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Biomedical subjects

R Newman

Publications and source records attributed to R Newman.

At least 19 recordsLinked to original sources
PubMed1998

Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro.

A cell-free system that mimics the reassembly of Golgi stacks at the end of mitosis requires two ATPases, NSF and p97, to rebuild Golgi cisternae. Morphological studies now show that alpha-SNAP, a component of the NSF pathway, can inhibit the p97 pathway, whereas p47, a component of the p97 pathway, can inhibit the NSF pathway. Anti-syntaxin 5 antibodies and a soluble, recombinant syntaxin 5 inhibited both pathways, suggesting that this t-SNARE is a common component. Biochemical studies confirmed this, showing that p47 binds directly to syntaxin 5 and competes for binding with alpha-SNAP. p47 also mediates the binding of p97 to syntaxin 5 and so plays an analogous role to alpha-SNAP, which mediates the binding of NSF.

Adenosine Triphosphatases↗
PubMed1997

p47 is a cofactor for p97-mediated membrane fusion.

At least two distinct ATPases, NSF and p97, are known to be involved in the heterotypic fusion of transport vesicles with their target membranes and the homotypic fusion of membrane compartments. The NSF-mediated fusion pathway is the best characterized, many of the components having been identified and their functions analysed. In contrast, none of the accessory proteins for the p97-mediated fusion pathway has been identified. Now we have identified the first such component, a protein of relative molecular mass 47,000 (p47), which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97). It is essential for the p97-mediated regrowth of Golgi cisternae from mitotic Golgi fragments, a process restricted to animal cells. As a homologue of p47 exists in budding yeast, this indicates that it might also be involved in other membrane fusion reactions catalysed by p97, such as karyogamy.

Adenosine Triphosphatases↗
PubMed1997

A primatized MAb to human CD4 causes receptor modulation, without marked reduction in CD4+ T cells in chimpanzees: in vitro and in vivo characterization of a MAb (IDEC-CE9.1) to human CD4.

A Primatized anti-CD4 monoclonal antibody (MAb), CE9.1, with V-domain from cynomolgus macaque (showing 92% homology with human consensus sequence V-domains), and a human IgG1 constant region, was characterized in vitro and in vivo in chimpanzees. This MAb binds human CD4 with Kd of 1.0 nM and was also able to bind to human IgG Fc receptors (Fc gamma R). However, despite being of the IgG1 subclass, CE9.1 did not bind to complement component C1q, nor did it mediate complement-dependent cytotoxicity. Examination of T cells from a number of species showed restricted reactivity for CE9.1, recognizing only human and chimpanzee CD4. In both human and chimpanzee MLRs, it had an IC50 of about 10.0 ng/mL. Therefore, a chimpanzee in vivo model was used to characterize CE9.1, CE9.1 caused transient decrease in the number of lymphocytes bearing the CD4 receptor starting at doses of 0.3 mg/kg in an in vivo dose ranging study in one chimpanzee. This effect was reversed within approximately 7 days. In a multiple high-dose study in which 10.0 mg/kg of CE9.1 was administered at intervals of 1-3 months, there was a dramatic loss of CD4 marker with a reciprocal increase in the number of CD3+ CD8- CD4- cells. The CD4 receptor was totally undetectable on these lymphocytes for 1-2 weeks, with a gradual, but complete, reversal within 4 weeks. We interpret these observations as receptor modulation because, although there was apparent loss of CD4+ lymphocytes, an equivalent number of CD3+CD8- T lymphocytes were present in circulation in all four chimpanzees treated with 10.0 mg/kg CE9.1. Even at this high dose, only limited reduction of CD4+ T lymphocytes was observed in these animals. These observations are in sharp contrast to what has been reported in rodents or in human clinical studies using other IgG1 mAbs to human CD4. CD8 counts, although variable, remained unaffected by CE9.1 treatment. No adverse events were observed following administration of CE9.1 to chimpanzees, and there was no detectable host immune responses to the Primatized MAb.

Animals↗
PubMed1997

The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin).

Malignant gliomas continue to be a significant source of mortality in young and middle aged adults. The introduction of new treatment strategies and multidisciplinary approaches has improved the outcome of patients with these tumors only slightly. Because retinoic acid has growth inhibitory activity against glioma and neuroblastoma cells in cultures, we assessed the efficacy of all-trans-retinoic acid in the treatment of recurrent cerebral gliomas. Thirty-six patients with recurrent cerebral gliomas were entered in the study and treated with 120 or 150 mg/ m2/day of all-trans-retinoic acid as a single agent. The drug was given for 3 weeks followed with one week of rest. Two blocks of 4 weeks constituted one course of treatment. One (3%) of 34 evaluable patients had a minor response and 14 (41%) had stable disease. In the rest of the patients (56%), tumors continued to progress despite treatment. The median time to progression of all evaluable patients was 8 weeks, and for the responders was 17 weeks. The higher dose level (150 mg/m2) was associated with high incidence of headache, which responded to dose reduction. The lower dose level was very well tolerated, with mild, mainly dermatological toxicity. All-trans-retinoic acid as a single agent has no significant activity against recurrent cerebral gliomas.

Adolescent↗
PubMed1997

Examination of renal donors as outpatients using intraarterial digital subtraction angiography and a pigtail catheter.

OBJECTIVE: We performed this study to assess the safety and efficacy of outpatient angiographic renal donor examination using a 3-French pigtail catheter, intraarterial digital subtraction angiography, and a progressively shortened examination time after the procedure. CONCLUSION: For 45 consecutive procedures performed, no complications were reported, and no diagnostic discrepancies were found in patients who proceeded to surgery. Using this method we were also able to eliminate the excretory urogram as well as reduce the total amount of contrast per procedure.

Adolescent↗
PubMed1996

VH gene usage is multiple myeloma: complete absence of the VH4.21 (VH4-34) gene.

The immunoglobin heavy chain variable region (VH) gene usage in multiple myeloma (MM) has not been reported, although a few studies have incidentally identified the VH gene rearranged in small cohorts of MM patients. We used a reverse transcriptase-polymerase chain reaction based technique to analyze the VH gene usage in MM. The VH sequences were obtained after amplification of bone marrow cDNA using the seven VH family-specific and constant region primers. The VH sequences of 72 patients were successfully identified. The frequency of VH family usage in decreasing order was VH3>VH4>VH1>VH5>VH2>VH6>VH7 and corresponded to the functional germline complexity of the VH families. Individual VH genes (VH1-69, VH3-9, VH3-23, and VH3-30) were overrepresented in our cohort of MM patients; some VH genes [VH3-49, VH3-53, and VH4.21 (VH4-34)], which are rearranged with increased frequency in normal circulating B cells, autoimmune diseases, and other B-cell malignancies, were not detected in any MM patient. Compared with germline sequences, an average of 8.8% (range, 2.7% to 16.5%) of the nucleotides had evidence of mutation within each VH sequence. Based on these results, we conclude that (1) the VH gene usage in MM is unique compared with other malignant and nonmalignant B-cell populations, (2) the physiologic process of clonal deletion functions to remove clones that have rearranged VH genes (VH4.21) capable of expressing antibodies, which recognize self-antigens, and (3) the complete lack of VH4.21 gene rearrangement may help to partially explain the paucity of autoimmune phenomena in MM.

Base Sequence↗
PubMed1995

Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity.

The lg VH region sequence in 48 patients with multiple myeloma (MM) was analyzed to characterize the malignant cell of origin. The sequences were obtained after amplification of bone marrow cDNA by using VH family-specific and CH primers, then compared with either directly sequenced patient germ-line or published VH gen sequences to assay for somatic mutation. Because somatic hypermutation of the VH gene occurs late in B cell development, its presence has been helpful in determining the cell of origin in other B cell malignancies. Overall, a median of 8.2% of the nucleotides had evidence of substitution within each VH gene sequence (range=2.7% to 16.5%), which is more prevalent than in any other reported tumor type. Strong evidence of prior antigenic selection pressure was also evident. The ratio of nucleotide substitutions that resulted in amino acid replacement was significantly higher in the complementarity-determining region than in the framework region (3.25 vs 1.56, respectively; p < 0.00005). No VH gene intraclonal diversity was noted, despite sequencing multiple clones (3-16) from each patient, nor was there evidence of further VH gene somatic mutation over the course of three patients' disease. These findings strongly imply that the malignant clone in MM evolves from a cell late in B cell development.

Amino Acid Sequence↗
PubMed1995

Sarcoid ranula. Its association with wide-spread sarcoidosis.

The presence of noncaseating granulomas in salivary tissue is a specific feature of sarcoidosis. We document the case of a healthy woman who presented with a sarcoid ranula of the sublingual salivary gland without any other manifestations of the disease. This sarcoid ranula subsequently progressed to symptomatic widespread sarcoidosis in a span of 7 months. An asymptomatic sarcoid ranula may thus possibly represent a precursor to widespread sarcoidosis.

Adult↗
PubMed1994

Mixed populations in influenza virus vaccine strains.

Human influenza viruses used for vaccine production have previously been adapted to grow in eggs. During egg adaptation, variants are selected and we have observed that more than one variant may derive in a single egg resulting in a mixed population. We have now investigated the extent of heterogeneity, due to host cell selection, of virus strains used for the manufacture of influenza vaccine for the 1991/1992 and 1992/1993 seasons. The A(H1N1) vaccine virus was homogeneous with respect to substitutions in the haemagglutinin deriving from egg adaptation. However, two A(H3N2) vaccine strains and the influenza B component, B/Yamagata/16/88, consisted of mixed populations, apparently due to their cultivation in eggs. The individual variants within B/Yamagata were isolated and found to be antigenically distinct. The ratios of these variants within different manufacturers' seed stocks varied to the extent that vaccine derived from them could be distinguished antigenically. Furthermore, derivation of high-growth reassortants from the A(H3N2) strains which involves passaging at limit dilution did not necessarily lead to a homogeneous virus population. The significance of these findings for the efficacy of vaccine is not known at present.

Base Sequence↗
PubMed1994

Glucose and insulin responses to barley products: influence of food structure and amylose-amylopectin ratio.

Postprandial glycemic and insulinemic responses and satiety with various barley products were evaluated in normal subjects. Also studied were the rate of in vitro starch digestion and the content of in vitro resistant starch (RS). Products tested were boiled intact (rice extender) and milled kernels (porridge) from four barley genotypes of Glacier with different amylose-amylopectin ratios (7-44% amylose). All barley products elicited lower metabolic responses and higher satiety scores when compared with white wheat bread. The lente behavior of the boiled flours was probably due to the viscous properties of the beta-glucans. However, the boiled flours produced higher glucose and insulin responses than did the corresponding boiled kernels. The impact of amylose: amylopectin on the metabolic responses was marginal. The high-amylose products released starch more slowly from a dialysis tubing during enzymic incubation of chewed samples compared with the corresponding products with less amylose. The RS content ranged from 0.4% in waxy to 5.6% in the high-amylose flour product (starch basis).

Adult↗
PubMed1994

Three-dimensional reconstruction of ultrafast chest CT for diagnosis and operative planning in a child with right pneumonectomy syndrome.

After receiving a neonatal right pneumonectomy for septic complications of unilateral pulmonary artery agenesis, a 2 1/2-year-old girl was referred to the Cardiothoracic Surgery Service for evaluation of increasing symptoms of wheezing and stridor. Extensive workup included a three-dimensional ultrafast CT image reconstruction that aided in the diagnosis and operative planning. Successful relief of the airway obstruction was achieved by aortic suspension and by placing a Silastic tissue expander prosthesis. Before operation, this child had been admitted to the hospital on 18 different occasions for respiratory symptoms. Six months after surgery, she is not receiving any medications and is symptom-free.

Airway Obstruction↗
PubMed1993

The haemagglutinins of influenza A (H1N1) viruses in the 'O' or 'D' phases exhibit biological and antigenic differences.

Influenza A (H1N1) viruses when initially isolated in mammalian cell cultures (MDCK cells) had different agglutination reactions with chicken and guinea-pig erythrocytes compared to the same viruses after passage. On first isolation the virus HA resembled the 'O' phase viruses described originally by Burnet and Bull and agglutinated mammalian but not avian erythrocytes. After passage, the virus HA resembled a classical 'D' phase virus and agglutinated both avian and mammalian erythrocytes. Monoclonal and polyclonal antisera detected antigenic differences between the HAs of the viruses in the 'O' and 'D' phases. The 'O' phase virus HA reacted preferentially with antibodies in post infection human antisera. Viruses in the 'O' phase replicated poorly in the allantoic cavity of embryonated hens' eggs whilst 'D' phase virus replicated in both MDCK cells and in embryonated hens' eggs. At least three distinguishable subpopulations of influenza A (H1N1) viruses may co-exist in clinical throat swab material, including viruses possessing HAs in the 'O' and 'D' phases and other 'D' phase viruses cultivable in embryonated hens' eggs but antigenically distinguishable from the corresponding 'D' phase virus in MDCK cells.

Adult↗
PubMed1993

A function approximation algorithm using sequential composition.

A new method for approximating one dimensional functions is developed based on structural capabilities of multilayer feedforward neural networks. It possesses notable but unproven convergence properties which are examined in a series of examples. It is shown that it outperforms conventional networks for complicated one dimensional problems. An adaptive version of the algorithm whose approximation changes to best use the data available is also presented. Experiments indicate that this method is very stable in the presence of noise. For straightforward function approximation however, other conventional routines generally perform better. Nevertheless, noise stability, adaptability and other properties make the new method useful in context.

Algorithms↗