Bruce Bennetts - Academia.edu (original) (raw)

Papers by Bruce Bennetts

American Journal of Obstetrics and Gynecology, 1996

OBJECTIVE: The levels of interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-... more OBJECTIVE: The levels of interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-lO, and granulocyte-macmphage colony-stimulating factor were measured in the peritoneal fluid of 15 patients with endometriosis to characterize the type of immune response that occurs at the site of endometriosis. STUDY DESIGN: Cytokine levels in peritoneal fluid obtained during laparoscopy from 15 patients and 12 controls undergoing tubal ligation were determined by enzyme-linked immunosorbent assay. RESULTS: The mean levels of interleukin-6 in patients with enclometriosis and controls were 797 _+ 407 pg/ml and 133 + 38 pg/ml, respectively (p < 0.02). Similarly, the mean concentration of interleukin-10 in peritoneal fluids of patients with endometriosis was significantly higher than that of controls (241 + 38 vs 128 + 21, p < 0.05). The levels of interleukin-2, interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor were not significantly different between the two study groups. CONCLUSIONS: The levels of interleukin-6 and interleukin-10 are increased in the peritoneal fluids of patients with endometriosis, suggesting enhanced macrophage activity in these patients. Increased interleukin-6 and interleukin-10 production may partially contribute to the disturbed immune regulation observed in patients with endometriosis. (AM J OBSTF GYNEOOL 1996;174:1522-6.)

Trends in Pharmacological Sciences, 1994

The organic nitrates are interesting examples of drugs that undergo biotransformation at their si... more The organic nitrates are interesting examples of drugs that undergo biotransformation at their site of action to generate the active form of the drug. Furthermore, tolerance to the vasodilator effects of organic nitrates is associated with impairment of this metabolic activation process. Despite considerable research effort, the intracellular processes and the chemical reaction pathways by which organic nitrates are converted to their active form are still unresolved. This review by Brian Bennett and colleagues summarizes the characteristics of organic-nitrate biotransformation in vascular smooth muscle, the difficulties encountered when assessing this biotransformation, and the evidence for the role of two identified vascular biotransformation systems (glutathione-S-transferases and the cytochrome P450 system) in the metabolic activation of organic nitrates.

Journal of Clinical Investigation, 1972

A B S T R A C T Antihemophilic globulin (AHF, factor VIII) levels were measured by a standard coa... more A B S T R A C T Antihemophilic globulin (AHF, factor VIII) levels were measured by a standard coagulation assay and by an immunological technique before and serially after infusion of fresh frozen plasma or cryoprecipitate into patients with von Willebrand's disease. Initial levels of AHF, measured both as procoagulant and as antigen, were low. Immediately after transfusions, the rise in levels of AHF-like antigen was compatible with the quantity of antigen present in the infused plasma or cryoprecipitate. Thereafter, levels of antigen declined rapidly and reached preinfusion values in approximately 24 hr. In contrast, procoagulant activity remained elevated, and sometimes continued to rise, for longer periods of time. One possible explanation of this finding is that the AHF molecule produced by patients with von Willebrand's disease, in response to transfusion of as yet unidentified factors, lacks the antigenic site associated with the normal AHF molecule or the inactive molecule produced by patients with hemophilia A.

Brain Research, 1993

Previous observations have shown that the striatum contains a population of neurones that display... more Previous observations have shown that the striatum contains a population of neurones that display immunoreactivity for calretinin. In order to morphologically characterize these neurones, sections of the rat striatum were immunostained to reveal calretinin and examined at both light and electron microscopic levels. The striatum contained a small population of calretinin-immunoreactive neurones, which were of medium-size (9-17 microns) and possessed few aspiny, infrequently branching dendrites which tapered to become very thin processes in their most distal portions. Although the calretinin-immunoreactive neurones were homogeneously distributed in the frontal plane, there was a marked rostrocaudal gradient with a much greater density of cells in the rostral than in the caudal parts of the striatum. At the ultrastructural level, calretinin-immunoreactive neurones were seen to possess an indented nucleus and to receive synaptic input from at least three types of boutons. In addition to the calretinin-immunoreactive neurones, the striatum also contained axons and terminal boutons that displayed immunoreactivity for calretinin. At least two types of immunoreactive terminals were identified, those forming symmetrical synaptic specialisations and those forming asymmetrical synaptic specialisations. Approximately 50% formed asymmetrical contacts with spines and 30% formed symmetrical synaptic contact with dendritic shafts. In an attempt to further chemically characterize the calretinin-containing neurones, double pre-embedding immunocytochemistry for calretinin and parvalbumin or choline acetyltransferase was carried out and calretinin immunocytochemistry was combined with histochemistry for NADPH-diaphorase. Analysis of these double-stained sections revealed that the population of calretinin-immunoreactive neurones was distinct from the populations of neurones containing parvalbumin, choline acetyltransferase or NADPH-diaphorase. It is concluded that: (1) on the basis of distribution, morphology, chemistry, ultrastructure and afferent synaptic input, the calretinin-immunoreactive neurones are distinct from the major classes of neurones that have been previously recognised in the striatum; (2) calretinin-immunoreactive terminals are heterogeneous and are probably derived from local calretinin-containing neurones and possibly other sources.

American Journal of Medical Genetics, 2003

Rett syndrome (RTT) is a clinically defined disorder that describes a subset of patients with mut... more Rett syndrome (RTT) is a clinically defined disorder that describes a subset of patients with mutations in the X-linked MECP2 gene. However, there is a high degree of variability in the clinical phenotypes produced by mutations in MECP2, even amongst classical RTT patients. In a large-scale screening project, this variability has been examined by looking at the effects of mutation type, functional domain affected and X-inactivation. Mutations have been identified in 60% of RTT patients in this study (25% of whom were atypical), including 23 novel mutations and polymorphisms. More mutations were found in classical patients (63%) compared to atypical patients (44%). All of the pathogenic mutations were de novo in patients for whom parent DNA was available for screening. A composite phenotype score was developed, based on the recommendations for reporting clinical features in RTT of an international collaborative group. This score proved useful for summarising phenotypic severity, but did not correlate with mutation type, domain affected or X-inactivation, probably due to complex interactions between all three. Other correlations suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain tend to lead to a more severe phenotype. Skewed X-inactivation was found in a large proportion (43%) of our patients, particularly in those with truncating mutations and mutations affecting the MBD. It is therefore likely that X-inactivation does modulate the phenotype in RTT. © 2003 Wiley-Liss, Inc.

American Journal of Human Genetics, 2004

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mut... more Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1GrA, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps-but is not identical to-that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

Human Immunology, 1997

Recent advances in the understanding and identification of chemokines and their receptors have pr... more Recent advances in the understanding and identification of chemokines and their receptors have provided evidence for their consideration as candidate loci with respect to genetic susceptibility/resistance to MS. Increased levels of the chemokine, macrophage inflammatory protein (MIP)-1␣, have been demonstrated in the cerebrospinal fluid of both patients with MS and mice with EAE, and anti-MIP-1␣ antibodies have been shown to prevent EAE.

European Journal of Human Genetics, 2003

We have investigated the interleukin-7 receptor (IL-7R) a-chain gene as a positional and function... more We have investigated the interleukin-7 receptor (IL-7R) a-chain gene as a positional and functional candidate gene for susceptibility to multiple sclerosis (MS), in view of its chromosomal location on 5p14-p12, a region that has shown suggestive linkage in MS genome screens, and its role in T-and B-cell proliferation and reactivity. Amplification and DNA sequencing of the IL-7Ra gene in pooled and individual samples identified 13 single nucleotide polymorphisms (SNPs), 11 of which are novel, including three in the promoter region, three in exons encoding amino-acid changes (ACC(Thr)66ATC(Ile), ATC(Ile)244ACC(Thr), ATC(Ile)336GTC(Val)), four in introns and one in the 3 0 untranslated region. Four IL-7R haplotypes were identified for nine SNPs, showing linkage disequilibrium across the gene, and allowing haplotype frequency determination from just three of the nine SNPs. Genotyping of the À504 polymorphism in 101 MS and 90 controls showed a suggestive (P ¼ 0.1) association of the T allele with MS; however, this was not supported by transmission disequilibrium testing in 186 MS trio families (P ¼ 0.8). There were trends towards an increase of the GTG+ haplotype (odds ratio ¼ 1.45), and underrepresentation of the TTA+ haplotype (OR ¼ 0.65) in DRB1*1501-positive MS cases, suggesting that larger sample sizes and comparison in more defined MS patient groups may support an association with the IL-7R gene. These polymorphisms would also be useful for studying genetic associations with other immunologic diseases.

Nature Medicine, 1997

White II clone differed considerably from that of JRFL and contained substitutions found in strai... more White II clone differed considerably from that of JRFL and contained substitutions found in strains displaying the syncytium inducing (SI) phenotype. 3 Consensus V3 sequences are presented in the figure. Results obtained using a V3-specific heteroduplex mobility assay were consistent with the viral sequence data; virus in the 1986 sample was relatively homogeneous and substantially different from JRFL, consistent with an SI strain. SI strains do not require CCR5 and can use CXCR4 as a coreceptor. 4 The presence of SI strains may explain this individual's rapid loss of CD4 lymphocytes, as SI strains are more virulent than NSI strains and their presence may abrogate the clinical advantage of CCR5⌬32 heterozygosity. 5 None of twelve other CCR5⌬32 homozygotes identified from MHCS were HIV-1 infected. Furthermore, although that genotype occurs in only 1% of whites, 1 it was present in five (29%) of 17 MHCS individuals who remained HIV-1uninfected despite heavy blood product exposure. Thus, CCR5⌬32 homozygosity provides strong relative resistance to parenterally acquired HIV-1 infection. In this exceptional case, the subject appears to have been infected with an HIV-1 strain that can use an alternative coreceptor.

Dna and Cell Biology, 1987

A preliminary account of the isolation of the first human kallikrein genomic clone, )IHGKl, descr... more A preliminary account of the isolation of the first human kallikrein genomic clone, )IHGKl, described herein has been reporled in abstract form (Schedlich et al.,19841. I ABSTRACT To isolate a human glandular kallikrein gene, a human genomic library was screened with a probe made from a mouse kallikrein cDNA (pMK-l). Overlapping clones were obtained and nucleotide sequence deter' mination showed that they together contained a human glandular preprokallikrein gene, hGK-l' of 5.2 kb. The gene encoded a unique preproprotein of 261 amino acids. The sequence of the mature 237-amino-acid protein had 6690 homology with the sequence predicted for human kallikrein synthesized in the pancreas, kidney, and salivary gland. Moreover, it had even stronger homology (7890) with human prostate-specific antigen. The latter lacks an aspartic acid residue essential for kallikrein-specific cleavage, whereas the se' quence of this new protein had all of the attributes needed to confer kallikrein-like specificity. Southern blotting indicated that the number of glandular kallikrein genes in man could be limited to three, a situation very different from mouse and ral, which each have a large multigene family. Furthermore, unlike kallikrein genes in the mouse, hGK-l was not closely linked to other human kallikrein genes. In other respects lhe structure of the human kallikrein gene resembled that in mouse: coding sequences in the five exons were organized similarly, homology was higher with other members of the kallikrein gene family in the same species, and the three key amino acid residues required by serine proteases for their catalytic activity, together with the residue that confers kallikrein-specific cleavage, were conserved and located on different exons. Thus, if hGK-l is expressed, its product represents a new, and possibly the only other enzyme with true kalli-kreinJike specificity in man.