Biomedical subjects

R A Feldman

Publications and source records attributed to R A Feldman.

At least 19 recordsLinked to original sources

PubMed2006

Third-party prospective evaluation of patient outcomes after dynamic graciloplasty.

BACKGROUND: Dynamic graciloplasty (DGP) is a complex procedure designed to improve bowel function in patients with end-stage faecal incontinence. Outcomes of DGP were examined in comparison with stoma formation or continued medical management. METHODS: This third-party evaluation comprised a prospective case-comparison study of patient-based and clinical outcomes at a London hospital. Forty-nine patients who underwent DGP during 5 years from 1997 were compared with 87 patients with similar bowel disorders who did not undergo DGP. Outcome measures were quality of life (QoL), symptoms, anxiety and depression. RESULTS: At 2 years after surgery, bowel-related QoL and continence had improved by more than 20 per cent compared with the preoperative status for two-thirds of patients who had DGP (P < 0.001). Two-thirds were continent all or most of the time, although one-third experienced disordered bowel evacuation. Large deteriorations on the Nottingham Health Profile pain score occurred in 11 of 34 patients who had DGP, compared with seven of 57 patients in comparison groups (P = 0.027). Patients in comparison groups experienced no significant changes in measured outcomes over the 2 years of follow-up. CONCLUSION: Although DGP is associated with a high level of morbidity, it deserves consideration as an alternative to life with severe and refractory faecal incontinence or stoma formation in people in whom conventional treatments have failed.

Adolescent↗

PubMed2003

Altered expression of sulfotransferases, glucuronosyltransferases and mrp transporters in FVB/mrp1-/- mice.

1. Genetically altered mice increasingly are being used in toxicology and pharmaceutical development. As such, knowledge of the compensatory activity of enzymes is critical when interpreting the results of studies using these animals. 2. The present study examined alterations in hepatic phase I and II enzyme activity, and alterations in phase III (transporter) RNA expression, between FVB mice and mice lacking the multidrug resistance-associated protein 1 (mrp1) gene (FVB/mrp1-/- mice). It was hypothesized that other transporters and phase I and II enzymes would be increased in the FVB/mrp1-/- mice, presumably as a compensatory mechanism. 3. No differences was found in hepatic cytochrome P450 activity between FVB and FVB/mrp1-/- mice, nor were there differences in the amount of total hepatic glutathione or in glutathione S-transferase enzyme activity. 4. However, sulfotransferase activity towards 2-naphthol was significantly increased by 2.6-fold in the FVB/mrp1-/- mice, whereas glucuronosyltransferase activity towards both 4-nitrophenol and testosterone was significantly reduced 1.5-fold. In addition, mrp2 RNA expression was significantly increased by 3.4-fold and mrp5 expression was significantly increased by 1.6-fold in the FVB/mrp1-/- mice. 5. Mice lacking mrp1 have significantly increased hepatic transcription of at least two other ATP-binding cassette transporters, as well as increased 2-naphthol sulfotransferase activity, presumably to compensate for the lack of mrp1.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2002

Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO).

Phosphatidylinositol (PI) 3-kinase plays an important role in a variety of biological processes, including proliferation and apoptosis. PI3-kinase is a heterodimer consisting of an 85 kDa adapter protein (p85) containing one SH3 domain and two SH2 domains and a 110 kDa catalytic subunit (p110). Recently an oncogenic form of p85 named p65-PI3K lacking the C-terminal SH2 domain has been cloned from an irradiation-induced murine thymic lymphoma and transgenic mice expressing p65-PI3K in T lymphocytes develop a lymphoproliferative disorder. Here we describe the cloning of a C-terminal truncated form of p85 expressed in a human lymphoma cell line (CO) with a T cell phenotype derived from a patient with Hodgkin's disease. As a result of a frame-shift mutation at amino acid 636, p76 is lacking most of the C-terminal SH2 domain, but contains the inter-SH2 domain and is associated with an active form of PI3-kinase. A PI3-kinase-dependent constitutive activation of Akt was detected in CO cells which was only partially reduced after serum starvation. Treatment of CO cells with the PI3-kinase inhibitor wortmannin resulted in a concentration-dependent inhibition of cell proliferation associated with an increased number of apoptotic cells. This is the first detection of a mutated form of the p85 subunit of PI3-kinase in human hematopoietic cells further underlining a potential role of PI3-kinase/Akt signaling in human leukemogenesis.

Apoptosis↗

PubMed2002

Long-term antibody responses following human infection with Campylobacter jejuni.

Epidemiological evidence suggests prior infection of humans by Campylobacter jejuni leads to protection against disease following further exposure. It is known that infections elicit strong antibody responses following the onset of disease and that antibody levels are elevated in putatively immune populations. To determine if systemic and mucosal antibodies induced by a confirmed infection remain at elevated levels for prolonged periods, repeat serum, saliva and urine samples were taken from campylobacter patients from 1 week and up to a year postinfection. Antibodies were monitored by ELISAs using three different antigen preparations: acid-glycine extracts (AE) of C. jejuni strain 81116 and an aflagellate mutant (R2), and a whole-cell R2 sonicate, and by Western blotting. Levels of serum IgG antibodies against 81116AE and R2 sonicate, but not R2AE, remained significantly raised over time when compared to a comparison population. Serum anti-sonicate IgA antibody levels were initially significantly raised but decreased over time to levels similar to the comparison group. There were no significant differences in levels of salivary IgA against the AEs. Anti-sonicate salivary IgA and IgG levels were initially significantly higher than in the comparison group. Both declined over time but the IgG levels remained significantly higher. Significant correlations were seen between serum IgG levels and age and duration of illness. Serum antibodies against flagellin, 40 kDa and 29 kDa antigens were still detectable in most patients up to a year postinfection, as were salivary antibodies to flagellin, the major outer-membrane protein and a 40 kDa antigen.

Adolescent↗

PubMed2001

Assessment of the efficacy and safety of Viagra (sildenafil citrate) in men with erectile dysfunction during long-term treatment.

Long-term efficacy and safety of sildenafil was assessed in 1008 patients with erectile dysfunction (ED) enrolled in four flexible-dose (25 - 100 mg), open-label, 36- or 52-week extension studies. After 36 and 52 weeks, 92% and 89% of patients felt that treatment with sildenafil had improved their erections. Responses to a Sexual Function Questionnaire indicated that 52 weeks of sildenafil treatment resulted in clinically significant improvements in the duration and firmness of erections, overall satisfaction with sex life, and the frequency of stimulated erections. Commonly reported adverse events (AEs) were headache, flushing, dyspepsia, and rhinitis, which were generally mild to moderate. Reports of abnormal vision were consistent with previous clinical trials. The occurrence of treatment-related cardiovascular AEs, such as hypertension, tachycardia, and palpitation, was <1%. Discontinuations due to treatment-related AEs were low (2%). Long-term therapy does not diminish the efficacy of sildenafil in patients with ED and remains well tolerated.

Administration, Oral↗

PubMed2001

Review article: would eradication of Helicobacter pylori infection reduce the risk of gastric cancer?

This article reviews the data on the epidemiology of gastric cancer, to determine if treatment of an asymptomatic individual can be justified. It reviews retrospective and prospective case-control studies of gastric cancer in Italy and other countries. Mucosa-associated lymphoid tissue lymphoma is associated with Helicobacter pylori infection. The risk of noncardia gastric cancer is higher (4-fold or greater) in those with H. pylori infection. Although no studies have shown prevention following treatment, eradication of asymptomatic H. pylori infection in an individual in the age group 40 or lower may be expected to reduce the risk of gastric cancer.

Case-Control Studies↗

PubMed2001

Health care and social work education in a changing world.

This article examines two major challenges that beset contemporary social work education, namely, rapid and dramatic macro-level changes that are occurring in the social, political, economic and demographic realms and, also, the slow speed at which curriculum changes occur in institutions of higher education. Primarily employing managed care as an example, a series of recommendations are offered to improve social work education concerning health care. Among them are more efficient mechanisms for introducing curriculum changes, greater emphasis on research and evaluations skills, systematic monitoring of health care programs, preparation of public impact reports, better utilization of modern information technologies, and the introduction of mini-courses that can be adapted readily to emerging health care and educational needs.

Curriculum↗

PubMed2001

Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis.

Infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is necessary for the development of KS. The HHV-8 lytic-phase gene ORF74 is related to G protein-coupled receptors, particularly interleukin-8 (IL-8) receptors. ORF74 activates the inositol phosphate/phospholipase C pathway and the downstream mitogen-activated protein kinases, JNK/SAPK and p38. We show here that ORF74 also activates NF-kappaB independent of ligand when expressed in KS-derived HHV-8-negative endothelial cells or primary vascular endothelial cells. NF-kappaB activation was enhanced by the chemokine GROalpha, but not by IL-8. Mutation of Val to Asp in the ORF74 second cytoplasmic loop did not affect ligand-independent signaling activity, but it greatly increased the response to GROalpha. ORF74 upregulated the expression of NF-kappaB-dependent inflammatory cytokines (RANTES, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Supernatants from transfected KS cells activated NF-kappaB signaling in untransfected cells and elicited the chemotaxis of monocytoid and T-lymphoid cells. Expression of ORF74 conferred on primary endothelial cells a morphology that was strikingly similar to that of spindle cells present in KS lesions. Taken together, these data, demonstrating that ORF74 activates NF-kappaB and induces the expression of proangiogenic and proinflammatory factors, suggest that expression of ORF74 in a minority of cells in KS lesions could influence uninfected cells or latently infected cells via autocrine and paracrine mechanisms, thereby contributing to KS pathogenesis.

Cells, Cultured↗

PubMed2001

Molecular evidence that Sclerolinum brattstromi is closely related to vestimentiferans, not to frenulate pogonophorans (Siboglinidae, Annelida).

Siboglinids, previously referred to as pogonophorans, have typically been divided into two groups, frenulates and vestimentiferans. Adults of these marine protostome worms lack a functional gut and harbor endosymbiotic bacteria. Frenulates usually live in deep, sedimented reducing environments, and vestimentiferans inhabit hydrothermal vents and sulfide-rich hydrocarbon seeps. Taxonomic literature has often treated frenulates and vestimentiferans as sister taxa. Sclerolinum has traditionally been thought to be a basal siboglinid that was originally regarded as a frenulate and later as a third lineage of siboglinids, Monilifera. Evidence from the 18S nuclear rDNA gene and the 16S mitochondrial rDNA gene presented here shows that Sclerolinum is the sister clade to vestimentiferans although it lacks the characteristic morphology (i.e., a vestimentum). The rDNA data confirm the contention that Sclerolinum is different from frenulates, and further supports the idea that siboglinid evolution has been driven by a trend toward increased habitat specialization. The evidence now available indicates that vestimentiferans lack the molecular diversity expected of a group that has been argued to have Silurian or possibly Cambrian origins.

Animals↗

PubMed2000

Bacterial rhodopsin: evidence for a new type of phototrophy in the sea.

Extremely halophilic archaea contain retinal-binding integral membrane proteins called bacteriorhodopsins that function as light-driven proton pumps. So far, bacteriorhodopsins capable of generating a chemiosmotic membrane potential in response to light have been demonstrated only in halophilic archaea. We describe here a type of rhodopsin derived from bacteria that was discovered through genomic analyses of naturally occuring marine bacterioplankton. The bacterial rhodopsin was encoded in the genome of an uncultivated gamma-proteobacterium and shared highest amino acid sequence similarity with archaeal rhodopsins. The protein was functionally expressed in Escherichia coli and bound retinal to form an active, light-driven proton pump. The new rhodopsin exhibited a photochemical reaction cycle with intermediates and kinetics characteristic of archaeal proton-pumping rhodopsins. Our results demonstrate that archaeal-like rhodopsins are broadly distributed among different taxa, including members of the domain Bacteria. Our data also indicate that a previously unsuspected mode of bacterially mediated light-driven energy generation may commonly occur in oceanic surface waters worldwide.

Aerobiosis↗

PubMed2000

Neutral and nonneutral mitochondrial genetic variation in deep-sea clams from the family vesicomyidae.

Nucleotide sequences at two mitochondrial genes from 57 individuals representing eight species of deep-sea clams (Vesicomyidae) were examined for variation consistent with the neutral model of molecular evolution. One gene, cytochrome oxidase subunit I (COI), deviated from the expectations of neutrality by containing an excess of intraspecific nonsynonymous polymorphism. Additionally, one species, Calyptogena kilmeri, showed a significant excess of rare polymorphism specifically at the COI locus. In contrast, a second mitochondrial gene, the large-subunit 16S ribosomal RNA gene (16S), showed little deviation from neutrality either between or within species. Together, COI and 16S show no deviation from neutral expectations by the HKA test, produce congruent phylogenetic relationships between species, and show correlated numbers of fixed differences between species and polymorphism within species. These patterns of both neutral and nonneutral evolution within the mitochondrial genome are most consistent with a model where intraspecific nonsynonymous polymorphism at COI is near neutrality. In addition to examining the forces of molecular evolution, we extend hypotheses about interspecific relationships within this family for geographical locations previously unexamined by molecular methods including habitats near the Middle Atlantic, the Aleutian Trench, and Costa Rica.

Animals↗

PubMed2000

Abnormal Stat activation, hematopoietic homeostasis, and innate immunity in c-fes-/- mice.

The c-fes protooncogene encodes a nonreceptor tyrosine kinase (Fes) implicated in cytokine receptor signal transduction, neutrophil survival, and myeloid differentiation. To determine the role of Fes in embryonic development and hematopoiesis, we engineered a null mutation of the murine c-fes locus. c-fes-/- mice are viable but not born in the expected Mendelian ratios. Live born c-fes-/- mice exhibit lymphoid/myeloid homeostasis defects, compromised innate immunity, and increased Stat activation in response to GM-CSF and IL-6 signaling. Therefore, increased cytokine responsiveness in the absence of Fes leads to abnormal myeloid proliferation and functional defects in the macrophage lineage.

Animals↗

PubMed2000

Construction and analysis of bacterial artificial chromosome libraries from a marine microbial assemblage.

Cultivation-independent surveys of ribosomal RNA genes have revealed the existence of novel microbial lineages, many with no known cultivated representatives. Ribosomal RNA-based analyses, however, often do not provide significant information beyond phylogenetic affiliation. Analysis of large genome fragments recovered directly from microbial communities represents one promising approach for characterizing uncultivated microbial species better. To assess further the utility of this approach, we constructed large-insert bacterial artificial chromosome (BAC) libraries from the genomic DNA of planktonic marine microbial assemblages. The BAC libraries we prepared had average insert sizes of 80 kb, with maximal insert sizes > 150 kb. A rapid screening method assessing the phylogenetic diversity and representation in the library was developed and applied. In general, representation in the libraries agreed well with previous culture-independent surveys based on polymerase chain reaction (PCR)amplified rRNA fragments. A significant fraction of the genome fragments in the BAC libraries originated from as yet uncultivated microbial species, thought to be abundant and widely distributed in the marine environment. One entire BAC insert, derived from an uncultivated, surface-dwelling euryarchaeote, was sequenced completely. The planktonic euryarchaeal genome fragment contained some typical archaeal genes, as well as unique open reading frames (ORFs) suggesting novel function. In total, our results verify the utility of BAC libraries for providing access to the genomes of as yet uncultivated microbial species. Further analysis of these BAC libraries has the potential to provide significant insight into the genomic potential and ecological roles of many indigenous microbial species, cultivated or not.

Archaea↗

PubMed2000

Quantitative culture of Helicobacter pylori from gastric juice: the potential for transmission.

The transmission of Helicobacter pylori may occur by spread of organisms from gastric juice which has been introduced into the mouth by gastro-oesophageal reflux. The aim of this study was to quantify the load of H. pylori present in gastric juice available for transmission. Gastric antral biopsy and gastric juice samples were collected from 108 adult dyspeptic patients undergoing routine upper gastroscopy and the presence of H. pylori was determined. In all, 54 (50%) of 108 patients gave positive results in the gastric antral biopsy rapid urease test and for H. pylori histology. The gastric juice of 40 (37%) of patients gave positive results for the urease A gene by PCR assay; 34 (31%) of patients were positive by these three tests and H. pylori was cultured from the gastric juice of 13 (38%) of these patients. The median count of H. pylori in gastric juice was 1.75 x 10(1) cfu/ml. Viable organisms in gastric juice may lead to transmission of H. pylori when refluxed or vomited into the mouth.

Adolescent↗

PubMed2000

Genetic variation among endosymbionts of widely distributed vestimentiferan tubeworms.

Vestimentiferan tubeworms thriving in sulfidic deep-sea hydrothermal vents and cold seeps are constrained by their nutritional reliance on chemoautotrophic endosymbionts. In a recent phylogenetic study using 16S ribosomal DNA, we found that endosymbionts from vent and seep habitats form two distinct clades with little variation within each clade. In the present study, we used two different approaches to assess the genetic variation among biogeographically distinct vestimentiferan symbionts. DNA sequences were obtained for the noncoding, internal transcribed spacer (ITS) regions of the rRNA operons of symbionts associated with six different genera of vestimentiferan tubeworms. ITS sequences from endosymbionts of host genera collected from different habitats and widely distributed vent sites were surprisingly conserved. Because the ITS region was not sufficient for distinguishing endosymbionts from different habitats or locations, we used a DNA fingerprinting technique, repetitive-extragenic-palindrome PCR (REP-PCR), to reveal differences in the distribution of repetitive sequences in the genomes of the bacterial endosymbionts. Most of the endosymbionts displayed unique REP-PCR patterns. A cladogram generated from these fingerprints reflected relationships that may be influenced by a variety of factors, including host genera, geographic location, and bottom type.

Animals↗

PubMed1999

A quantitative focus assay for titration of retroviruses that encode human granulocyte-macrophage colony-stimulating factor (GM-CSF).

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a haematopoietic growth factor that regulates proliferation, differentiation, and effector functions of monocyte-macrophages and granulocytic cells. Because of the ability of this cytokine to enhance immune functions of antigen-presenting cells, retroviruses encoding GM-CSF have been used to transduce GM-CSF into murine and human tumour cells as part of autologous tumour vaccine strategies. We have previously shown that NIH 3T3 cells engineered to express functional human GM-CSF receptors (hGMR-NIH 3T3), become fully transformed when these cells are incubated in the presence but not in the absence of human GM-CSF. In this study we have used these hGM-CSF conditional transformants to devise a sensitive focus assay to titrate retroviruses encoding hGM-CSF, using MFG-hGM-CSF/Psi-CRIP as our model virus. This helper-free amphotropic retrovirus, which has been frequently used to transduce hGM-CSF into tumour cells, was quite transforming in our indicator cell line, exhibiting virus titres well above 10(5)FFU/ml. The transformation-based assay described here allows rapid determination of the titre of hGM-CSF-viruses, and may serve as a model for development of quantitative assays for other cytokine-encoding viruses of clinical importance.

3T3 Cells↗

PubMed1999

Salmonellosis in North Thames (East), UK: associated risk factors.

We assessed the rate of salmonella infections and risk factors associated with infection in North East Thames in 1993. Cases of culture confirmed infection were identified through microbiology laboratories and environmental health officers in the North East Thames. A total of 1730 cases were reported and 209 of these individuals (those who could be contacted within a 3-week interval after onset of symptoms) and matched controls were interviewed by telephone. In addition randomly selected controls were interviewed over a 4-month period about recent gastric acid lowering medication and antimicrobial ingestion. Sixty-six serotypes were identified: S. enteritidis was isolated from 1179 (69%) cases, S. typhimurium from 221 (13%), S. virchow from 77 (4%) and S. newport 25 (1%). Infections were more frequent in summer months. Highest rates were documented in children under 2 years of age for S. enteritidis (108/100,000) and under 1 year for S. typhimurium (36/100,000). Using the Townsend score, highest isolation rates of S. enteritidis were in more prosperous areas (36/100,000 vs. 27/100,000; odds ratio (OR) 1.3, 95% confidence intervals (CIs) 1.2-1.6, P < 0.0001), while for S. typhimurium, there was no relation between deprivation index and isolation rates areas (6.4/100,000 vs. 6.1/100,000; OR 1.1, 95% CIs 0.8-1.5, P = 0.77). The case control study showed a significant association between ingestion of products containing raw eggs and S. enteritidis infection (8/111 cases vs. 0/110 controls; OR undefined, lower 95% CIs 3.4). Individuals with salmonella infection were significantly more likely to have travelled abroad in the week before the onset of illness [42/186 (23%) vs. 1/182 (0.5%); OR 40, 95% CIs = 5.5-291, P < 0.001] and to report gastroduodenal disease [11/143 (7%) vs. 3/143 (2%); OR 5.0, 95% CIs = 1.1-23, P = 0.04]. There was an association between illness and gastric acid-lowering medications [unmatched controls OR 22.3 (95% CIs 1.5-3.7, P = 0.0002), matched controls OR 3.7 (95% CIs 1.0-3.8, P = 0.07)], but no association with antimicrobial ingestion.

Adolescent↗

PubMed1999

Comparison of the effects of anaerobic and micro-aerophilic incubation on resistance of Helicobacter pylori to metronidazole.

To assess the influence of incubation conditions on the resistance of Helicobacter pylori this study compared the effect of micro-aerophilic and anaerobic incubation followed by micro-aerophilic incubation on the measurement of metronidazole resistance of 102 H. pylori isolates, by both disk diffusion and Epsilometer (E)-tests. Anaerobic incubation for 24 h before micro-aerophilic incubation for 48 h consistently increased metronidazole activity in both assay methods. Although statistically significant, this was microbiologically less significant, as only 4 of 102 isolates gave discrepant readings (all four were resistant in micro-aerophilic conditions but susceptible in anaerobic/micro-aerophilic conditions). In all four cases variation was by a few millimeters in zone size (i.e., all were close to the cut-off point). There was 100% agreement between disk diffusion and E-test results. Of 104 observations (52 duplicate assays: 13 strains, two atmospheric conditions, two methods of determining resistance) there was 100% intra-observer and inter-observer agreement with regard to susceptibility and resistance status for both E-test and disk diffusion methods. Anaerobic incubation followed by micro-aerophilic incubation had little effect on the estimation of prevalence of metronidazole resistance and seemed to add little, if any, significant advantage over micro-aerophilic incubation alone.

Aerobiosis↗