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Biomedical subjects

D Marshall

Publications and source records attributed to D Marshall.

At least 55 records · Page 3Linked to original sources
PubMed1999

TH cells primed during influenza virus infection provide help for qualitatively distinct antibody responses to subsequent immunization.

The quality of the primary Ab-forming cell (AFC) response in cervical lymph nodes and mediastinal lymph nodes of mice to intranasal influenza virus was strongly influenced by viral replicative capacity. IgA secretors were prominent in the early AFC response to infectious virus in mediastinal lymph nodes, while IgG expression was more frequent among isotypically switched AFC in cervical lymph nodes of the same mice; this pattern was reversed in the response to inactivated virus. Influenza viruses A/Puerto Rico/8/34 (A/PR8) and A/X-31 share six of eight genome segments, differing only in hemagglutinin (H1 in A/PR8, H3 in A/X-31) and neuraminidase (N1 in A/PR8, N2 in A/X-31) genes. These viruses therefore elicit extensively cross-reactive TH populations, though their glycoproteins are serologically unrelated. Mice recovered from an A/X-31 infection thus mount a primary B cell response against A/PR8 glycoproteins, when challenged with the latter virus, though this response can call upon memory TH cells. To assess the impact of memory TH populations on a primary Ab response, we compared the AFC response to inactivated A/PR8 in naive mice and mice that had cleared an A/X-31 infection. A/X-31 immune mice mounted a more vigorous AFC response against A/PR8 H1 and N1 glycoproteins than naive animals, when immunized intranasally with inactivated A/PR8. However the distribution of isotypes among H1/N1-specific AFC in lymph nodes of A/X-31-primed mice resembled that of naive mice. Evidently, in this functional context, memory TH cells retained the ability to help Ab responses different in quality from that generated during their primary reaction.

Administration, Intranasal↗
PubMed1999

TNF-alpha and IL-1 sequentially induce endothelial ICAM-1 and VCAM-1 expression in MRL/lpr lupus-prone mice.

Dysfunctional leukocyte-endothelial interactions are thought to play a key role in systemic lupus erythematosus pathogenesis. We questioned the importance of TNF-alpha and IL-1 for endothelial activation in MRL/lpr lupus-prone mice. Endothelial ICAM-1 and VCAM-1 expression increased significantly with disease evolution in kidney, heart, and brain, as shown by i.v. injected radiolabeled Ab uptake. Lung endothelial VCAM-1 also increased, while lung endothelial ICAM-1 did not rise above a high basal level. Immunoassays showed a significantly raised circulating level of TNF-alpha by 14 wk, with levels of circulating IL-1alpha and IL-1beta being additionally raised by 20 wk. With 14-wk-old MRL/lpr, anti-TNF-alpha antiserum inhibited expression of ICAM-1 and VCAM-1 by endothelial cells cultured with sera in vitro, and uptake of anti-ICAM-1 and anti-VCAM-1 mAb in lung, kidney, brain, and heart in vivo. In contrast, both anti-TNF-alpha and anti-IL-1 antisera were required for maximal inhibition in vitro and in vivo at 20 wk. These data indicate that TNF-alpha is largely responsible for the early up-regulation of endothelial ICAM-1 and VCAM-1, but that IL-1 enhances expression in late disease. Our observations provide novel insights of possible relevance to understanding endothelial activation in systemic lupus erythematosus, and highlight an approach that can be extended to dissecting other chronic inflammatory diseases.

Animals↗
PubMed1999

Vascular endothelial cell expression of ICAM-1 and VCAM-1 at the onset of eliciting contact hypersensitivity in mice: evidence for a dominant role of TNF-alpha.

We have studied vascular endothelial activation and increased expression of ICAM-1 and VCAM-1 at the onset of the elicitation phase of oxazolone contact hypersensitivity in mice. By measuring the local uptake of i.v. administered radiolabeled anti-ICAM-1 and anti-VCAM-1 mAb, we found that endothelial ICAM-1 and VCAM-1 was increased by 4 h after challenge, 2 h later than the first peak of ear swelling and 125I-labeled human serum albumen uptake. Increased expression of endothelial ICAM-1 and VCAM-1 was significantly greater in sensitized animals than in naive animals. Anti-TNF-alpha antiserum significantly inhibited both the increase in ear thickness (p < 0.01), and the up-regulation of ICAM-1 and VCAM-1 expression (p < 0.01 for both) at 4 h. In contrast, the combination of anti-IL-1alpha and IL-1beta had only a small inhibitory effect on ICAM-1 expression (p < 0.05) and no significant effect on increased ear thickness or on VCAM-1 expression. A mixture of anti-TNF-alpha, anti-IL-1alpha, and IL-1beta was no more inhibitory for endothelial ICAM-1 and VCAM-1 expression than anti-TNF-alpha alone. ICAM-1 and VCAM-1 expression at 4 h was unaffected by a combination of mAb against alpha4 and beta2 integrins, whereas expression at 24 h was significantly inhibited (p < 0.05), suggesting that the release of TNF-alpha and other cytokines involved in the initiation of the response may not require leukocyte traffic or other leukocyte functions involving these integrins. We conclude that the early up-regulation of endothelial ICAM-1 and VCAM-1 during the elicitation of contact hypersensitivity is primarily due to the immune-dependent local release of TNF-alpha.

Animals↗
PubMed1999

In vitro assessment of Lipiodol-targeted radiotherapy for liver and colorectal cancer cell lines.

Intra-arterial Lipiodol has been used to deliver targeted therapies to primary, and some metastatic, liver cancers. Targeted radiotherapy has been used by substituting the iodine in Lipiodol with 131Iodine (131I). Early clinical results are encouraging, but the variable response may partly depend on local pharmacokinetics. This study evaluated the in vitro cytotoxic effects of 131I-Lipiodol on human hepatocellular carcinoma (Hep-G2), human colorectal metastatic cancer (SW620), human colorectal hepatic cancer (LoVo) and human umbilical vein endothelial cells (HUVEC) cell lines. The cell cultures were exposed to 131I-Lipiodol for 48 h, following which cell counts and viability were assessed by haemocytometer, S-Rhodamine uptake and radioactivity assay. The effect of exposure to control Lipiodol, 131I-Lipiodol and 131I alone was evaluated. 131I-Lipiodol was cytotoxic against all the cancer cell lines but not against the non-malignant (HUVEC) cell line. The cytotoxicity effects were very similar in all the cancer cell lines. There were no cytotoxic effects following exposure to plain 131I in any of the cell lines (malignant and non-malignant). A similar trend was seen with radioactivity counts using a gamma counter. The cytotoxic effect of 131I-Lipiodol had a graded effect with an increase in cytotoxicity following the increase in the radioactive dose. This study showed that there was a marked cytotoxic effect by 131I-Lipiodol on all the cancer cell lines. There was no difference between the controls and the 131Iodine. This suggests that effective 131I-Lipiodol targeted therapy is dependent on the uptake and retention of Lipiodol by malignant cells.

Cell Division↗
PubMed1999

The electron microscope appearance of the subchondral bone plate in the human femoral head in osteoarthritis and osteoporosis.

The subchondral bone plate supports the articular cartilage in diarthrodial joints. It has a significant mechanical function in transmitting loads from the cartilage into the underlying cancellous bone and has been implicated in the destruction of cartilage in osteoarthritis (OA) and its sparing in osteoporosis (OP), but little is known of its composition, structure or material properties. This study investigated the microscopic appearance and mineral composition of the subchondral bone plate in femoral heads from patients with OA or OP to determine how these correspond to changes in composition and stiffness found in other studies. Freeze-fractured full-depth samples of the subchondral bone plate from the femoral heads of patients with osteoarthritis, osteoporosis or a matched control group were examined using back scattered and secondary emission scanning electron microscopy. Other samples were embedded and polished and examined using back-scattered electron microscopy and electron probe microanalysis. The appearances of the samples from the normal and osteoporotic patients were very similar, with the subchondral bone plate overlayed by a layer of calcified cartilage. Osteoporotic samples presented a more uniform fracture surface and the relative thicknesses of the layers appeared to be different. In contrast, the OA bone plate appeared to be porous and have a much more textured surface. There were occasional sites of microtrabecular bone formation between the trabeculae of the underlying cancellous bone, which were not seen in the other groups, and more numerous osteoclast resorption pits. The calcified cartilage layer was almost absent and the bone plate was apparently thickened. The appearance of the osteoarthritic subchondral bone plate was, therefore, considerably different from both the normal and the osteoporotic, strongly indicative of abnormal cellular activity.

Aged↗
PubMed1999

Chronic pyelonephritis in association with neuropathic bladder.

Progressive chronic pyelonephritis (CPN) leading to renal failure was, in the past, a mode of death in children with meningomyelocele (MMC). With more sophisticated management modalities, renal failure is now uncommon, but the problem of CPN still remains. In this series of 100 children with MMC, 39% have CPN. It is significantly more common in girls than in boys. There is a strong relationship between CPN and vesico-ureteric reflux (VUR). There is no association with raised bladder pressure. The majority of CPN arises in children under the age of 4 years, but damaged kidneys can continue to deteriorate. Although chronic renal failure is rarely seen in children with MMC, there is a risk that this may merely be postponed into adulthood.

Chronic Disease↗
PubMed1999

Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic.

The sperm chromatin structure assay (SCSA) was used to measure over 500 human semen samples from two independent studies: Study I, 402 samples from 165 presumably fertile couples wishing to achieve pregnancy over 12 menstrual cycles; Study II, samples from 115 patients seeking fertility counselling. The SCSA measures susceptibility to DNA denaturation in situ in spermatozoa exposed to acid for 30 s, followed by acridine orange staining. SCSA data from the male partners of 73 couples (group 1) achieving pregnancy during months 1-3 of Study I were used as the standard of 'sperm chromatin compatible with high fertility' and were significantly different from those of 40 couples (group 3) achieving pregnancy in months 4-12 (P < 0.01) and those of male partners of 31 couples (group 4) not achieving pregnancy (P < 0.001). Group 2 contained couples who had a miscarriage. SCSA values for Study II were almost twice that of the Study I fertility standards. Within-couple repeatability tended to be less for group 3 than for groups 1, 2 or 4. Based on logistic regression, spermatozoa with denatured DNA (cells outside the main population, COMP alpha t) were the best predictor for whether a couple would not achieve pregnancy. Some 84% of males in group 1 had COMP alpha t < 15%, while no couples achieved pregnancy in group 1 with > or = 30% COMP alpha t, a threshold level considered not compatible with good fertility. Using selected cut-off values for chromatin integrity, the SCSA data predicted seven of 18 miscarriages (39%).

Chromatin↗
PubMed1999

Increased prevalence of sicca complex and fibromyalgia in patients with irritable bowel syndrome.

OBJECTIVE: As many as 70% of patients with fibromyalgia complain of the symptoms of irritable bowel syndrome (IBS), but there is a clinical impression that IBS patients do not suffer from fibromyalgia as frequently. The sicca complex (dry eyes and mouth) is also commonly observed in fibromyalgia, but its prevalence in IBS has not been evaluated. Our objective was to assess the frequency of fibromyalgia and sicca complex in secondary care patients with IBS. METHODS: Forty-six secondary care patients with IBS and 46 healthy controls were assessed by a rheumatologist for the presence of fibromyalgia and objective evidence of sicca complex (Schirmer and Rose-Bengal tests). Psychological status was also assessed (HAD questionnaire). RESULTS: Thirteen (28%) IBS patients suffered from fibromyalgia, compared with five (11%) controls, a difference of 17% (95% confidence intervals [CI], 2-33%). Fifteen (33%) IBS patients versus three (6%) controls had sicca complex, a difference of 27% (95% CI, 11-45%). CONCLUSIONS: These results suggest that the prevalence of fibromyalgia in IBS is approximately half that of IBS in fibromyalgia. Furthermore, sicca complex seems to be another complaint that should be added to the list of extracolonic manifestations of IBS. Study of the overlap between functional disorders presenting to different specialties may give new insights into the pathophysiology of these puzzling conditions.

Adult↗
PubMed1998

Transient expression of neurofascin by oligodendrocytes at the onset of myelinogenesis: implications for mechanisms of axon-glial interaction.

Cell adhesion molecules (CAMs) must play a crucial role in both the initiation and signalling of axon-glial contact. However, the proteins that permit myelinating oligodendrocytes to recognize the axons that they ensheath in the developing CNS are unknown. By a subtractive cDNA library strategy, we have identified neurofascin as a powerful candidate for such a molecule. Neurofascin is strongly but transiently up-regulated in oligodendrocytes at the onset of myelinogenesis. Once oligodendrocytes have engaged their target axons the protein plays no further part, since the expression of the gene declines precipitously, in contrast to that of the major myelin component proteolipid protein, which remains elevated. After the initial surge of neurofascin expression in oligodendrocytes, there is a shift to a predominantly neuronal localization that persists into adulthood. Hence neurofascin in oligodendrocytes is unlikely to serve a function in the stabilization of the multilamellar sheath around the axon. The major neurofascin isoform of oligodendrocytes contains the third fibronectin type 3 (FNIII) repeat but lacks the mucin-like domain which supports the view that neurofascin isoforms are differentially expressed in the nervous system. Among the genes that are up-regulated during the terminal differentiation of the oligodendrocyte, neurofascin is unique in displaying a transient pattern of expression at the early stages of myelination. We propose that this CAM not only has a role in mediating axon recognition but also signals axonal contact through its links with the actin cytoskeleton.

Animals↗
PubMed1998

International collaboration in health technology assessment: a study of technologies used in management of osteoporosis.

A collaborative study was undertaken by members of the International Network of Agencies for Health Technology Assessment (INAHTA). The evidence of the effectiveness of bone density measurement and selected treatments in preventing fractures in later life was reviewed. There was fair evidence that bone density measurement can predict risk of fractures and that hormone replacement therapy and intranasal salmon calcitonin preserve bone mass and decrease the risk of fractures. However, it was estimated that only 1-7% of hip fractures would be prevented if these technologies were used in a screening program for menopausal women. Results of the assessment were endorsed by 13 INAHTA members, disseminated widely and provided input to policy and further work in this area. The project demonstrated the feasibility of international collaborative health technology assessment.

Bone Density↗
PubMed1998

The effectiveness of bone density measurement and associated treatments for prevention of fractures. An international collaborative review.

This review assesses the evidence regarding the effectiveness of bone density measurement (BDM) screening and related interventions--hormone replacement therapy (HRT) and intranasal salmon calcitonin (SCT[N])--in menopausal women to prevent fractures in later life. Data sources included systematic reviews of evidence and relevant primary studies identified through literature searches on MEDLINE and EMBASE. Study selection included trials of BDM screening programs, prospective studies examining the predictive value of BDM, randomized controlled trials, cohort studies, and case-control studies of HRT and SCT (N). The evidence was evaluated using a classification system incorporating study design and quality. Outcomes were measured in terms of relative risk of fracture for a 1 SD decrease in bone mineral density below the age-adjusted mean, relative risks or odds ratios for fractures associated with treatments, and proportion of hip fractures potentially prevented by BDM screening linked to treatments. Fair evidence from prospective cohort studies suggests that BDM can predict the risk of fractures, but not with high accuracy. Fair evidence from low-quality randomized controlled trials and observational studies suggests that HRT and SCT(N) are efficacious in preventing fractures. Good evidence supports the efficacy of these treatments in preserving bone mass, but there is fair evidence that the effect wears off after cessation of therapy. There is little evidence on the impact of screening menopausal women with BDM in association with HRT or SCT(N) treatment. Estimates based on combining existing evidence regarding the predictive value of BDM and efficacy of HRT suggests that 1-7% of hip fractures might be prevented.

Administration, Intranasal↗
PubMed1998

Specific encapsidation of nodavirus RNAs is mediated through the C terminus of capsid precursor protein alpha.

Flock house virus (FHV) is a small icosahedral insect virus with a bipartite, messenger-sense RNA genome. Its T=3 icosahedral capsid is initially assembled from 180 subunits of a single type of coat protein, capsid precursor protein alpha (407 amino acids). Following assembly, the precursor particles undergo a maturation step in which the alpha subunits autocatalytically cleave between Asn363 and Ala364. This cleavage generates mature coat proteins beta (363 residues) and gamma (44 residues) and is required for acquisition of virion infectivity. The X-ray structure of mature FHV shows that gamma peptides located at the fivefold axes of the virion form a pentameric helical bundle, and it has been suggested that this bundle plays a role in release of viral RNA during FHV uncoating. To provide experimental support for this hypothesis, we generated mutant coat proteins that carried deletions in the gamma region of precursor protein alpha. Surprisingly, we found that these mutations interfered with specific recognition and packaging of viral RNA during assembly. The resulting particles contained large amounts of cellular RNAs and varying amounts of the viral RNAs. Single-site amino acid substitution mutants showed that three phenylalanines located at positions 402, 405, and 407 of coat precursor protein alpha were critically important for specific recognition of the FHV genome. Thus, in addition to its hypothesized role in uncoating and RNA delivery, the C-terminal region of coat protein alpha plays a significant role in recognition of FHV RNA during assembly. A possible link between these two functions is discussed.

Amino Acid Sequence↗
PubMed1997

Squamous cell carcinoma of the floor of mouth: a 20-year review.

BACKGROUND: This study retrospectively examines our treatment choices and outcomes with patients diagnosed with squamous cell cancer of the floor of mouth. Because of our division's past strong surgical bias in the treatment of this disease, we have assessed the results of a patient population treated largely by surgical extirpation. This clinical information has been used to draw conclusions and formulate treatment paradigms for patients with floor of mouth cancer. METHODS: Four hundred fifty patients with the diagnosis of squamous cell carcinoma of the oral cavity received their primary treatment at Roswell Park Cancer Center (RPCI) from 1971 to 1991. Ninety-nine had disease originating in the floor of mouth and are the basis of this retrospective review. RESULTS: Forty-three percent of the patients had early-stage disease (stage I or II). Five-year survival for stages I through IV was 95%, 86%, 82%, and 52%, respectively. The incidence of occult cervical metastases for clinical stage I patients was 21%. For clinical stage II patients, the incidence was 62%. Local control of patients treated with surgery alone was 81%. The regional control rate for these patients was 71%. In patients where negative margins were achieved (> or = 5 mm), the local recurrence rate was 13%, regardless of T stage. Eleven percent of the patients underwent a course of postoperative radiotherapy; all had stage IV disease. When compared with advanced-stage patients undergoing surgery alone, there was a significantly improved regional control rate and a trend toward enhanced survival in the patients receiving adjuvant radiotherapy. CONCLUSIONS: There is a significantly high incidence of occult metastatic disease (21%) for T1 lesions or greater in floor of mouth cancer to warrant elective treatment of regional lymphatics. In patients treated with surgery alone with negative margins, the local control rate was 90% versus 62% when the margins were close or positive. Adjunctive radiotherapy showed a statistically significant (p = .005) increased regional control in patients with stage IV disease. Adjunctive radiotherapy is warranted for increased regional control of disease; good local control can be achieved in floor of mouth cancer with surgery alone when negative margins are obtained.

Adult↗
PubMed1997

Cytomegalovirus infection in children with human immunodeficiency virus infection.

OBJECTIVES: To determine retrospectively the prevalence of positive cytomegalovirus (CMV) cultures in pediatric patients with human immunodeficiency virus infection. METHODS: We reviewed the records of 273 children with human immunodeficiency virus infection referred to the Pediatric Branch of the National Cancer Institute for whom CMV cultures were performed between January, 1991, and October, 1994. RESULTS: Of this group 189 patients (69%) had negative CMV cultures and 84 (31%) had positive cultures. The prevalence of CMV-related disease was 9% for the entire group, including 4 (2.1%) patients with negative CMV cultures. Among the 84 patients with positive CMV cultures, 21 (25%) had evidence of CMV disease. Patients with positive CMV cultures had a statistically significant decrease in survival in the presence of severe immunocompromise defined as an age-corrected CD4 count of < 21%. Nine of 35 (26%) autopsies performed demonstrated evidence of CMV disease, including 7 patients with disseminated CMV disease. CONCLUSIONS: Although CMV disease appears to be less frequent in children than adults, CMV infection still contributes significantly to morbidity and mortality in this population, especially when combined with severe immunosuppression.

AIDS-Related Opportunistic Infections↗