Biomedical subjects
J Pritchard
Publications and source records attributed to J Pritchard.
The use of different grades of lactose as a carrier for aerosolised salbutamol sulphate.
Five different grades of lactose namely, anhydrous lactose, medium lactose, regular lactose, lactose crystals and foremost lactose were fractionated under similar conditions to obtain a size range of 63-90 microm and were characterised using laser diffraction and time-of-flight particle sizing techniques, scanning electron microscopy, optical microscopy image analysis, thermal gravimetric analysis and differential scanning calorimetry. Each of these lactose fractions were then blended separately with micronised salbutamol sulphate in a ratio of 67.5:1 (w/w). The mixing uniformity and percentage recovery of salbutamol sulphate in the powder blends were analysed using a validated HPLC method. The deposition profiles of the drug were determined using a 5-stage liquid impinger after aerosolisation at 60 l min(-1) via a Rotahaler. Despite the identical processing conditions, the lactose fractions were shown to differ in particle size, size distribution and concentrations of fine particles. The particles from each fraction also exhibited different surface textures and dissimilar DSC thermograms. However, all the blends of the lactose with salbutamol sulphate were found to have a relatively high uniformity of salbutamol sulphate content, as suggested by a coefficient of variation of less than 3.2%. Anhydrous and medium lactose produced a more efficient delivery of salbutamol sulphate when aerosolised from the Rotahaler in comparison to other grades of lactose. For example, the fine particle fraction (FPF) and fine particle dose (FPD) of drug from formulations containing anhydrous lactose were 13.4+/-4.2% and 57.3+/-17.6 microg, respectively, which were approximately two times higher than the respective values of the formulation containing regular lactose. Medium lactose resulted in drug FPF (7. 9+/-2.7%) and FPD (32.4+/-11.8 microg), which were significantly (ANOVA P<0.05) higher than the same parameters obtained using lactose crystals, foremost lactose and regular lactose. More efficient drug delivery from anhydrous lactose may be partly attributed to the relatively higher concentration of fine lactose in this grade of carrier, although it showed a rougher surface than the other grades of lactose. However, the relatively high FPF of the drug from medium lactose may have been due to the relatively small mean particle size and smooth surface of the particles. Therefore, the source and grade of lactose may have a substantial effect on drug delivery from dry powder inhaler formulations and care should be taken in establishing appropriate quality control parameters when selecting an appropriate grade of carrier.
Bilateral ovarian involvement at presentation in metastatic (stage 4) neuroblastoma.
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Plasma adrenal, gonadal, and conjugated steroids following long-term exercise-induced negative energy balance in identical twins.
There are few reports of the change in sex hormone levels accompanying a weight change in men, although an excessive decline in testosterone (TESTO) has been described as an associate of stress-induced weight loss. Plasma levels of cortisol, TESTO, dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), androsterone glucuronide (ADT-G), and androstane-3alpha, 17beta-diol glucuronide (3alphaDIOL-G) were measured in seven pairs of sedentary male monozygotic twins (age, 21.0 +/- 0.8 years; body mass index [BMI], 26.2 +/- 5.5 kg/m2) before and after 93 days of standardized submaximal (50% to 55% maximum oxygen consumption) cycle-ergometer exercise. A total energy deficit of 244 +/- 9.7 MJ induced significant changes (P < .0001) in body weight ([BW] -5.0 +/- 2.2 kg) and body fatness measures. Plasma TESTO and DHEA-S increased and 3alphaDIOL-G decreased. The increase in TESTO was a significant inverse correlate of loss in all measures of body fat, particularly central adiposity (r = -.58 to -.86, P < .001, fat loss-adjusted). Lower postexercise levels of 3alphaDIOL-G correlated positively with decreased body composition measures (r = .65 to .68, P < .01). The increase in plasma TESTO accompanying the loss of abdominal visceral fat (AVF) was greater in men with lower fasting insulin levels (P < .0001). The baseline within-twin-pair resemblance in TESTO and 3alphaDIOL-G (intraclass correlation coefficients [ICC] = .83 and .78, respectively, P < .01) was lost with intervention. Cortisol, DHEA-S, and ADT-G developed within-twin-pair similarity (ICC adjusted for fat loss: cortisol, .72; ADT-G, .62, P < .05; DHEA-S, .85, P < .002). We conclude that a steroid profile characterized by high TESTO and low androgen metabolite levels accompanied the changes in body composition and body fat distribution generated by the exercise-induced negative energy balance. Furthermore, these changes were characterized by a significant resemblance within identical-twin pairs.
The impact of higher education for post-registration nurses on their subsequent clinical practice: an exploration of students' views.
In recent years there has been a large increase in the number of qualified nurses in the United Kingdom, who have raised the academic level of their nursing qualification to diploma level or above. Correspondingly, there has been little research that assesses the value of post-registration education offered by universities. In particular, there is a paucity of research regarding the effects of courses on the subsequent clinical practice of participants. Studies of post-registration education appear to be small scale and limited in scope. This paper examines the views of diplomates as to the effect of a Diploma in Professional Studies in Nursing course on clinical practice. A questionnaire was sent to all nurses (n = 169), from the first seven cohorts, who successfully completed the course. A response rate of 66.8% (n = 113) was achieved. The respondents reported themselves to be more questioning, more able to apply research findings and to have a wider knowledge for practice following completion of the course. The findings are discussed, limitations of the study addressed and recommendations for further research are made.
Colon involvement in Langerhans' cell histiocytosis.
BACKGROUND: Langerhans' cell histiocytosis (LCH), a granulomatous disorder of unknown cause, most often affects the bony skeleton and skin. Obvious gut involvement is uncommon, and colon involvement has been cited in only a small number of case reports, probably because most patients who have LCH with diarrhoea and/or failure to thrive are not investigated by colonoscopy and biopsy. The current study was conducted to determine the incidence of symptomatic colon involvement among patients with multisystem LCH treated at a single institution. METHOD: A retrospective review of cases in hospital records and the literature. RESULTS: Of the 275 children with LCH in the database, 5 were identified as having biopsy-confirmed colonic involvement. Another 14 cases were identified by a literature review. CONCLUSION: Colonic involvement in patients with multisystem LCH is probably more common than currently recognised. In addition to the other investigations recommended by the Writing Group of the Histiocyte Society, it is recommended that patients with any symptoms suggestive of gut involvement undergo colonoscopy and biopsy of the colonic mucosa.
Use of indomethacin in Langerhans cell histiocytosis.
BACKGROUND: Because prostaglandin (PG) E2 has been identified in the bone lesions of Langerhans cell histiocytosis (LCH), we speculated that indomethacin, a potent PG inhibitor, may be useful in patients with symptomatic LCH involving the bony skeleton. PROCEDURE: We used indomethacin to treat patients in whom we wanted to avoid steroids or chemotherapy, or in whom these treatments did not provide complete symptom relief. Ten children with bony LCH between 1984 and 1995 were treated; six had single-system bone disease and four had multisystem disease involving the bony skeleton and other organs. RESULTS: The dose of indomethacin ranged from 1 to 2.5 mg/kg/day (9-200 mg/day) in divided doses and was given for 1-16 weeks (mean, 6 weeks). Eight patients had a complete response to treatment, defined as complete resolution of symptoms for 4 weeks. One patient was withdrawn from treatment because of concern regarding the potential of indomethacin to induce seizures and a second patient, with suppurative skin lesions overlying a lytic skull defect, did not respond. CONCLUSIONS: Indomethacin is a useful therapy for LCH involving the bony skeleton and may have a role as first-line treatment in single-system bone disease. Whether it has a specific role in slowing disease progression or merely acts as an analgesic has not yet been established.
Labyrinthine involvement in Langerhans' cell histiocytosis.
BACKGROUND: Langerhans' cell histiocytosis, a rare condition caused by the proliferation of abnormal Langerhans' cells ('LCH cells') and an accompanying granulomatous infiltrate, can affect several organs including the ear. External and middle ear involvement are common with a reported incidence as high as 61%. The bony labyrinth is resistant to erosion by the granulation tissue, thereby protecting the cochlea and vestibular structures. Probably for this reason, involvement of the inner ear is rare, with few case reports in the literature. PATIENTS: We report two girls, one with bilateral and the other with unilateral mastoid involvement, in whom there was invasion of the labyrinth. The first girl had 'single system' LCH affecting only bone and developed an acute hearing loss due to invasion of the cochlea, while the second had both bone and skin involvement and labyrinthine involvement was diagnosed on imaging prior to the onset of labyrinthine symptoms. CONCLUSION: Inner ear involvement can lead to permanent deafness, which may be prevented by early institution of treatment. Threatened inner ear involvement requires urgent systemic medical therapy with steroids, possibly combined with chemotherapy.
12000 miles for parental reassurance.
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Loss of heterozygosity for the short arm of chromosome 7 in sporadic Wilms tumour.
Cytogenetic analysis of Wilms tumours (WT) have shown that abnormalities involving chromosome 7 occur in approximately 25% of tumours. In some cases, these abnormalities involve deletions of the short arm, and are seen as the sole cytogenetic change, strongly suggesting the presence of a tumour suppressor gene in this location. Since loss of heterozygosity (LOH) studies have been crucial in defining chromosomal regions involved in Wilms tumorigenesis, we have analysed 40 sporadic Wilms tumours using a panel of 10 microsatellite polymorphic markers distributed along the length of the chromosome arm. In our series, four tumours (10%) showed allelic loss for 7p markers which is twice the background rate of LOH in WT. The shortest common region of overlap of LOH was located between markers D7S517-D7S503 in band 7p21-15. In one tumour there was evidence for a homozygous, interstitial deletion at a locus within this region. These findings provide strong evidence for the existence of a tumour suppressor gene involved in Wilms tumorigenesis and defines the critical region of the chromosome involved.
Radiotherapy omitted in the treatment of selected children under 3 years of age with stage III favorable histology Wilms tumor.
BACKGROUND: Current treatment of stage III favorable histology (FH) Wilms tumor is surgery, radiotherapy to residual disease, and "triple" chemotherapy (vincristine, dactinomycin, and doxorubicin) for 12 months. This study tests the hypothesis that some stage III patients, especially very young children with minimal residual abdominal disease, might be successfully treated without radiotherapy, thereby avoiding the adverse late effects associated with radiotherapy. PROCEDURE: From 1984, radiotherapy was omitted from the treatment of 8 carefully selected children who were younger than 3 years of age at diagnosis with stage III Wilms tumor by virtue of microscopic residual disease after surgery and whose lymph nodes were not involved by tumors. They were followed with bimonthly abdominal ultrasound examinations to assess local control. RESULTS: Follow-up is now from 2 to 12 years (median 6 years) and 7 of the 8 children are alive and well with no abdominal recurrence. One child relapsed in the lungs and despite further treatment died of progressive disease. The disease-free survival (DFS) and overall survival (OS) are therefore both 87.5%. CONCLUSIONS: The DFS and OS in this admittedly small sample are consistent with the survival rates for stage III FH Wilms tumor in the first United Kingdom Children's Cancer Study Group (UKCCSG), North American (NWTS), and European (SIOP) Wilms Tumor studies, Larger numbers of patients are needed to determine whether or not this treatment approach is generally applicable, but we conclude that some children in this stage III "substage" may be treated successfully without radiotherapy.
Controversies and new approaches to treatment of Langerhans cell histiocytosis.
There continues to be genuine ambivalence as to whether Langerhans cell histiocytosis (LCH) is a primary neoplastic or immuno-dysregulatory disorder. Treatment strategies have moved from one camp to the other depending upon the most current alleged successes or failures. This has been particularly true for patients who fall outside of the sphere where treatment is minimal or where known treatment approaches are clearly beneficial. However, there is growing evidence that LCH is both the result of clonal proliferation of Langerhans cells and the immunologic consequence of increased cellular activation. This new knowledge should be the basis for the development of new therapeutic approaches for patients with LCH and its complications.
Actinomycin D, hepatic toxicity and Wilms' tumour--a mystery explained?
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Supercritical fluid processing of materials from aqueous solutions: the application of SEDS to lactose as a model substance.
PURPOSE: The objective of the work was to study the factors influencing the crystallisation of alpha-lactose monohydrate from aqueous solution using the Solution Enhanced Dispersion by Supercritical Fluids (SEDS) technique. METHODS: An aqueous solution of alpha-lactose monohydrate is dispersed with a homogeneous mixture of carbon dioxide-ethanol/methanol using a co-axial nozzle. Crystallised lactose particles were analysed for water content by Karl-Fisher analysis, anomeric composition by Differential Scanning Calorimetry (DSC) and characterised for crystallinity by powder X-ray diffraction and morphology by scanning electron microscopy. RESULTS: Water content in the lactose recrystallised with ethanol was higher compared to the product obtained with methanol as cosolvent. Rate of crystallisation could be altered by varying the CO2 flow thereby modifying the water content in the lactose. At low flow rates of CO2, the crystallisation occurred in a cosolvent rich antisolvent phase causing rapid crystallisation whereas high flow rates of CO2 favoured a much slower crystallisation mechanism in the water rich phase. As a consequence, the morphology changed from thin long bands to large agglomerated chunks with mean particle size between 5 and 31 microns. CONCLUSIONS: The SEDS process is an efficient method for forming micron sized particles of water-soluble compounds with controlled physico-chemical properties.
Loss of heterozygosity on chromosome 16 in sporadic Wilms' tumour.
To establish whether loss of heterozygosity (LOH) for chromosome 16q in Wilms' tumours confers an adverse prognosis, DNA from 40 Wilms' tumour/normal pairs were analysed using highly polymorphic microsatellite markers along the length of 16q. Fifteen per cent of tumours showed LOH for 16q. Although the common region of allele loss spanned the 16q24-qter region, a second distinct region of LOH was identified in 16q21. Five out of six tumours showing LOH were either (1) high stage or (2) low stage with unfavourable histology. In addition, there was a higher mortality rate in patients showing LOH for 16q than those that did not. These data strongly support the suggestion that LOH for 16q is associated with an adverse prognosis.
Diarrhea after resection of advanced abdominal neuroblastoma: a common management problem.
BACKGROUND: After resection of advanced abdominal neuroblastoma, children may have persistent postoperative diarrhea. Until recently, the magnitude of this problem had not been appreciated. METHODS: To assess the incidence, severity, and management of chronic postoperative diarrhea in these patients, we reviewed the case notes of all children with stage III or IV abdominal and pelvic neuroblastoma who underwent tumor resection in our hospital between January 1985 and September 1996. We classified the severity of diarrhea as follows: mild, less than 3 loose stools per day; moderate, 3 to 5 loose stools per day; and severe, more than 5 loose stools per day and/or urgency, incontinence, or nocturnal diarrhea. RESULTS: Seventy-seven children underwent resection during this period, and 23 (30%) had postoperative diarrhea, classified as mild in 11 patients, moderate in 7, and severe in 5. Dissection around the superior mesenteric and celiac arteries was associated with a significantly higher incidence of diarrhea. Fifteen children (65%) received treatment with loperamide, which reduced but did not abolish symptoms. Twelve children subsequently died of progressive neuroblastoma. Of the 11 surviving children (mean duration of follow-up, 8.4 years), 8 have persistent loose stools. CONCLUSIONS: Diarrhea, probably resulting from disruption of the autonomic nerve supply to the gut during clearance of tumor from the major vessels of the retroperitoneum, is common after resection of advanced abdominal neuroblastoma. Many children require long-term treatment to slow intestinal peristalsis, and a few have severe and unremitting diarrhea. More effective medical management of this complication is needed.
Germline bottlenecks and the evolutionary maintenance of mitochondrial genomes.
Several features of the biology of mitochondria suggest that mitochondria might be susceptible to Muller's ratchet and other forms of evolutionary degradation: Mitochondria have predominantly uniparental inheritance, appear to be nonrecombining, and have high mutation rates producing significant deleterious variation. We demonstrate that the persistence of mitochondria may be explained by recent data that point to a severe "bottleneck" in the number of mitochondria passing through the germline in humans and other mammals. We present a population-genetic model in which deleterious mutations arise within individual mitochondria, while selection operates on assemblages of mitochondria at the level of their eukaryotic hosts. We show that a bottleneck increases the efficacy of selection against deleterious mutations by increasing the variance in fitness among eukaryotic hosts. We investigate both the equilibrium distribution of deleterious variation in large populations and the dynamics of Muller's ratchet in small populations. We find that in the absence of the ratchet, a bottleneck leads to improved mitochondrial performance and that, over a longer time scale, a bottleneck acts to slow the progression of the ratchet.
Renal transplantation in the management of bilateral Wilms' tumour (BWT) and of Denys-Drash syndrome (DDS).
BACKGROUND: Wilms' tumour (WT) occurs bilaterally in approximately 5-7% of affected children. In some patients, complete surgical removal of the malignant tissue cannot be achieved without bilateral total nephrectomy. In Denys-Drash syndrome (DDS), bilateral nephrectomy is indicated both because of the associated nephropathy usually progressing rapidly to end-stage renal failure and because of the high risk of WT development in any residual renal tissue. METHODS: Case records of patients with a diagnosis of either bilateral WT (BWT) or DDS, who underwent bilateral nephrectomy and subsequent renal transplantation between 1980 and 1996 at the Hospital for Sick Children, London, were reviewed. RESULTS: Allogeneic renal transplantation was performed in two children with BWT and four with DDS, three of whom had developed unilateral WT by the time their kidneys were removed. Renal transplantation was performed 15-49 months after bilateral nephrectomy at a mean age of 45 (26-76) months, with a minimum of 1 year tumour-free survival after completion of chemotherapy in those with WT. One patient died after renal transplantation. Five children had a favourable outcome, with a mean follow-up of 80 (29-121) months post-renal transplantation. CONCLUSION: Advances in dialysis and transplantation programmes for young children offer the potential for a marked improvement in the prognosis for patients with BWT and for those with DDS.