Oxygenation: Follow-up to Age 7 Years

Abstract: OBJECTIVE: The UK Collaborative ECMO trial provided an opportunity to describe mortality and morbidity associated with a neonatal ECMO policy compared with conventional management. The improved survival in the ECMO group was not offset by an increase in disability at 4 years, but the children were too young to assess educational and other longer-term impacts. The objective of this study was to assess the longer-term impact of these policies at age 7 years. METHODS: A psychologist assessed 90 of the 100 children available for follow-up without prior knowledge of treatment allocation. The assessments took place at the children's schools within 3 months of their 7th birthdays. RESULTS: Sixty-eight of 89 (76%) children recorded a cognitive level within the normal range. Learning problems were similar in the 2 groups, and there were notable difficulties with spatial and processing tasks. A higher respiratory morbidity and increased risk of behavioral problems among children treated conventionally persisted. Progressive sensorineural hearing loss was found in both groups. CONCLUSIONS: The underlying disease processes appear to be the major influence on morbidity at 7 years. The beneficial influence of an ECMO policy is still present at 7 years.

Rechallenge with clozapine following leucopenia or neutropenia during previous therapy.

Abstract: Background Further treatment with clozapine is contraindicated in any patient who has previously experienced leucopenia or neutropenia during clozapine therapy. Aims To investigate the results of such a rechallenge in 53 patients. Method An analysis was made of the demographic, haematological and outcome data of patients in the UK and Ireland who were rechallenged with clozapine following leucopenia or neutropenia during previous clozapine therapy. Results Of 53 patients who were rechallenged, 20 (38%) experienced a further blood dyscrasia. In 17 of these 20 patients (85%) the second blood dyscrasia was more severe ( P <0.001), in 12 (60%) it lasted longer ( P =0.0368) and in 17 (85%) it occurred more quickly on rechallenge ( P <0.001). Of the original 53 patients, 55% (29 patients) are still receiving clozapine. Conclusions No clear risk factor for repeat blood dyscrasias was identified. Despite this, after risks and benefits have been considered, rechallenge may well be justified in some patients.

Methicillin-resistant Staphylococcus aureus on orthopaedic wards: incidence, spread, mortality, cost and control.

Abstract: We examined the rates of infection and colonisation by methicillin-resistant Staphylococcus aureus (MRSA) between January 2003 and May 2004 in order to assess the impact of the introduction of an MRSA policy in October 2003, which required all admissions to be screened. Emergency admissions were treated prophylactically and elective beds ring-fenced. A total of 5594 admissions were cross-referenced with 22 810 microbiology results. The morbidity, mortality and cost of managing MRSA-carrying patients, with a proximal fracture of the femur were compared, in relation to age, gender, American Society of Anaesthesiologists grade and residential status, with a group of matched controls who were MRSA-negative. In 2004, we screened 1795 of 1796 elective admissions and MRSA was found in 23 (1.3%). We also screened 1122 of 1447 trauma admissions and 43 (3.8%) were carrying MRSA. All ten ward transfers were screened and four (40%) were carriers (all p < 0.001). The incidence of MRSA in trauma patients increased by 2.6% per week of inpatient stay (r = 0.97, p < 0.001). MRSA developed in 2.9% of trauma and 0.2% of elective patients during that admission (p < 0.001). The implementation of the MRSA policy reduced the incidence of MRSA infection by 56% in trauma patients (1.57% in 2003 (17 of 1084) to 0.69% in 2004 (10 of 1447), p = 0.035). Infection with MRSA in elective patients was reduced by 70% (0.56% in 2003 (7 of 1257) to 0.17% in 2004 (3 of 1806), p = 0.06). The cost of preventing one MRSA infection was £3200. Although colonisation by MRSA did not affect the mortality rate, infection by MRSA more than doubled it. Patients with proximal fractures of the femur infected with MRSA remained in hospital for 50 extra days, had 19 more days of vancomycin treatment and 26 more days of vacuum-assisted closure therapy than the matched controls. These additional costs equated to £13 972 per patient. From this experience we have been able to describe the epidemiology of MRSA, assess the impact of infection-control measures on MRSA infection rates and determine the morbidity, mortality and economic cost of MRSA carriage on trauma and elective orthopaedic wards.

Pituitary apoplexy: retrospective review of 30 patients--is surgical intervention always necessary?

Abstract: The objective of this article is to review clinical outcomes in patients presenting with pituitary apoplexy and compare the results of conservative and surgical management. It took the form of a retrospective review of 30 patients (23M, 7F; age range: 17-86 years) with pituitary apoplexy diagnosed between 1988 and 2004. Presenting features included headache in 27 patients, 'collapse' in three and vomiting in 14. Complete blindness occurred in four patients, monocular blindness in two, decreased visual acuity in 12, visual field loss in 10 and ophthalmoplegia in 15. Only five had no initial visual deficit. CT was the initial mode of imaging in 22 patients: three such scans were initially reported as 'normal' and a further 10 as pituitary tumour only, with no haemorrhage. Ten patients proceeded to early pituitary surgery and 20 were managed conservatively. There was one death 24 days after admission in a patient with multiple co-morbidities. Of the six patients with blindness, three (two conservatively treated) regained partial vision. Of the remaining 19 patients with visual deficits, 10 (two surgically treated) recovered fully and eight (four surgically treated) partly so. At latest follow-up the following pituitary hormone deficiencies were identified: ACTH 19; TSH 20; testosterone 18; ADH (diabetes insipidus) eight. Later recurrence of a pituitary adenoma was observed in seven cases (including six of the 10 surgically treated patients). There was no evidence that those patients managed surgically had a better outcome. Early neurosurgical intervention may not be required in most patients presenting with pituitary apoplexy.

Phase I Evaluation of Intranasal Trivalent Inactivated Influenza Vaccine with Nontoxigenic Escherichia coli Enterotoxin and Novel Biovector as Mucosal Adjuvants, Using Adult Volunteers

Abstract: Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-μg doses of hemagglutinin from each virus strain with either 3, 10, or 30 μg of heat-labile Escherichia coli enterotoxin (LTK63) and 990 μg of a supramolecular biovector; one intranasally vaccinated group was given 7.5-μg doses of hemagglutinin with 30 μg of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 μg hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 μg LTK63 with the biovector, occurring in 7/15 (47%; P = 0.0103), 8/15 (53%; P = 0.0362), and 14/15 (93%; P = 0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 μg LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P = 0.0491) and B/Guandong (P = 0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.

Cost-effectiveness of neonatal extracorporeal membrane oxygenation based on 7-year results from the United Kingdom Collaborative ECMO Trial.

Abstract: OBJECTIVE. To assess the long-term cost-effectiveness of extracorporeal membrane oxygenation (ECMO) for mature newborn infants with severe respiratory failure. METHODS. A prospective economic evaluation was conducted alongside a pragmatic randomized, controlled trial in which 185 infants were randomly allocated to ECMO (n = 93) or conventional management (n = 92) and then followed up to 7 years of age. Information about their use of health services during the follow-up period was combined with unit costs (£, 2002–2003 prices) to obtain a net cost per child. The cost-effectiveness of neonatal ECMO was expressed in terms of incremental cost per additional life year gained and incremental cost per additional disability-free life year gained. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves and net benefit statistics at alternative willingness-to-pay thresholds held by decision-makers for an additional life year and for an additional disability-free life year. RESULTS. Over 7 years, neonatal ECMO was effective at reducing known death or severe disability. Mean health service costs during the first 7 years of life were £30270 in the ECMO group and £10229 in the conventional management group, generating a mean cost difference of £20041 that was statistically significant. The incremental cost per life year gained was estimated at £13385. The incremental cost per disability-free life year gained was estimated at £23566. At the notional willingness-to-pay threshold of £30000 for an additional life year, the probability that neonatal ECMO is cost-effective at 7 years was estimated at 0.98. This translated into a mean net benefit of £24362 for each adoption of neonatal ECMO rather than conventional management. CONCLUSIONS. This study provides rigorous evidence of the cost-effectiveness of neonatal ECMO during childhood.

The Importance of Careful Blood Processing in Isolation of Cell‐Free DNA

Abstract: In healthy individuals, the source of cell-free plasma DNA is predominantly apoptotic, whereas, increased plasma DNA integrity is seen in cancer patients. Therefore, it is important to carefully isolate absolutely "cell-free" plasma DNA. Plasma DNA from 30 healthy females was analyzed using 4 PCR amplicons of increasing size, comparing standard blood processing with additional centrifugation steps prior to DNA extraction. Cellular DNA contamination, indicated by positive amplicons >300 bp was eliminated only after the extra centrifugation step. This highlights the importance of careful processing in preparation of cell-free plasma DNA as a tool for cancer detection and we recommend the use of a microcentrifuge spin, prior to DNA extraction.

Prevalence of atopic dermatitis in Leicester: a study of methodology and examination of possible ethnic variation.

Abstract: A study was undertaken to investigate and compare various methods of estimating the prevalence of atopic dermatitis (AD), and to investigate a possible ethnic difference in our local community. Preschool children attending routine child health surveillance clinics and Social Services day nurseries were examined by a trained observer, and their parents were interviewed. In addition, general practice records from a health centre were scrutinized. Three hundred and twenty-two children aged 1-4 years were examined, and the point prevalence of AD was 14% [95% confidence interval (CI) 10-18]. There was no apparent ethnic difference in prevalence. Twenty-seven per cent (95% CI 22-32) of parents reported that their children had suffered from 'eczema' at some time. General practitioners' records contained a diagnosis of 'eczema' in 32% (95% CI 28-36) of 446 children aged 1-4 years. It is clear that methodology must be carefully standardized if comparisons are to be made between different studies. Accurate estimations of the prevalence of AD can probably only be obtained by examination of a population sample by a trained observer. However, the estimates obtained in this study are high, and would tend to support existing evidence that the prevalence of AD is rising.

Distal femoral fractures: A review of fixation methods

Abstract: The treatment of distal femoral fractures has evolved; nevertheless, these fractures remain difficult to treat and carry an unpredictable prognosis. Over the years, many different strategies have been used with varying success. This review outlines the problems presented by distal femoral fractures and the results of current surgical techniques.

A simple, reproducible method for monitoring the treatment of tumours using dynamic contrast-enhanced MR imaging.

Abstract: Dynamic contrast-enhanced MR imaging (DCE-MRI) may act as a biomarker for successful cancer therapy. Simple, reproducible techniques may widen this application. This paper demonstrates a single slice imaging technique. The image acquisition is performed in less than 500 ms making it relatively insensitive to respiratory motion. Data from phantom studies and a reproducibility study in solid human tumours are presented. The reproducibility study showed a coefficient of variation (CoV) of 19.1% for Ktrans and 15.8% for the initial area under the contrast enhancement curve (IAUC). This was improved to 16 and 13.9% if tumours of diameter less than 3 cm were excluded. The individual repeatability (the range within which individual measurements are expected to fall) was 30.6% for Ktrans and 26.5% for IAUC for tumours greater than 3 cm diameter. This approach to DCE–MRI image acquisition can be performed with standard clinical scanners, and data analysis is straightforward. For treatment trials with 10 patients in a cohort, the CoV implies that the method would be sensitive to a treatment effect of greater than 18%. The individual repeatability is well inside the 40% change shown to be important in clinical studies using this DCE–MRI technique.

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.

Abstract: The outcome of high-dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty-three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60-200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant-related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6-54 months) and the median time to best response was 6.5 months. Four of 17 evaluable patients (24%) became dialysis-independent at a median of 5 months post-HDT/stem cell transplantation. At a median follow-up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5-year survival in about one-third of patients.

Meniscal Extrusion in Young Athletes: Associated Knee Joint Abnormalities

Abstract: OBJECTIVE. The objective of our study was to assess the rate of meniscal extrusion and its connection with common meniscal and joint abnormalities.MATERIALS AND METHODS. MR signs of meniscal extrusion were evaluated retrospectively in 24 rugby and soccer players (40 knees) who are currently free of pain in the knee, impaired mobility, and joint swelling. The control group consisted of 23 consecutive active individuals (36 knees) with no history of knee problems. The criterion for extrusion of the meniscus was defined as a distance of 3 mm or more between the peripheral border of the meniscus and the edge of the tibial plateau measured on coronal images.RESULTS. Forty-eight percent of the athletes' knees and 30% of the control subjects' knees showed evidence of meniscal extrusion. Among the athletes, a significant association between meniscal extrusion and joint effusion (11 cases), meniscal tears (seven cases), and anterior cruciate ligament (ACL) tear (four cases) was found (p ≤ 0.004). In the control gr...

Trends in elective hand surgery referrals from primary care.

Abstract: INTRODUCTIONTwo prospective audits of activity in a hand unit were performed, in 1989–1990 and during 2000–2001, to identify trends in elective hand surgery referrals from primary care PATIENTS AND METHODSTwo 6-month prospective audits of activity in a hand unit were performed, including elective referrals from primary care Data were collected on all in-district referrals with elective hand disorders Cross boundary flow was identified to permit assessment of changes in referrals by diagnosis over a decade RESULTSThere was a 36% increase in health authority referrals for elective hand surgery over the decade (from 289 to 392 per 100,000 of population per year) The number of elective hand surgery operations rose 34% over the decade (from 149 to 199 operations per 100,000 of population per year) Carpal tunnel syndrome (the commonest reason for elective referral) almost doubled (from 597 to 112 per 100,000 of population per year) Referrals for ganglion, the second most common elective referral, rose m

Airway function measurements and the long-term follow-up of survivors of preterm birth with and without chronic lung disease.

Abstract: This seventh paper in a review series on different aspects of chronic lung disease following preterm birth focuses on the current knowledge of respiratory symptoms, airway function, airway hyperresponsiveness, and exercise capacity from childhood to adulthood. This paper further considers the long-term implications of these studies for both future research and clinical practice.

Nodular prurigo responds to cyclosporin

Abstract: Summary Nodular prurigo is a distressing disease which is difficult to treat. Two patients with severe nodular prurigo were treated with cyclosporin for periods of 36 and 24 weeks, respectively, using doses of 3–4.5 mg/kg per day. In both cases there was a reduction in the severity of pruritus after 2 weeks of treatment. In one patient there was a considerable, although incomplete response, and in the other almost complete resolution of the disease was achieved. The improvement was maintained throughout the treatment period, and the drug was generally well tolerated, although in one patient there was a rise in serum creatinine during treatment, which later returned to normal.