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Biomedical subjects

G L Nichols

Publications and source records attributed to G L Nichols.

At least 19 recordsLinked to original sources
PubMed2005

Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma.

In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30-50 mg/m2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400-850 mg/m2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.

Adolescent↗
PubMed2003

Outbreaks of infectious disease associated with private drinking water supplies in England and Wales 1970-2000.

In England and Wales over the last 30 years there have been 25 reported outbreaks of infection, associated with private water supplies (PWS). The majority (16 outbreaks) were reported after the introduction of enhanced surveillance. Although PWS only serve 0.5% of the population, 36% of drinking water outbreaks are associated with PWS. The main pathogen, campylobacter, was implicated in 13 (52%) outbreaks. Most reported outbreaks (88%) occurred in commercial or Category Two supplies, which potentially affect larger populations. The main factors implicated in these outbreaks are temporary or transient populations, treatment (lack or failure), the presence of animals and heavy rains. The public health problem associated with PWS could be prevented by the identification and understanding of risk factors, by the proper protection of water sources and adequate treatment and maintenance. This could be facilitated through the introduction of a risk assessment as part of a scheme for PWS.

Communicable Disease Control↗
PubMed2002

An investigation into the microflora of heroin.

In 2000, an unusual increase of morbidity and mortality among illegal injecting drug users in the UK and Ireland was reported and Clostridium novyi was identified as the likely source of the serious infection, although infections due to C. botulinum and Bacillus cereus were also reported. Because heroin was a possibile source of infection, this study investigated the microflora of heroin samples seized in England during 2000 and 2002. Two methods were developed for the examination of the microflora of heroin. The first consisted of suspension of the drug in maximum recovery diluent (MRD) which was inoculated directly into Clostridium Botulinum Isolation Cooked Meat Broth (CBI). The second method rendered the heroin soluble in citric acid, concentrated particulate material (and bacterial cells) by filtration and removed heroin residues by washing with citric acid and phosphate-buffered saline before placing the filter in CBI broth. Duplicate CBI broths from both methods were incubated without heating and after heating at 60 degrees C for 30 min. Subcultures were made after incubation for 7 and 14 days on to eight different solid media. The methods were evaluated with heroin samples spiked with either C. botulinum or C. novyi spore suspensions; recovery of 10 spores in the original sample was demonstrated. Fifty-eight heroin samples were tested by citric acid solubilisation and 34 by the MRD suspension technique. Fifteen different gram-positive species of four genera were recognised. No fungi were isolated. Aerobic endospore-forming bacteria (Bacillus spp. and Paenibacillus macerans) were the predominant microflora isolated and at least one species was isolated from each sample. B. cereus was the most common species and was isolated from 95% of all samples, with B. licheniformis isolated from 40%. Between one and five samples yielded cultures of B. coagulans, B. laterosporus, B. pumilus, B. subtilis and P. macerans. Staphylococcus spp. were isolated from 23 (40%) samples; S. warneri and S. epidermidis were the most common and were cultured from 13 (22%) and 6 (10%) samples respectively. One or two samples yielded cultures of S. aureus, S. capitis and S. haemolyticus. The remainder of the flora detected comprised two samples contaminated with C. perfringens and two samples with either C. sordellii or C. tertium. Multiple bacterial species were isolated from 43 (74%) samples, a single species from the remaining 15. In 13 samples B. cereus alone was isolated, in one B. subtilis alone and in one sample B. pumilus alone. C. botulinum and C. novyi were not isolated from any of the heroin samples. Recommendations for the optimal examination of the microflora of heroin are given.

Bacillus cereus↗
PubMed2001

Cryptosporidium meleagridis from humans: molecular analysis and description of affected patients.

OBJECTIVES: To genetically characterize an unusual genotype of Cryptosporidium from the stools of humans with diarrhoea and to identify risk factors in the affected patients. METHODS: DNA was extracted from human faeces where Cryptosporidium oocysts were detected by light microscopy. Cryptosporidial gene fragments from six different loci were analysed by PCR alone, PCR/RFLP and by DNA sequencing. Oocysts were characterized by light and immunofluorescence microscopy and epidemiological data was collected from the affected patients. RESULTS: Analysis of the Cryptosporidium oocyst wall protein (COWP) gene amplified from > 2000 human faecal samples identified 19 patients all of which produced an unusual RFLP profile. Subsequent DNA sequence analysis of this and an additional four genetic loci (including 18S rRNA sequences) confirmed these as a homogeneous group which was genetically distinct from Cryptosporidium parvum. The isolates were identified as Cryptosporidium meleagridis since the gene sequences were identical to those from this species recovered from birds. Conventional microscopy showed oocysts indistinguishable from C. parvum and reacted strongly with two different commercially available anti-oocyst monoclonal antibodies. None of the patients showed risk factors unusual for cryptosporidiosis; however, ten of the cases occurred during the summer/autumn, six had a history of foreign travel, four were co-infected with Giardia, two were HIV positive, and six were without identifiable immunocompromising factors. CONCLUSIONS: This study further confirms that C. meleagridis, in addition to C. parvum, is involved in human disease. The study also highlights the lack of basic information on the host range of this genus of parasites, the complexity of the transmission routes involved in human cryptosporidiosis, and the value of molecular techniques in identify hitherto unrecognised differences in Cryptosporidium from human faeces.

Adolescent↗
PubMed2000

A survey of the microbiological quality of private water supplies in England.

Results from statutory testing of private water supplies in nine Public Health Laboratories in England were compiled, and the effects of supply class, source, treatment and location on water quality were examined. A total of 6551 samples from 2911 supplies was examined, over a 2-year period, of which 1342 (21%) samples, and 949 (33%) supplies on at least one occasion, failed current regulations for Escherichia coli. Total coliforms, including E. coli, were detected in 1751 (27%) samples from 1215 (42%) supplies. The percentage of samples positive for E. coli was highest in summer and autumn, and lowest in winter. Samples taken from larger supplies and from boreholes were less frequently contaminated than those from other sources. Chlorination, filtration or UV light treatment improved the bacteriological quality of supplies, but still resulted in a low level of compliance with the regulations. The public health implications of the study are discussed.

Chlorine↗
PubMed2000

Molecular epidemiological analysis of Cryptosporidium spp. in the United Kingdom: results of genotyping Cryptosporidium spp. in 1,705 fecal samples from humans and 105 fecal samples from livestock animals.

Cryptosporidium present in 1,705 fecal samples from humans and 105 from livestock animals were analyzed by PCR-restriction fragment length polymorphism of the Cryptosporidium oocyst wall protein. Overall, genotype 1 (human exclusive type) was detected in 37.8% of the samples from humans, genotype 2 (broad host range) was detected in 61.5%, a third genotype designated genotype 3 (Cryptosporidium meleagridis) was detected in 0.3%, and both genotypes 1 and 2 were recovered from 0.4%. All samples from livestock yielded genotype 2. Among 469 patients infected during eight drinking water-related outbreaks, five outbreaks were predominantly due to genotype 1, and three were due to genotype 2. Fifty-four samples were collected from patients involved with five swimming pool-associated outbreaks: two outbreaks were due to genotype 1, one was due to genotype 2, and the remaining two involved both genotypes 1 and 2. Among 26 family outbreaks and 1 children's nursery outbreak (2 to 3 members per group), the same genotype was recovered from the different members of each outbreak: 13 were due to genotype 1, and 14 were due to genotype 2. In eighteen patients reporting contact with animals and/or farms, genotype 1 was recovered from one patient and genotype 2 was recovered from the remaining 17. Among the sporadic cases, there were distinct geographical and temporal variations in the distribution of the genotypes. The spring peak in cases was due to genotype 2. Genotype 1 was significantly more common in patients infected during the late-summer-autumn peak and in those with a history of foreign travel.

Animals↗
PubMed2000

Food-borne protozoa.

Pathogenic protozoa are commonly transmitted to food in developing countries, but food-borne outbreaks of infection are relatively rare in developed countries. The main protozoa of concern in developed countries are Toxoplasma, Cryptosporidium and Giardia, and these can be a problem in immunocompromised people. Other protozoa such as Entamoeba histolytica, Cyclospora cayetanensis and Sarcocystis can be a food-borne problem in non-industrialised countries. C. cayetanensis has emerged as a food-borne pathogen in foods imported into North America from South America. Microsporidia may be food-borne, although evidence for this is not yet available. The measures needed to prevent food-borne protozoa causing disease require clear assessments of the risks of contamination and the effectiveness of processes to inactivate them. The globalisation of food production can allow new routes of transmission, and advances in diagnostic detection methods and surveillance systems have extended the range of protozoa that may be linked to food.

Animals↗
PubMed1999

Translocation (4;15)(p16;q24): a novel reciprocal translocation in a patient with BCR/ABL negative myeloproliferative syndrome progressing to blastic phase.

A patient with BCR/ABL negative myeloproliferative syndrome with a 46,XY,del(3)(q21), t(4;15)(p16;q24) karyotype is described. Fluorescence in situ hybridization performed with chromosomes 4 and 15 painting probes confirmed a novel reciprocal (4;15) translocation. The absence of crkl tyrosine phosphorylation, no activation of the abl kinase as measured by autophosphorylation, and a normal-size abl transcript suggest an alternative mechanism for leukemogenesis to that operative in Ph positive BCR/ABL positive chronic myeloid leukemia. A number of genes potentially relevant to tumorigenesis, some involving the ras signaling pathway, map to the 4p16 and 15q24 chromosome regions.

Acute-Phase Reaction↗
PubMed1999

Genetic characterization of Cryptosporidium strains from 218 patients with diarrhea diagnosed as having sporadic cryptosporidiosis.

Samples of whole feces in which Cryptosporidium oocysts were recognized by hospital laboratories were collected from 218 patients with diarrhea. All samples were reexamined by light microscopy, and oocysts were detected in 211 samples. A simple and rapid procedure for the extraction of DNA from whole feces was developed, and this was used to amplify fragments of the Cryptosporidium outer wall protein (COWP), the thrombospondin-related adhesive protein C1 (TRAP-C1), and the 18S rRNA genes by PCR. For seven samples oocysts were not detected by microscopy and DNA failed to be amplified by the three PCR procedures. Among the 211 samples "positive" by microscopy, the sensitivities of PCRs for the 18S rRNA, COWP, and TRAP-C1 gene fragments were 97, 91, and 66%, respectively. The sensitivities of all three PCR procedures increased with increasing numbers of oocysts as observed by microscopy. Two genotypes of the COWP and TRAP-C1 genes can be detected by PCR-restriction fragment length polymorphism analysis. With this series of samples, the same genotypes of the COWP and TRAP-C1 genes always segregated together. A combined genotyping data set was produced for isolates from 194 samples: 74 (38%) were genotype 1 and 120 (62%) were genotype 2. Genotype 2 was detected in a significantly greater proportion of the samples with small numbers of oocysts, and genotype 1 was detected in a significantly greater proportion of the samples with larger numbers of oocysts. There were no significant differences in the distribution of the genotypes by patient sex and age. The distribution of the genotypes was significantly different both in patients with a history of foreign travel and in those from different regions in England.

Adolescent↗
PubMed1999

The microbiological quality of cooked rice from restaurants and take-away premises in the United Kingdom.

The microbiological quality of 4,162 samples of cooked rice from restaurants and take-away premises in the United Kingdom was examined, including ready-to-eat rice purchased at point-of-sale and rice that was stored precooked for reheating on demand. The majority of point-of-sale cooked rice samples (1,855 of 1,972; 94%) were of acceptable microbiological quality, but 15 (1%) samples were of unacceptable quality (Bacillus spp. and B. cereus, > or = 10(5) CFU/g; Escherichia coli, > or = 10(4) CFU/g), indicating a potential risk to health. The prevalence of Bacillus spp., B. cereus, and E. coli was significantly greater in precooked stored rice than in point-of-sale cooked rice (P < 0.005 to 0.0005). Bacillus spp. (> or = 10(4) CFU/g), B. cereus (> or = 10(4) CFU/g), and E. coli (> or = 10(2) CFU/g) were present in 7%, 2%, and 9% of precooked stored samples, respectively, compared to 2%, 0.5%, and 1%, respectively in point-of-sale samples. Although final heating at the point of sale reduces the levels of microorganisms present in rice it will not inactivate the B. cereus emetic toxin if present. Rice from Indian premises was of poorer microbiological quality than that from Chinese and other premises. Although most point-of-sale cooked rice samples (94%) were of an acceptable microbiological quality, evidence from this study indicates that the microbiological quality of cooked rice sold from certain outlets in the UK is of concern.

Bacillus↗
PubMed1997

Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients.

An important step in the oncogenic transformation of hemopoietic cells and the subsequent development of leukemia is the proliferation of tumor cells in the absence of exogenous growth factors. In most cases of chronic myelocytic leukemia and in some cases of acute myelocytic leukemia and acute lymphocytic leukemia, the bcr-abl oncogene is involved in this process. Although the BCR-Abl oncoprotein demonstrates enhanced tyrosine kinase activity in leukemic cells, the mechanism by which this leads to growth factor independence remains poorly defined. One proposed mechanism is the activation of cytokine signal transduction pathways, possibly by an autocrine loop involving IL-3 and/or granulocyte-macrophage CSF. Examination of several different cell lines expressing BCR-Abl demonstrates that some of these cells have constitutive activation of the JAK/STAT signaling pathway. We have found the constitutive activation of STAT5 in most, but not all, cell lines expressing BCR-Abl. This constitutive activation of STAT5 is variably associated with a corresponding activation of JAK kinases. Ab blocking studies show that the activation of STAT5 in these cell lines cannot be attributed to the activation of an IL-3/granulocyte-macrophage CSF-driven autocrine loop. Interestingly, samples of peripheral blood cells derived from patients with acute myelocytic leukemia and chronic myelocytic leukemia, which express BCR-Abl, demonstrate constitutive activation of STAT family members. These studies suggest that in a variety of leukemic states, BCR-Abl may use a bypass mechanism to activate cytokine signal transduction pathways.

Animals↗
PubMed1994

Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells.

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome in clonally derived hematopoietic precursors and their progeny. The Ph chromosome arises from a translocation that deregulates the c-ABL protein tyrosine kinase, giving it transforming potential and increased kinase activity. We observed a unique 39-kD tyrosine phosphoprotein (pp39), previously reported in blastic CML cell lines, in neutrophils from 50 cases of chronic phase CML. This protein was prominently and constitutively tyrosine-phosphorylated in CML neutrophils and was not phosphorylated in normal neutrophils. Stimulation of normal neutrophils with cytokines and agonists did not induce tyrosine phosphorylation of proteins migrating in the region of pp39, and the phosphorylation state of pp39 in CML neutrophils was not affected by kinase inhibitors known to downregulate the ABL kinase. The pp39 was not phosphorylated in hematopoietic cells from healthy donors or from patients with Ph chromosome-negative myeloproliferative disorders. Using micro amino acid sequencing of purified preparations of pp39, we identified pp39 as CRKL protein, which is consistent with recent immunologic studies in the blastic K562 cell line. Immunoblotting with anti-CRKL antibodies showed the presence of CRKL protein in CML cells and cell lines as well as in antiphosphotyrosine immunoprecipitates from CML cells. Our results suggest that pp39 CRKL in CML neutrophils may be stably tyrosine-phosphorylated by the BCR/ABL kinase at an early stage of myeloid differentiation when the ABL kinase is active. CRK, CRKL, and other SH2 (SRC homology domain)/SH3-containing proteins function as adaptor molecules in nonreceptor tyrosine kinase signalling pathways. Although the CRKL protein is present in normal neutrophils, it is not tyrosine-phosphorylated, and the inability to induce such phosphorylation in normal neutrophils suggests a special role of this phosphoprotein in the pathogenesis of CML. Constitutive phosphorylation of CRKL is unique to CML, indicating that it may be a useful target for therapeutic intervention.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Small cell carcinoma of the esophagus. The Memorial Hospital experience 1970 to 1987.

During the period 1970 to 1987, 11 patients with small cell carcinoma of the esophagus were treated at Memorial Sloan-Kettering Cancer Center, New York. This rare tumor was responsible for 1.1% of all patients with esophageal tumors seen on the inpatient services during that period. Using a clinical staging system similar to that employed in small cell cancer of the lung, eight of 11 patients had extensive disease. Although responses were seen to multidrug combination chemotherapy regimens used alone or with sequential radiation, the overall prognosis for small cell esophageal cancer was poor, with a median survival of 7.5 months. Only one patient lived for greater than 2 years.

Aged↗
PubMed1980

Differential effects of lesions in medial and dorsal raphe of the rat: latent inhibition and septohippocampal serotonin levels.

Rats received either 0 or 30 preexposures to a tone which was later used as a conditioned stimulus (CS) in a two-way avoidance task. Tone preexposure resulted in retarded conditioning in normal animals and animals with dorsal raphe lesions. This latent inhibition effect, however, was not present in animals with medial raphe lesions. The failure of CS preexposure to retard conditioning in animals with medial raphe lesions was not due to differences in auditory sensitivity or shock reactivity. Biochemical analysis indicated that whereas medial raphe lesions significantly reduced serotonin in the septohippocampal complex, dorsal raphe lesions had no such effect. The results are discussed in terms of the differing roles of the mesolimbic and mesostriatal serotonergic systems in learning to ignore irrelevant stimuli.

Acoustic Stimulation↗