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D Brown

Publications and source records attributed to D Brown.

At least 145 records · Page 8Linked to original sources
PubMed2000

Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491.

Neisseria meningitidis causes bacterial meningitis and is therefore responsible for considerable morbidity and mortality in both the developed and the developing world. Meningococci are opportunistic pathogens that colonize the nasopharynges and oropharynges of asymptomatic carriers. For reasons that are still mostly unknown, they occasionally gain access to the blood, and subsequently to the cerebrospinal fluid, to cause septicaemia and meningitis. N. meningitidis strains are divided into a number of serogroups on the basis of the immunochemistry of their capsular polysaccharides; serogroup A strains are responsible for major epidemics and pandemics of meningococcal disease, and therefore most of the morbidity and mortality associated with this disease. Here we have determined the complete genome sequence of a serogroup A strain of Neisseria meningitidis, Z2491. The sequence is 2,184,406 base pairs in length, with an overall G+C content of 51.8%, and contains 2,121 predicted coding sequences. The most notable feature of the genome is the presence of many hundreds of repetitive elements, ranging from short repeats, positioned either singly or in large multiple arrays, to insertion sequences and gene duplications of one kilobase or more. Many of these repeats appear to be involved in genome fluidity and antigenic variation in this important human pathogen.

Antigenic Variation↗
PubMed2000

A reduced compartmental model of the mitral cell for use in network models of the olfactory bulb.

We have developed two-, three- and four-compartment models of a mammalian olfactory bulb mitral cell as a reduction of a complex 286-compartment model [1]. A minimum of three compartments, representing soma, secondary (basal) dendrites and the glomerular tuft of the primary dendrite, is required to adequately reproduce the behaviour of the full model over a broad range of firing rates. Adding a fourth compartment to represent the shaft of the primary dendrite gives a substantial improvement. The reduced models exhibit behaviours in common with the full model which were not used in fitting the model parameters. The reduced models run 75 or more times faster than the full model, making their use in large, realistic network models of the olfactory bulb practical.

Ion Channels↗
PubMed2000

Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release.

When thyroglobulin (Tg) is endocytosed by thyrocytes and transported to lysosomes, thyroid hormones (T4 and T3) are released. However, some internalized Tg is transcytosed intact into the bloodstream, thereby avoiding proteolytic cleavage. Here we show that megalin (gp330), a Tg receptor on thyroid cells, plays a role in Tg transcytosis. Following incubation with exogenous rat Tg at 37 degrees C, Fisher rat thyroid (FRTL-5) cells, a differentiated thyroid cell line, released T3 into the medium. However, when cells were incubated with Tg plus either of two megalin competitors, T3 release was increased, suggesting that Tg internalized by megalin bypassed the lysosomal pathway, possibly with release of undegraded Tg from cells. To assess this possibility, we performed experiments in which FRTL-5 cells were incubated with either unlabeled or (125)I-labeled Tg at 37 degrees C to allow internalization, treated with heparin to remove cell surface-bound Tg, and further incubated at 37 degrees C to allow Tg release. Intact 330-kDa Tg was released into the medium, and the amount released was markedly reduced by megalin competitors. To investigate whether Tg release resulted from transcytosis, we studied FRTL-5 cells cultured as polarized layers with tight junctions on permeable filters in the upper chamber of dual chambered devices. Following the addition of Tg to the upper chamber and incubation at 37 degrees C, intact 330-kDa Tg was found in fluids collected from the lower chamber. The amount recovered was markedly reduced by megalin competitors, indicating that megalin mediates Tg transcytosis. We also studied Tg transcytosis in vivo, using a rat model of goiter induced by aminotriazole, in which increased release of thyrotropin induces massive colloid endocytosis. This was associated with increased megalin expression on thyrocytes and increased serum Tg levels, with reduced serum T3 levels, supporting the conclusion that megalin mediates Tg transcytosis. Tg transcytosis is a novel function of megalin, which usually transports ligands to lysosomes. Megalin-mediated transcytosis may regulate the extent of thyroid hormone release.

Amitrole↗
PubMed2000

Response to different measles vaccine strains given by aerosol and subcutaneous routes to schoolchildren: a randomised trial.

BACKGROUND: More than one dose of measles vaccine is necessary for the sustained control of measles. The aerosol route is thought to be more immunogenic for booster doses than traditional subcutaneous injections, so we did a randomised comparative trial of aerosol and subcutaneous measles vaccines in South African schoolchildren. METHODS: 4327 schoolchildren (aged 5-14 years), assigned by block randomisation of classrooms, received standard titre doses of either Schwarz or Edmonston-Zagreb measles vaccines subcutaneously or by aerosol. Blood samples for antibody assay were collected before vaccination, at 1 month, and 1 year after vaccination. The main endpoints (antibody titres at 1 month and 1 year) were compared between groups. FINDINGS: 992 children had antibody titre data available for all timepoints. 14 (3.6%) of 385 children who received Edmonston-Zagreb vaccine by aerosol were seronegative 1 year after vaccination, compared with 28 (8.6%) of 326 children who received Edmonston-Zagreb subcutaneous vaccine and 39 (13.9%) of 281 children who received Schwarz subcutaneous vaccine. At 1 month, 326 (84.7%) children who received aerosol Edmonston-Zagreb vaccine had seroconverted, compared with 257 (78.8%) who received subcutaneous Edmonston-Zagreb vaccine and 176 (62.6%) who received subcutaneous Schwarz vaccine. At 1 month, only 116 (22.7%) of 511 children in the Schwarz aerosol group had seroconverted; this aerosol vaccine had no detectable potency after 2 min of nebulisation. There were no serious side-effects: about 5% of children in each group had a rash within 2 weeks of vaccination. INTERPRETATION: An aerosol vaccination method that uses currently available devices and a suitably stable vaccine is effective and acceptable. This form of delivery is adaptable to mass campaigns, avoids the risks associated with injections, and could help measles eradication.

Administration, Inhalation↗
PubMed2000

Characterisation of rotavirus G9 strains isolated in the UK between 1995 and 1998.

G9P[6] and G9P[8] rotavirus strains were identified during 1995/96 through the molecular epidemiological surveillance of rotavirus strains circulating in the UK between 1995 and 1998. An increase in the incidence and spread of sporadic infections with rotavirus genotype G9P[8] across the UK was detected in the two following seasons. Partial sequencing of the VP7 gene showed that all the UK strains shared a high degree of homology and were related very closely to G9 strains from the US and from symptomatic infections in India (> or =96% homology). The UK strains were related more distantly to the apathogenic Indian strain 116E (85-87.8% homology). Phylogenetic analysis revealed clustering of the UK strains into 3 different lineages (I to III) and into two sub-lineages within lineage I. There were correlations between VP7 sequence clustering, the P type and the geographical origin of the G9 strains. Partial sequencing of the VP4 gene showed high degree of homology (>98%) among all the P[6] strains, and the sequences obtained from the P[8] strains clustered into 2 of the 3 global lineages described for P[8] strains associated with other G types. These data suggest that G9 strains may be a recent importation into the UK, and that G9P[8] strains may have emerged through reassortment in humans between G9P[6] strains introduced recently and the more prevalent cocirculating G1, G3 and G4 strains that normally carry VP4 genes of P[8] type.

Aged↗
PubMed2000

Distinct epidemiological patterns of Norwalk-like virus infection.

Norwalk-like viruses (NLV) are important economically as a cause of both sporadic gastroenteritis in the community and large outbreaks in hospitals and other institutional settings. Despite the description of several antigenic types relatively little is known about the epidemiology of these individual types. NLVs were detected by electron microscopy in faecal specimens from 706 outbreaks of gastroenteritis that represented 68% of all outbreaks of non-bacterial gastroenteritis. These outbreaks took place in the counties of West and North Yorkshire and Humberside during six winter seasons between July 1992 and June 1998. NLV strains from 671 outbreaks were typed by antigen capture enzyme linked immunosorbent assays (ELISA) based on antisera made to recombinant virus-like particles of three antigenically distinct NLVs; Norwalk (NV), Mexico (MXV) and Grimsby (GRV) viruses. GRV was the predominant strain for five of the six winter seasons and overall was associated with 61% of NLV outbreaks. MXV was responsible for a single epidemic peak in the winter of 1993/94 but was also observed at other times throughout the study period. NV was only associated with two outbreaks in 1994 that were epidemiologically linked. Strains from the remaining 32% of outbreaks were non-reactive in all three ELISA. Thus, a single NLV antigenic type seems to have predominated during the period 1992 to 1998 in the UK.

Adult↗
PubMed2000

EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis.

Hereditary multiple exostoses (HME) is a genetically heterogeneous disease characterized by the development of bony protuberances at the ends of all long bones. Genetic analyses have revealed HME to be a multigenic disorder linked to three loci on chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes have been cloned and defined as glycosyltransferases involved in the synthesis of heparan sulfate. EST database analysis has demonstrated additional gene family members, EXT-like genes (EXTL1, EXTL2, and EXTL3), not associated with a HME locus. The mouse homologs of EXT1 and EXT2 have also been cloned and shown to be 99% and 95% identical to their human counterparts, respectively. Here, we report the identification of the mouse EXTL1 gene and show it is 74% identical to the human EXTL1 gene. Expression studies of all three mouse EXT genes throughout various stages of embryonic development were carried out and whole-mount in situ hybridization in the developing limb buds showed high levels of expression of all three EXT genes. However, in situ hybridization of sectioned embryos revealed remarkable differences in expression profiles of EXT1, EXT2, and EXTL1. The identical expression patterns found for the EXT1 and EXT2 genes support the recent observation that both proteins form a glycosyltransferase complex. We suggest a model for exostoses formation based on the involvement of EXT1 and EXT2 in the Indian hedgehog/parathyroid hormone-related peptide (PTHrP) signaling pathway, an important regulator of the chondrocyte maturation process.

Amino Acid Sequence↗
PubMed2000

The role of panendoscopy in the management of mucosal head and neck malignancy-a prospective evaluation.

BACKGROUND: It is common practice for a panendoscopy to be included in the evaluation of patients with mucosal head and neck malignancies. Whether this intervention is efficient or cost-effective has not been established in our patient population. METHODS: Two hundred twenty-four patients with squamous cell carcinoma involving the oral cavity, pharynx, larynx, or neck were evaluated prospectively with panendoscopy and chest x-ray with or without barium swallow. One hundred fifty-four patients had newly diagnosed tumors and 70 were previously diagnosed and currently undergoing symptom-directed investigations. RESULTS: The incidence of synchronous primary tumors was 2.6% (4 of 154); pulmonary, 1.3%; head and neck mucosa, 1.3%; and esophageal, 0%. There was no associated morbidity. CONCLUSIONS: Although there was no associated morbidity, our head and neck oncology group is of the opinion that routine panendoscopy is not warranted. Specific indications for this investigation are discussed.

Barium Sulfate↗
PubMed2000

Integrate-and-fire models with nonlinear leakage.

Can we express biophysical neuronal models as integrate-and-fire (IF) models with leakage coefficients which are no longer constant, as in the conventional leaky IF model, but functions of membrane potential and other biophysical variables? We illustrate the answer to this question using the FitzHugh-Nagumo (FHN) model as an example. A novel IF type model, the IF-FHN model, which approximates to the FHN model, is obtained. The leakage coefficient derived in the IF-FHN model has nonmonotonic relationship with membrane potential, revealing at least in part the intrinsic mechanisms underlying the FHN models. The IF-FHN model correspondingly exhibits more complex behaviour than the standard IF model. For example, in some parameter regions, the IF-FHN model has a coefficient of variation of the output interspike interval which is independent of the number of inhibitory inputs, being close to unity over the whole range, comparable to the FHN model as we noted previously (Brown et al., 1999).

Computer Simulation↗
PubMed2000

Geographic variation in allergic fungal rhinosinusitis.

Allergic fungal rhinosinusitis (AFRS) has a worldwide distribution. This survey of 20 otolaryngologic practices throughout the United States confirmed a variation in the frequency of AFRS relative to endoscopic sinus procedures performed for all other diagnoses. The highest incidence occurred in Memphis, Tennessee at 23%, with three other southern practices reporting a frequency of at least 10%. In the northern locations the frequency ranged from 0 to 4%. No correlation with mould counts was demonstrated, possibly because of incomplete mould data relative to most of the surgical locations.

Humans↗
PubMed2000

Antiepidermal growth factor receptor antibodies augment cytotoxicity of chemotherapeutic agents on squamous cell carcinoma cell lines.

Recent literature by Fan et al (1993) demonstrated that addition of cisplatin and monoclonal antibody to the epidermal growth factor receptor (EGFR MAb) of the human squamous cell carcinoma (SCC), A431, eradicated gross tumors in nude mice. To determine whether a combination of either cisplatin or 5-fluorouracil (5-FU) with EGFR MAb could affect an SCC other than the A431 tumor model, an assay using 2 human tongue SCC cell lines, BroTo and SCC-25, was performed. Cells were pretreated with 1.25 microgram/mL cisplatin or 10 microgram/mL 5-FU. After a 4-hour incubation period, cisplatin-treated cells were washed with phosphate-buffered saline solution. Various concentrations of EGFR MAb were then added, and after a 24-hour incubation period, an MTT cell growth assay was performed. SCC-25 cells exhibited a greater decrease in growth with the addition of 16 nmol/L EGFR MAb to cisplatin compared with the cytotoxicity of cisplatin alone (P < 0.001). However, this combination did not produce similar results with BroTo cells (P > 0.05). The combination of EGFR MAb and 5-FU produced a growth inhibition versus control (unexposed cells) in both cell lines (P < 0.05). These findings suggest the possible augmentation of the activity of chemotherapeutic agents, cisplatin and/or 5-FU, with the addition of EGFR MAb on SCC cell lines other than A431.

Antibodies, Monoclonal↗
PubMed2000

Pentoxifylline fails to improve organ dysfunction and survival when used in the resuscitation of a porcine model of haemorrhage and abdominal sepsis.

Pentoxifylline is a phosphodiesterase inhibitor, known to suppress tumour necrosis factor-alpha production and improve cardiopulmonary parameters and survival in animal models of sepsis. Using a porcine model of abdominal trauma resulting from the combined insults of haemorrhage and infection, a randomised placebo-controlled trial was conducted of pentoxifylline (20 mg/kg bolus followed by 20 mg/kg infusion over 1 h) administered in addition to a colloid resuscitation regimen. Female Large White pigs (45-60 kg) were bled 40% of their blood volume and peritonitis was induced using E. coli (O18: K1: H7) in an autoclaved faecal suspension. Animals were resuscitated with either colloid alone (n=5) or colloid plus pentoxifylline (n=5). Pentoxifylline attenuated increases in mean arterial and pulmonary artery pressures and reduced both systemic and pulmonary vascular resistance. It worsened the lactic acidosis associated with 'septic shock' and failed to reduce serum TNF-alpha levels. Pentoxifylline, in the high doses used in this study, does not have a role as an adjunct to resuscitation in this clinically relevant model of trauma.

Animals↗
PubMed2000

Mapping of quantitative trait loci for ethanol preference in quasi-congenic strains.

Ethanol preference, a component of alcoholism, has been known for four decades to differ greatly between C57BL/6 and BALB/c inbred mouse strains. For mapping quantitative trait loci (QTLs) that affect ethanol preference, we used a set of B6.C Recombinant QTL Introgression (RQI) strains, which carry about 5% of the donor BALB/cJ (C) genome on a C57BL/6ByJ (B6) background. After characterizing males of the progenitor and RQI strains for variations in ethanol preference, we scanned their genome for polymorphisms at 244 dinucleotide-repeat marker loci known to differ between B6 and C. Because of the introgression of BALB/c-type QTLs onto the B6 background, some strains showed ethanol preference significantly lower or higher than that of the background strain, suggesting that genetic interaction between ethanol preference QTLs and the background can be operative. The genomic region showing the strongest influence on ethanol preference was on mouse chromosome 15, and corresponds to human chr.12q11-q13.

Alcohol Drinking↗
PubMed2000

Functional analysis of a RPD3 histone deacetylase homologue in Arabidopsis thaliana.

Histone acetylation is modulated through the action of histone acetyltransferase and deacetylase, which play key roles in the regulation of eukaryotic gene expression. We have screened the expressed sequence tag database with the yeast histone deacetylase RPD3 sequence and identified two Arabidopsis homologues, AtRPD3A and AtRPD3B. The deduced amino acid sequences of AtRPD3A and AtRPD3B show high overall homology (55% identity) to each other. AtRPD3A encodes a putative protein of 502 amino acids with 49% identity to the yeast RPD3. AtRPD3B encodes a putative protein of 471 amino acids and shares 55% amino acid identity with the yeast RPD3. Northern analysis indicated that AtRPD3A was highly expressed in the leaves, stems, flowers and young siliques of Arabidopsis plants, whereas the AtRPD3B transcript was not detected in these organs. An AtRPD3A fusion protein repressed transcription when directed to a promoter driving a reporter gene, indicating a role for AtRPD3A protein in gene repression. Arabidopsis plants were transformed with a gene construct comprising a truncated AtRPD3A cDNA in the antisense orientation driven by a strong constitutive promoter, -394tCUP. Antisense expression of AtRPD3A resulted in decreased endogenous AtRPD3A transcript and delayed flowering in transgenic Arabidopsis plants, suggesting that the transition from the vegetative to reproductive phase of development could be affected by histone acetylation. Our study demonstrates the important role of histone deacetylases in plant growth and development.

Amino Acid Sequence↗
PubMed2000

Structural analysis of the KGD sequence loop of barbourin, an alphaIIbbeta3-specific disintegrin.

Disintegrins constitute a class of small proteins that inhibit platelet aggregation by binding to the fibrinogen receptor, also referred to as integrin alphaIIbbeta3. Contrarily to other disintegrins that bind to a series of integrins via their Arg-Gly-Asp domain, the recognition site of barbourin contains a Lys-Gly-Asp sequence that ensures its specificity towards alphaIIbbeta3. In this article, a three-dimensional model of barbourin is proposed using homology modeling and large-scale molecular dynamics simulations. The conformations of the Lys-Gly-Asp sequence of barbourin are analyzed and compared to those of peptidomimetics that exhibit similar specificity towards alphaIIbbeta3. The tryptophan residue following the Lys-Gly-Asp sequence of the binding domain is shown to play a crucial role in the biological activity and the specificity of barbourin. Our results suggest that this disintegrin anchors to the binding pocket of the gamma-chain of fibrinogen rather than to those of the Arg-Gly-Asp sequence.

Amino Acid Sequence↗
PubMed2000

Increased calcium influx in a monocytic cell line on exposure to ultrafine carbon black.

Ultrafine particles have been shown to induce pro-inflammatory effects both in vivo and in vitro. Increased expression of pro-inflammatory genes probably requires the activation of specific transcription factors such as nuclear factor kappa B (NF-kappaB) via a number of possible pathways including Ca2+ and reactive oxygen species. The fluorescent dye fura 2, was used to measure cytosolic Ca2+ in the human monocytic cell line, Monomac 6 on exposure to 66 microg x mL(-1) of either ultrafine carbon black (ufCB; diameter 14 nm), carbon black (CB; diameter 260 nm), quartz (diameter 1.45 microm), or medium alone. UfCB but not fine CB induced a 1.6-fold increase (p<0.01) in the resting cytosolic Ca2+ concentration of Monomac 6 cells. In addition ufCB induced a 2.6-fold increase (p<0.001) in the response to the endoplasmic reticulum Ca2+- adenosine triphosphatase (ATPase) inhibitor, thapsigargin, suggesting the Ca2+ release-activated Ca2+ current across the plasma membrane was enhanced. This response was inhibited by the removal of extracellular Ca2+ and by the Ca2+ channel blocker, verapamil. In addition, ufCB stimulated the entry of extracellular Mn2+. Finally, the antioxidants mannitol and nacystelin both inhibited the effects of ufCB on the response to thapsigargin. These data suggest that ultrafine carbon black particles stimulated an increase in cytosolic Ca2+, possibly through the entry of extracellular Ca2+ via Ca2+ channels in the plasma membrane. The particles may in part activate the opening of Ca2+ channels via a mechanism involving reactive oxygen species.

Calcium↗