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N Brown

Publications and source records attributed to N Brown.

At least 19 recordsLinked to original sources
PubMed2001

An integrated physical map of 8q22-q24: use in positional cloning and deletion analysis of Langer-Giedion syndrome.

We have developed an integrated map for a 35-cM area of human chromosome 8 surrounding the Langer-Giedion syndrome deletion region. This map spans from approximately 8q22 to 8q24 and includes 10 hybrid cell intervals, 89 polymorphic STSs, 118 ESTs, and 37 known genes or inferred gene homologies. The map locations of 25 genes including osteoprotegerin, syndecan-2, and autotaxin have been refined from the general locations previously reported. In addition, the map has been used to indicate the location of nine deletions in patients with Langer-Giedion syndrome and trichorhinophalangeal syndrome type I to demonstrate the potential usefulness of the map in the analysis of these complex syndromes. The map will also be of interest to anyone trying to clone positionally disease genes in this region, such as Cohen syndrome (8q22-q23), Klip-Feil syndrome (8q22.2), hereditary spastic paraplegia (8q24), and benign adult familial myoclonic epilepsy (8q23.3-q24.1).

Child↗
PubMed2001

Comparative analysis of reproductive cycles in female Persian gazelle (Gazella subgutturosa subgutturosa) (Central Asia) and sand gazelle (Gazella subgutturosa marica) (Arabian Peninsula).

This study was conducted at the Bukhara breeding centre (Ouzbekistan, Central Asia) on Persian gazelles (Gazella subgutturosa subgutturosa) and at Thumammah (Saudi Arabia) on sand gazelles (Gazella subgutturosa marica). Plasma prolactin (PRL) and progesterone were determined in groups of females. Because these females were under two different photoperiods (20 degrees N in Saudi Arabia and 40 degrees N in Uzbekistan), some Persian females were treated with melatonin implants. Both groups of females living in natural environment in Uzbekistan and in Saudi Arabia exhibited an estrus (autumn and early winter) and an anestrus season (spring and summer). Both groups of females exhibited estrous and anestrous seasons. The estrous season was shorter in females from Uzbekistan. During the anestrous season, progesterone concentrations remained at basal levels in Persian gazelles (Uzbekistan) while in sand gazelles (Saudi Arabia) hormonal concentrations were higher than in Persian gazelles until August and decreased to similar concentrations in September-October. Moreover, the pattern of PRL significantly differed in the two groups. Persian gazelles exhibited a clear seasonal pattern with significantly high levels of PRL in June whereas in the sand gazelle PRL did not rise significantly in summer and fluctuated widely. Melatonin treatment significantly depressed PRL concentrations but did not affect the length of the estrous season in Persian gazelles, suggesting that the reproductive cycle was entrained by an endogenous rhythm.

Anestrus↗
PubMed2001

A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B.

Seventy-seven liver transplant candidates were enrolled in a multicenter study in which patients were treated with lamivudine (100 mg daily) without the adjunctive use of hepatitis B immune globulin. Treatment was begun while patients awaited liver transplantation and continued after transplantation. All were hepatitis B surface antigen (HBsAg) positive, and 61% had detectable hepatitis B e antigen (HBeAg) and HBV DNA when treatment was begun. Forty-seven underwent liver transplantation and 30 did not. Median study participation was 38 months (range, 2.7-48.5) in the transplanted patients and 26 months (range, 0.1-37) in the nontransplanted group. Twenty-five of 42 (60%) transplanted patients with 12 or more weeks of posttransplantation follow-up were HBsAg negative at the last study visit. At treatment week 156, 13 of 22 (59%) remained HBsAg negative, and all 9 reinfected patients were HBV-DNA positive before treatment. In the nontransplanted patients, HBeAg was initially detectable in 20 of 27 (74%) but this decreased to 3 of 17 (18%) after 104 weeks of treatment, and significant improvement in biochemical parameters was observed. HBV-DNA polymerase mutants were detected in 15 (21%) and 6 (20%) of the transplanted and nontransplanted patients, respectively. When compared with historical cohorts, lamivudine-treated patients appeared to have improved survival, and transplanted patients had a decrease in the rate of recurrent HBV infection. Lamivudine therapy was partially effective in preventing recurrent HBV infection when given before and after transplantation. Thus, future trials using a combination of HBIg and lamivudine are needed to assess the optimal prophylactic therapy.

Adult↗
PubMed2000

Coordinated regulation of fetal and maternal prostaglandins directs successful birth and postnatal adaptation in the mouse.

Cyclooxygenase (COX)-derived prostaglandins (PGs) regulate numerous maternal-fetal interactions during pregnancy. PGs stimulate uterine contractions and prepare the cervix for parturition, whereas in the fetus, PGs maintain patency of the ductus arteriosus (DA), a vascular shunt that transmits oxygenated placental blood to the fetal systemic circulation. However, the origin and site of action of these PGs remain undefined. To address this, we analyzed mice lacking COX-1 (null mutation) or COX-2 (pharmacologic inhibition) or pups with a double null mutation. Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that COX-1(-/-) females experience parturition failure that is reversible by exogenous PGs. Using embryo transfer experiments, we also show that successful delivery occurs in COX-1(-/-) recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition. Although patency of the DA is PG dependent, neither COX-1 nor COX-2 expression was detected in the fetal or postnatal DA, and offspring with a double null mutation died shortly after birth with open DAs. These results suggest that DA patency depends on circulating PGs acting on specific PG receptors within the DA. Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor.

Adaptation, Physiological↗
PubMed2000

An investigation of the rigor of interpretation rules for STRs derived from less than 100 pg of DNA.

By increasing the PCR amplification regime to 34 cycles, we have demonstrated that it is possible routinely to analyse <100 pg DNA. The success rate was not improved (without impairing quality) by increasing cycle number further. Compared to amplification of 1 ng DNA at 28 cycles, it was shown that increased imbalance of heterozygotes occurred, along with an increase in the size (peak area) of stutters. The analysis of mixtures by peak area measurement becomes increasingly difficult as the sample size is reduced. Laboratory-based contamination cannot be completely avoided, even when analysis is carried out under stringent conditions of cleanliness. A set of guidelines that utilises duplication of results to interpret profiles originating from picogram levels of DNA is introduced. We demonstrate that the duplication guideline is robust by applying a statistical theory that models three key parameters - namely the incidence of allele drop-out, laboratory contamination and stutter. The advantage of the model is that the critical levels for each parameter can be calculated. This information may be used (for example) to determine levels of contamination that can be tolerated within the strategy employed. In addition we demonstrate that interpreting one banded loci, where allele dropout could have occurred, using LR=1/2f(a) was conservative provided that the band was low in peak area. Furthermore, we demonstrate that an apparent mis-match between crime-stain and a suspect DNA profile does not necessarily result in an exclusion. The method used is complex, yet can be converted into an expert system. We envisage this to be the next step.

Alleles↗
PubMed2000

Suppression of atrial myosin gene expression occurs independently in the left and right ventricles of the developing mouse heart.

Many cardiac genes are broadly expressed in the early heart and become restricted to the atria or ventricles as development proceeds. Additional transcriptional differences between left and right compartments of the embryonic heart have been described recently, in particular for a number of transgenes containing cardiac regulatory elements. We now demonstrate that three myosin genes which become transcriptionally restricted to the atria between embryonic day (E) 12.5 and birth, alpha-myosin heavy chain (MHC), myosin light chain (MLC) 1A and MLC2A, are coordinately downregulated in the compact myocardium of the left ventricle before that of the right ventricle. alpha-MHC protein also accumulates in the right, but not left, compact ventricular myocardium during this period, suggesting that this transient regionalization contributes to fktal heart function. dHAND and eHAND, basic helix-loop-helix transcription factors known to be expressed in the right and left ventricles respectively at E10. 5, remain regionalized between E12.5 and E14.5. Downregulation of alpha-MHC, MLC1A, and MLC2A in iv/iv embryos, which have defective left/right patterning, initiates in the morphological left (systemic) ventricle regardless of its anatomical position on the right or left hand side of the heart. This points to the importance of left/right ventricular differences in sarcomeric gene expression patterns during fktal cardiogenesis and indicates that these differences originate in the embryo in response to anterior-posterior patterning of the heart tube rather than as a result of cardiac looping. Dev Dyn 2000;217:75-85.

Animals↗
PubMed2000

Fatal Mycobacterium bovis BCG infection in TNF-LT-alpha-deficient mice.

Neutralization of TNF or disruption of TNF-R1 leads to fatal Mycobacterium bovis BCG infection. Here we used TNF-LT-alpha-deficient mice to test whether a complete disruption of TNF and LT-alpha reduces further host resistance to BCG infection. The bacterial burden especially in the lungs of TNF-LT-alpha-deficient mice was significantly increased and the mice succumbed to infection between 8 and 10 weeks. In the absence of TNF-LT-alpha the granulomatous response was severely impaired and delayed. The cells in the granulomas of TNF-LT-alpha-deficient mice expressed low levels of MHC class II and ICAM-1. They contained a few T cells and F4/80-positive macrophages expressing little iNOS and acid phosphatase activity. By contrast, the lethal action of endotoxin was dramatically reduced in BCG-infected TNF-LT-alpha-deficient mice. In summary, in the absence of TNF-LT-alpha the recruitment and activation of mononuclear cells in response to BCG infection were significantly delayed and reduced resulting in immature granulomas allowing uncontrolled fatal infection.

Animals↗
PubMed2000

Oral uracil and Ftorafur plus leucovorin: pharmacokinetics and toxicity in patients with metastatic cancer.

PURPOSE: To assess the pharmacokinetics of Ftorafur (tegafur, FT), 5-fluorouracil (5-FU), and uracil in 31 cancer patients who were enrolled in phase I studies of oral uracil and FT (UFT). The correlation between pharmacokinetic parameters and toxic effects of UFT was evaluated. METHODS: Uracil and FT were orally administered in a 4:1 molar ratio at FT doses of 200-400 mg/m2 per day. Patients also received leucovorin at 150 mg/day. Daily doses were divided into three doses and administered at 8-h intervals for 28 consecutive days. Plasma FT concentrations were measured by high-performance liquid chromatography, and plasma 5-FU and uracil concentrations were determined using gas chromatography-mass spectrometry. National Institutes of Health Common Toxicity Criteria were used for assessment of toxicity. RESULTS: The concentrations of FT, 5-FU, and uracil showed wide interpatient variations. Maximum plasma concentrations (Cp(max)) of all three compounds were achieved in 0.3 to 4.0 h. At the various study doses, the terminal half-life (t 1/2beta) of FT ranged from 3.9 to 5.9 h, the area under the concentration-versus-time curve (AUC0-6h) ranged from 16,220 to 52,446 (ng/ml)h, the total clearance (ClT) ranged from 100 to 175 ml/min, and the steady-state volume of distribution (Vd(ss)) ranged from 18.3 to 28.7 l. The 5-FU generated from FT had an apparent distribution half-life (t 1/2alpha) and an apparent elimination half-life (t 1/2beta) of 0.3-1.3 h and 4.9-7.0 h, respectively. The AUC0-6h of 5-FU ranged from 120 to 325 (ng/ml)h. Uracil had a t 1/2alpha of 0.2-0.5 h and the level quickly returned to the endogenous level. The AUC0-6h for uracil ranged from 605 to 3764 (ng/ml)h, the ClT ranged from 3225 to 7748 ml/min, and the Vd(ss) ranged from 341 to 1354 l. The Cp(max) and AUC0-6h of both FT and uracil were significantly correlated with FT doses (P-values of 0.0244 and 0.0112) and with uracil doses (P-values of 0.0346 and 0.0083), respectively. In addition to interpatient variations, intrapatient variations were also observed in six patients who had pharmacology studies done on days 1 and 26+/-2 at the same study dose. We found that the repeated treatment with UFT caused cumulative increases in the values of Cp(max), Ctrough, and AUC0-6h of FT and 5-FU. The major toxic effects observed were diarrhea and nausea and vomiting. The occurrence of these toxic effects correlated significantly with the Cp(max) and AUC0-6h of 5-FU. CONCLUSIONS: The pharmacology studies showed that FT and uracil were readily absorbed orally and that FT was rapidly converted to 5-FU. The preliminary findings suggest that determination of plasma levels of 5-FU after oral administration of UFT may help predict subsequent toxic effects.

Tegafur↗
PubMed2000

The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.

Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.

Connexins↗
PubMed2000

The bottom line: the effect of written expert witness statements on juror verdicts and information processing.

Mock jurors recruited from jury rolls were either not given written statements of expert witnesses' direct testimony or were provided with such statements before or after the presentation of that testimony. Presentation of the statements before the testimony and cross-examination provided jurors with a schema that allowed them to distinguish more effectively among the claims of four differentially worthy plaintiffs because they processed more probative evidence than other jurors. Jurors in receipt of written statements before the testimony found the evidence to be more comprehensible than other jurors. Jurors provided with written statements following testimony and cross-examination were able to differentiate between the most and least severely injured plaintiffs, whereas jurors not in receipt of any written statements were unable to differentiate among any of the differentially worthy claimants. The limitations of this case management technique and of the study are discussed.

Adult↗
PubMed2000

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

Allosteric Site↗
PubMed2000

Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences.

Single-nucleotide polymorphisms (SNPs) have been explored as a high-resolution marker set for accelerating the mapping of disease genes. Here we report 48,196 candidate SNPs detected by statistical analysis of human expressed sequence tags (ESTs), associated primarily with coding regions of genes. We used Bayesian inference to weigh evidence for true polymorphism versus sequencing error, misalignment or ambiguity, misclustering or chimaeric EST sequences, assessing data such as raw chromatogram height, sharpness, overlap and spacing, sequencing error rates, context-sensitivity and cDNA library origin. Three separate validations-comparison with 54 genes screened for SNPs independently, verification of HLA-A polymorphisms and restriction fragment length polymorphism (RFLP) testing-verified 70%, 89% and 71% of our predicted SNPs, respectively. Our method detects tenfold more true HLA-A SNPs than previous analyses of the EST data. We found SNPs in a large fraction of known disease genes, including some disease-causing mutations (for example, the HbS sickle-cell mutation). Our comprehensive analysis of human coding region polymorphism provides a public resource for mapping of disease genes (available at http://www.bioinformatics.ucla.edu/snp).

Base Sequence↗
PubMed2000

Correction of defective host response to Mycobacterium bovis BCG infection in TNF-deficient mice by bone marrow transplantation.

Tumour necrosis factor-alpha (TNF) plays a central role in the recruitment and activation of mononuclear cells in mycobacterial infection. In the absence of type 1 TNF receptor, Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection of mice is not contained, leading to fatal disease. Because type 1 TNF receptor binds both TNF and lymphotoxin-a, we used TNF-deficient mice to determine the specific role of TNF in the host resistance to BCG infection. The bacterial burden of the lungs of TNF-deficient mice was substantially increased and the mice succumbed to pneumonia between 8 and 12 weeks with a defective granuloma response. Atypical granulomas developed by 4 weeks expressing low levels of MHC class II, intracellular adhesion molecule (ICAM-1), CD11b and CD11c. Macrophages showed little signs of activation and had low levels of acid phosphatase activity and inducible nitric oxide synthase (INOS) expression. Despite the defective cellular recruitment, the chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1alpha), were increased in broncho-alveolar lavage fluid of TNF-deficient mice. The defective host response was corrected by the transplantation of normal bone marrow cells into irradiated TNF-deficient mice. These results demonstrate that TNF derived from hemopoietic cells rather than from mesenchymal origin are essential for a normal host response to BCG infection. Furthermore, TNF dependent expression of adhesion molecules may be essential for the recruitment of mononuclear cells for the formation of bactericidal BCG granulomas.

Acid Phosphatase↗
PubMed2000

Increased resistance to mycobacterial infection in the absence of interleukin-10.

Interleukin-10 (IL-10) down-regulates T helper type 1 cell and macrophage functions. As IL-10 is induced along with tumour necrosis factor (TNF) and IL-12 in mycobacterial infection, we asked whether endogenous IL-10 plays a role in the antimycobacterial response. We demonstrate here that IL-10-deficient mice eliminate Mycobacterium bovis Calmette-Guérin bacillus faster than wild-type mice. Granulomas are significantly larger, containing more CD-11b- and CD11c-positive antigen-presenting cells and T cells, and the expression of major histocompatibility complex class II and intracellular adhesion molecule-1 is increased. Macrophages in granulomas of IL-10-deficient mice express high levels of TNF, acid phosphatase and inducible nitric oxide synthase (iNOS). Finally, an increased cutaneous delayed-type hypersensitivity reaction to mycobacterial proteins is further evidence of an augmented cell-mediated immune response. In conclusion, the cell-mediated immunity is enhanced in the absence of IL-10, resulting in a robust granuloma response, which accelerates the clearance of mycobacteria. Therefore, endogenous IL-10 attenuates mycobacterial immunity.

Animals↗
PubMed2000

Mental health service user involvement in nurse education: exploring the issues.

This paper reports on findings and issues arising from a study designed to promote mental health service users' involvement in a preregistration nursing curriculum. Users' views about the knowledge, skills and attributes required by mental health nurses were explored to inform the curriculum design. Strategies that would facilitate long term, active user involvement in the design and delivery of the curriculum were also explored. Findings are presented with concurrent discussion of issues arising from the research process in relation to user involvement in education. The issue of 'conflict' explores findings relating to users' views of a 'good' mental health nurse and inherent conflicts between user and professional views are highlighted. The representativeness of the research participants is explored and debated in relation to service user involvement in nurse education. Finally, the concepts of 'involvement' and 'tokenism' are discussed and recommendations made about how active user involvement in nurse education can be achieved.

Curriculum↗
PubMed2000

Mortality of patients admitted with a suspected acute myocardial infarction in whom the diagnosis is not confirmed.

AIMS: To examine the survival of patients admitted with a suspected acute myocardial infarction in whom the diagnosis was not confirmed ('possible myocardial infarction'). METHODS AND RESULTS: A cohort study based on the Nottingham Heart Attack Register of 1716 sequential patients discharged alive from two acute teaching hospitals following admission in 1992. The main outcome was mortality following hospital discharge after 5 years of follow-up. Survival of the cohort of patients in whom myocardial infarction was suspected but not confirmed was 58% (95% C.I. 56 to 60%) after 5 years of follow-up, compared with an expected survival of 76% in an age/sex matched general population. Patients with ECG abnormalities that were not diagnostic of myocardial infarction had a 5-year survival of 56%, compared with 77% in those without such changes (P<0.00001). In the 703 patients who died in the first 5 years of follow-up, the cause of death was cardiovascular in at least 53% of cases. Survival following hospital discharge was worse than that in patients discharged alive in the same year following a confirmed myocardial infarction (63% vs 69% after 4 years of follow-up P=0.0016). CONCLUSION: Patients in this study had a substantially increased risk of death in the 5 years after discharge from hospital, compared with an age- and sex-matched population, and worse than patients discharged following a confirmed myocardial infarction. Almost half of those with ECG changes at the time of their admission died over the next 5 years. As over half of all deaths in this cohort were due to cardiovascular causes, further work is needed to identify patients at high and low risk of subsequent mortality who may warrant investigation and treatment following hospital discharge.

Aged↗
PubMed2000

Relationship of vascular maturation in breast cancer blood vessels to vascular density and metastasis, assessed by expression of a novel basement membrane component, LH39.

Angiogenesis, the formation of new vessels, has been demonstrated to be an indicator of prognosis in breast cancer patients. The extent of differentiation of the tumour vessels may affect access of peripheral white cells and egress or invasion of tumour cells. This has not been assessed in relation to tumour microvessel density or other variables and may be a marker of vascular remodelling. LH39 is a monoclonal antibody recognizing an epitope located at the lamina lucida of mature small veins and capillaries but not in newly formed vessels. To study vascular differentiation in breast tumours, we examined the vascular maturation index (VMI) in 12 normal and 50 breast carcinomas and this was correlated with different clinicopathological variables including angiogenesis. Mature vessels were defined by staining with antibodies to both LH39 and to CD31, using double immunohistochemistry, whereas immature vessels stained only for CD31. VMI was defined as the % fraction of mature vessels (LH39-positive) / total number of vessels (CD31-positive). The VMI was significantly higher in normal (54-68.5%; median 66.5%) than in tumours (0-47%; median 8.8%) (P = 0.0005). There was a significant inverse correlation between the tumour VMI and nodal status (Fisher's exact test, P = 0.01) and between high VMI and low thymidine phosphorylase (TP) expression (Mann-Whitney U-test, P= 0.01). No significant association between VMI and tumour size, oestrogen receptor, epidermal growth factor receptor, grade, angiogenesis, patient age, or E-selectin was seen. There was a significant reduction in relapse-free survival (P = 0.01) with high angiogenesis. These findings show that the VMI gives new information on the mechanism of tumour angiogenesis independently from microvessel quantitation, there is a wide variation in the differentiation of tumour vasculature but the degree of capillary differentiation is not associated with quantitative angiogenesis. The VMI identifies a subset of patients who have a high chance of regional node involvement.

Adult↗