Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?
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Adolescent↗
Biomedical subjects
G Nichols
Publications and source records attributed to G Nichols.
Reducing the risks of transmitting gastrointestinal infections in home paddling pools.
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Adult↗
The spectrum of myelodysplastic syndromes post-solid organ transplantation: a single institutional experience.
An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48-64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis.
Biopsy↗
Outbreaks of waterborne infectious intestinal disease in England and Wales, 1992-2003.
We reviewed the epidemiological and microbiological characteristics of 89 reported outbreaks of waterborne infectious intestinal disease affecting 4321 people in England and Wales over the period 1992-2003. Public water supplies were implicated in 24 outbreaks (27%), private water supplies in 25 (28%), swimming pools in 35 (39%) and other sources in five outbreaks (6%). Cryptosporidium was implicated in 69% of outbreaks, Campylobacter sp. in 14%, Giardia in 2%, E. coli O157 in 3% and Astrovirus in 1%. From 2000, there was a consistent decline in the number of outbreaks of waterborne disease associated with public water supplies. The incidence rate of outbreaks in recipients of private water supplies may be as high as 35 times the rate in those receiving public water supplies (1830 vs. 53 per million population). Private water suppliers need to be aware of the importance of adequate treatment and the prevention of faecal contamination of storage water. Swimming-pool operators need to ensure chlorination and in particular adequate filtration measures are in place.
Communicable Diseases↗
Genetic analysis of Cryptosporidium from 2414 humans with diarrhoea in England between 1985 and 2000.
The characterization of Cryptosporidium using DNA extracted from whole faecal samples collected from 2414 humans with diarrhoea in England between 1985 and 2000 where cryptosporidial oocysts were detected using conventional methods is described. Characterization was achieved by PCR/RFLP and DNA sequencing of fragments of the Cryptosporidium oocyst wall protein and the 18S rDNA genes. Cryptosporidium parvum was detected in 56.1 % of cases, Cryptosporidium hominis in 41.7 % and a mixture of C. parvum and C. hominis in 0.9 %. In the remainder of cases, Cryptosporidium meleagridis (0.9 %), Cryptosporidium felis (0.2 %), Cryptosporidium andersoni (0.1 %), Cryptosporidium canis (0.04 %), Cryptosporidium suis (0.04 %) and the Cryptosporidium cervine type (0.04 %) were detected.
Adolescent↗
Culture of Helicobacter pylori from domestic water samples--the impact of strain variation on growth on solid and in liquid media.
Helicobacter pylori is an important global human pathogen and there is growing evidence from PCR assays that contaminated drinking water might be a possible source of infection in some circumstances. There are no validated protocols for direct isolation but various culture media have been developed for possible environmental sampling. Our aim here was to investigate how inter-strain variation might affect the interpretation of results with such media. Two laboratory adapted reference strains and four recent clinical isolates were tested on four solid media and in ten liquid media. Considerable variation was found between strains in their ability to recover on the different media after stress exposure (suspension in sterile tap water). Generally, clinical isolates were less robust than the laboratory-adapted strains and, overall, the former required longer recovery times. Our findings highlighted the importance of using a range of isolates for evaluations, as examination of laboratory-adapted strains alone did not provide an accurate representation of the utility of media that may be used to recover H. pylori from water.
Culture Media↗
Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy.
One of the challenges of cancer therapeutics is to discover targets unique to the tumor cell population. Constitutively activated tyrosine kinases play a role in the malignant phenotype in a number of different cancers. While the kinases may be present in the normal cell, the cancer cell is often dependent upon the activation of the kinase for the maintenance of malignant growth. Inhibition of kinase activation may therefore selectively inhibit malignant proliferation. In the case of chronic myelogenous leukemia (CML), the activated tyrosine kinase (BCR-ABL) is due to a chromosomal translocation that defines this disease, and is necessary for malignant transformation. Imatinib mesylate (Gleevec, Novartis) is a small molecule tyrosine kinase inhibitor, developed through the chemical modification to be selected for a small number of tyrosine kinases present in human cells. This agent is also orally bioavailable and has been found to be effective in clinical trials. We have learned much through the clinical use of this agent. 1) Specific targeting of activated signal transduction pathways may be effective in inhibiting cancer cells. 2) Cancer cells may not only be inherently resistant to small molecule inhibitors, but may also develop resistance after exposure to the inhibitor. 3) Increased knowledge regarding critical signal transduction pathways, the structure of the molecules that are being targeted and the inhibitors themselves, will allow us to understand resistance as it develops and create new molecules to bypass resistance. We will discuss imatinib as an important example of the success and pitfalls of targeted therapeutics for cancer.
Benzamides↗
Cryptosporidium outbreak linked to interactive water feature, UK: importance of guidelines.
A need for national guidelines relating to interactive water features was highlighted following three outbreaks of cryptosporidiosis in the United Kingdom, all of which were related to public water features. In August 2003 the Health Protection Agency South West of England was notified of an outbreak of cryptosporidiosis associated with an interactive water feature designed for water play within an adventure park. The water feature was implicated following samples with a high coliform count and the presence of faecal coliforms. A case was defined as any child (younger than 16 years of age) who had visited the park during August and who subsequently had gastrointestinal symptoms and a faecal sample positive for cryptosporidium. Seventy one children were identified in the cohort. This outbreak of cryptosporidiosis was characterised by a very high attack rate (89%), relatively severe in duration (median 8 days) and had a relatively high hospital admission (16% of cases). The epidemic curve was consistent with a point source of infection, which corresponded to the date 80% of the cohort visited the park. This outbreak has similarities to two other cryptosporidiosis outbreaks reported in England in 2003 that involved public water features. These outbreaks raise issues about the operation and maintenance of water-based recreational attractions that very often involve children. The paper reflects on the basic control measures that can be taken and highlights the need for guidelines, especially since such attractions are becoming increasingly common. The Pool Water Treatment Advisory Group in United Kingdom has now produced guidelines.
Child↗
Variant translocation with a deletion of derivative (9q) in a case of Philadelphia chromosome positive (Ph +) essential thrombocythemia (ET), a variant of chronic myelogenous leukemia (CML) with a poor prognosis.
Patients presenting with thrombocytosis require thorough clinical and laboratory evaluation to determine whether they suffer from essential thrombocythemia or another myeloproliferative disorder. This distinction becomes increasingly relevant as targeted agents become available to treat specific myeloproliferative diseases. Cytogenetic testing plays a major role in this analysis. This study presents a patient with Philadelphia chromosome positive (Ph + ) thrombocytosis and a cryptic der(9q)t(5;9)t(9;22) not found by conventional cytogenetics, whose disease progressed within 2 years to typical myeloblastic crisis of CML. It discusses the entity of Ph + ET, the utility of molecular cytogenetic testing in the diagnosis of this unusual disease entity and the importance of cytogenetic testing in the prognosis of ET.
Aged↗
Detection of Helicobacter pylori by PCR but not culture in water and biofilm samples from drinking water distribution systems in England.
AIMS: To investigate treated water distribution systems in England as a source of Helicobacter pylori. METHODS AND RESULTS: Water and biofilms were obtained from 11 domestic and seven educational properties and from hydrants, reservoirs and water meters supplied by three water utilities. Samples were cultured on nonselective and antibiotic containing media combined with immunomagnetic separation concentration. Viable helicobacters were not detected in any of the 151 samples but Helicobacter-specific PCR assays detected DNA in 26% of samples from domestic properties, schools and hydrants with the highest frequency in biofilms (42%). Direct sequencing of six selected amplicons confirmed >95% sequence homology to H. pylori. CONCLUSIONS: While viable helicobacters were not isolated, evidence was obtained for the presence of Helicobacter DNA, including that of H. pylori. Biofilms on surfaces within water distribution systems may act either as sites for the passive accumulation of helicobacters or as potentially important reservoirs of infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings strengthen evidence that H. pylori may be transmitted through drinking water. However, there is currently no evidence that viable cells can survive the disinfection levels used in UK mains supplies and the health risk from this source remains unclear.
Base Sequence↗
Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.
A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.
Adolescent↗
Therapy-related myelodysplastic syndrome after autologous stem cell transplantation for breast cancer.
Therapy-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) are serious complications of chemotherapy and radiotherapy for cancer. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may be associated with an increased incidence of these complications. The frequency of t-MDS/AML after ASCT for breast cancer is uncertain. We reviewed our database of 379 consecutive breast cancer ASCT patients treated with alkylator-based chemotherapy, followed for a median of 1.52 years (range 0-8.97), with a median survival of 6.16 years. Three patients have developed tMDS/AML. The probability of developing this complication at 5 years is 0.032 in our series. We have used pathologic, cytogenetic and molecular methods to evaluate which portions of therapy may have predisposed to the development of this complication. Cytogenetic abnormalities were not found in the stem cell harvests of these patients by metaphase analysis or by fluorescence in situ hybridization (FISH). One patient demonstrated a clonal X chromosome inactivation pattern in her stem cell harvest, indicating pre-transplant chemotherapy may have been responsible for the development of her leukemia. As two of our patients developed this complication at greater than 4 years post-transplant, the number of cases may increase with longer follow-up. While the incidence appears to be low, further prospective and retrospective analysis will be necessary to determine which portions of therapy predispose to the development of t-MDS/AML in patients undergoing ASCT for treatment of breast cancer.
Acute Disease↗
An outbreak of serious illness and death among injecting drug users in England during 2000.
An outbreak of serious illness and death occurred in injecting drug users during 2000 in Scotland, Ireland and England. National and international collaboration was necessary for the investigation and management of this outbreak. In England and Wales active case-finding was initiated, coupled with standardised data collection and microbiological investigation of cases. Twenty-six definite or probable cases were identified in England between 1 April and 31 Aug. 2000; 17 of these occurred in the North. The overall case fatality was 50% (13/26). The principal apparent risk factor was a history of intramuscular or subcutaneous injection of heroin and the limited duration of the outbreak suggested that the problem might have been related to a particular supply of heroin. Clostridium novyi was isolated from two English cases. Taken in conjunction with contemporaneous microbiological and epidemiological results from Scottish and Irish cases, the probable aetiology for this outbreak was infection with C. novyi associated with both a particular supply of heroin and the method of preparation and injection used. A 'toolkit' was distributed in Sept. 2000 to all Consultants for Communicable Disease Control in England and Wales to assist them with the ongoing surveillance, investigation and management of this condition. Lessons learned have been used to produce guidance for the investigation and management of outbreaks of unexplained serious illness of possible infective aetiology.
Adult↗
Sponsorship, authorship and accountability.
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Authorship↗
Reduction of paclitaxel-induced peripheral neuropathy with glutamine.
PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.
Activities of Daily Living↗
Characterisation of the influence of micronisation on the crystallinity and physical stability of revatropate hydrobromide.
Micronised particles of revatropate hydrobromide were observed to agglomerate when stored in uncontrolled conditions. Dynamic vapour sorption (DVS), isothermal microcalorimetry, microscopy and particle size measurement by laser diffraction have been used to study micronised revatropate hydrobromide. The rate and extent of agglomeration were dependent on the energy of the micronisation process, the sampling point for bulk within the mill and the humidity during storage. The agglomeration was attributed to the recrystallisation of disordered regions on the particles of revatropate hydrobromide generated during micronisation. This recrystallisation was assessed qualitatively and quantitatively, compared against spray-dried amorphous material, using DVS and isothermal microcalorimetry, respectively. A correlation was established between the energy of micronisation and the level of disorder within the micronised powder. A comparison of the DVS profiles of freshly prepared and aged micronised revatropate hydrobromide suggests an increased physical stability for the aged material.
Adsorption↗
The microbiological quality of ice used to cool drinks and ready-to-eat food from retail and catering premises in the United Kingdom.
A survey of 4,346 samples of ice from retail and catering premises examined 3,528 samples (81%) used to cool drinks and 144 samples (3%) from food displays. For 674 samples (15%), the origin was not recorded. Most samples of ice used to cool drinks or ready-to-eat food on displays did not contain coliforms, Escherichia coli, or enterococci. Of the ice used to cool drinks, 9% contained coliforms, 1% E. coli, and 1% enterococci in excess of 10(2) CFU/100 ml, and 11% had an aerobic plate count at 37 degrees C in excess of 10(3) CFU/ml. The microbiological quality of ice used to cool drinks was poorer when melt water was present in the ice buckets. Ice used in food displays was more contaminated than ice used to cool drinks, with 23% containing coliforms, 5% E. coli, and 8% enterococci at 10(2) CFU/100 ml or more. Twenty-nine percent of samples had an aerobic plate count greater than 10(3) CFU/ml. Ice that had been used to cool shellfish was of a lower microbiological quality than samples used to cool ready-to-eat fish, salads, or dairy produce. Samples of ice produced in commercial production facilities were of higher microbiological quality than samples of ice that were not. The microbiological quality of ice was dependent on the type of use, the type of premises, and the type and place of production. Although most ice samples were of acceptable microbiological quality, evidence from this study suggests that the microbiological quality of ice prepared and used at certain premises in the UK is a cause for concern.
Colony-Forming Units Assay↗
Microbiological standards for water and their relationship to health risk.
Maintenance of the microbiological quality of water has been used as an important means of preventing waterborne disease throughout the twentieth century. The commonest microbiological tests done on water are for coliforms and Escherichia coli (or faecal coliform). This paper reviews the legislative and other guidance for microbial standards in drinking and bathing waters and considers evidence for the relationship between the microbiological quality of water and risk to human health. In the past measures of the microbiological quality of water correlated well with risks of acquiring gastrointestinal disease. More recent work suggests that gastrointestinal disease is more strongly associated with the presence of enterococci than of E. coli. New diseases such as cryptosporidiosis have been shown to cause outbreaks of waterborne disease when levels of conventional microbiological parameters are satisfactory. In response to this, and because of failure of prosecution in one outbreak, the United Kingdom (UK) Government has introduced new legislation that requires water providers to perform a risk assessment on their water treatment facilities and to implement continuous monitoring for cryptosporidium. A new European directive on drinking water has been introduced and legislation on cryptosporidium in drinking water has been proposed in the UK.
Animals↗