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Biomedical subjects

M Grove

Publications and source records attributed to M Grove.

At least 19 recordsLinked to original sources
PubMed2005

The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions.

OBJECTIVE: To identify the proportion of patients with inflammatory arthritis who remain on methotrexate in the medium to long term and the incidence of side-effects in clinical practice. METHOD: The study population comprised all patients with inflammatory arthritis treated with methotrexate and monitored in clinics under the auspices of Staffordshire Rheumatology Centre. Two clinical auditors collected data retrospectively from the computer database used to support monitoring of patients on disease-modifying anti-rheumatic drugs. Information was collected on duration of treatments and reasons for stopping treatment. For patients identified as having potentially serious side-effects or who died whilst taking methotrexate, further information on their outcome was collected from patients' medical notes and where applicable post mortem reports and death registers. RESULTS: Between 1986 and 1999, 673 patients were treated with methotrexate, of whom 551 had a diagnosis of rheumatoid arthritis. From the Kaplan-Meier analysis, the probability of patients remaining on treatment 5 yr after starting methotrexate was 0.74. Three hundred and sixteen patients stopped methotrexate between 1986 and 1999. In 117 patients, the methotrexate was restarted. Seventy-two patients (10.7% of all patients) stopped because of inefficacy or patient choice or situation. Thirty-seven patients (5.5%) stopped methotrexate due to abnormal haematology (usually low neutrophils). Thirty-seven patients (5.5%) stopped methotrexate due to abnormalities in liver function tests. Life-threatening side-effects were identified in 12 patients (1.8%). These included six pneumonitis, five cytopenias and one disseminated varicella zoster. Two of these patients (0.3%) died, one from pneumonitis and one from disseminated varicella zoster. A total of 25 patients (3.7%) died while taking methotrexate and four died (0.6%) within 3 months of stopping methotrexate. One death (0.15%) was directly attributable to methotrexate (methotrexate pneumonitis). CONCLUSION: This study has shown that methotrexate is well tolerated in clinical practice in the medium to long term. It has produced accurate data on the incidence of adverse effects of methotrexate in a local population in a non-research setting. It has identified the incidence of life-threatening side-effects to be 1.7% with one death (0.15%) directly due to methotrexate. This information should prove useful when recommending such treatment to patients with inflammatory arthritis.

Adolescent↗
PubMed2000

The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19.

c-Abl is a nonreceptor tyrosine kinase that we have recently linked to growth factor receptor signaling. The c-Abl kinase is ubiquitously expressed and localizes to the cytoplasm, plasma membrane, cytoskeleton, and nucleus. Thus, c-Abl may regulate signaling processes in multiple subcellular compartments. Targeted deletion or mutation of c-Abl in mice results in a variety of phenotypes, including splenic and thymic atrophy and lymphopenia. Additionally, lymphocytes isolated from specific compartments of c-Abl mutant mice have reduced responses to a variety of stimuli and an increased susceptibility to apoptosis following growth factor deprivation. Despite these observations, little is known regarding the signaling mechanisms responsible for these phenotypes. We report here that splenic B cells from c-Abl-deficient mice are hyporesponsive to the proliferative effects of B cell Ag receptor (BCR) stimulation. The c-Abl kinase activity and protein levels are elevated in the cytosol following activation of the BCR in B cell lines. We show that c-Abl associates with and phosphorylates the BCR coreceptor CD19, and that c-Abl and CD19 colocalize in lipid membrane rafts. These data suggest a role for c-Abl in the regulation of B cell proliferation downstream of the BCR, possibly through interactions with CD19.

Animals↗
PubMed2000

Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma.

Asthma is a major cause of morbidity worldwide with prevalence and severity still increasing at an alarming pace. Hallmarks of this disease include early-phase bronchoconstriction with subsequent eosinophil infiltration, symptoms that may be mimicked in vivo by the complement-derived C3a anaphylatoxin, following its interaction with the single-copy C3aR. We analyzed the pathophysiological role of the C3a anaphylatoxin in a model of experimental OVA-induced allergic asthma, using an inbred guinea pig strain phenotypically unresponsive to C3a. Molecular analysis of this defect revealed a point mutation within the coding region of the C3aR that creates a stop codon, thereby effectively inactivating gene function. When challenged by OVA inhalation, sensitized animals of this strain exhibited a bronchoconstriction decreased by approximately 30% in comparison to the corresponding wild-type strain. These data suggest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies.

Administration, Inhalation↗
PubMed2000

Collective singlet excitations and evolution of raman spectral weights in the 2D spin dimer compound SrCu2(BO3)(2)

Raman light scattering of the two-dimensional quantum spin system SrCu2(BO3)(2) shows a rich structure in the magnetic excitation spectrum, including several well-defined bound state modes at low temperature, and a scattering continuum and quasielastic light scattering contributions at high temperature. The key to the understanding of the unique features of SrCu2(BO3)(2) is the presence of strong interactions between well-localized triplet excitations in the network of orthogonal spin dimers realized in this compound.

Journal Article↗
PubMed2000

Stripe conductivity in La1.775Sr0.225NiO4

We report Raman light-scattering and optical conductivity measurements on a single crystal of La1.775Sr0.225NiO4 which exhibits incommensurate charge-stripe order. The extra phonon peaks induced by stripe order can be understood in terms of the energies of phonons that occur at the charge-order wave vector Q(c). A strong Fano antiresonance for a Ni-O bond-stretching mode provides clear evidence for finite dynamical conductivity within the charge stripes.

Journal Article↗
PubMed2000

Hot and dry deep crustal xenoliths from tibet

Anhydrous metasedimentary and mafic xenoliths entrained in 3-million-year-old shoshonitic lavas of the central Tibetan Plateau record a thermal gradient reaching about 800 degrees to 1000 degrees C at a depth of 30 to 50 kilometers; just before extraction, these same xenoliths were heated as much as 200 degrees C. Although these rocks show that the central Tibetan crust is hot enough to cause even dehydration melting of mica, the absence of hydrous minerals, and the match of our calculated P-wave speeds and Poisson's ratios with seismological observations, argue against the presence of widespread crustal melting.

Journal Article↗
PubMed2000

Localization and phosphorylation of Abl-interactor proteins, Abi-1 and Abi-2, in the developing nervous system.

Abl-interactor (Abi) proteins are targets of Abl-family nonreceptor tyrosine kinases and are required for Rac-dependent cytoskeletal reorganization in response to growth factor stimulation. We asked if the expression, phosphorylation, and cellular localization of Abi-1 and Abi-2 supports a role for these proteins in Abl signaling in the developing and adult mouse nervous system. In mid- to late-gestation embryos, abi-2 message is elevated in the central and peripheral nervous systems (CNS and PNS). Abi-1 mRNA is present, but not enhanced, in the CNS, and is not observed in PNS structures. Abi proteins from brain lysates undergo changes in apparent molecular weight and phosphorylation with increasing age. In the postnatal brain, abi-1 and abi-2 are expressed most prominently in cortical layers populated by projection neurons. In cultured neurons, Abi-1 and Abi-2 are concentrated in puncta throughout the cell body and processes. Both Abi and Abl proteins are present in synaptosomes and growth cone particles. Therefore, the Abi adaptors exhibit proper expression patterns and subcellular localization to participate in Abl kinase signaling in the nervous system.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Assessing Watershed-Scale, Long-Term Hydrologic Impacts of Land-Use Change Using a GIS-NPS Model.

Land-use change, dominated by an increase in urban/impervious areas, has a significant impact on water resources. This includes impacts on nonpoint source (NPS) pollution, which is the leading cause of degraded water quality in the United States. Traditional hydrologic models focus on estimating peak discharges and NPS pollution from high-magnitude, episodic storms and successfully address short-term, local-scale surface water management issues. However, runoff from small, low-frequency storms dominates long-term hydrologic impacts, and existing hydrologic models are usually of limited use in assessing the long-term impacts of land-use change. A long-term hydrologic impact assessment (L-THIA) model has been developed using the curve number (CN) method. Long-term climatic records are used in combination with soils and land-use information to calculate average annual runoff and NPS pollution at a watershed scale. The model is linked to a geographic information system (GIS) for convenient generation and management of model input and output data, and advanced visualization of model results.The L-THIA/NPS GIS model was applied to the Little Eagle Creek (LEC) watershed near Indianapolis, Indiana, USA. Historical land-use scenarios for 1973, 1984, and 1991 were analyzed to track land-use change in the watershed and to assess impacts on annual average runoff and NPS pollution from the watershed and its five subbasins. For the entire watershed between 1973 and 1991, an 18% increase in urban or impervious areas resulted in an estimated 80% increase in annual average runoff volume and estimated increases of more than 50% in annual average loads for lead, copper, and zinc. Estimated nutrient (nitrogen and phosphorus) loads decreased by 15% mainly because of loss of agricultural areas. The L-THIA/NPS GIS model is a powerful tool for identifying environmentally sensitive areas in terms of NPS pollution potential and for evaluating alternative land use scenarios for NPS pollution management.

Journal Article↗
PubMed1998

Human anaphylatoxin C4a is a potent agonist of the guinea pig but not the human C3a receptor.

The interaction of human anaphylatoxin C4a with the guinea pig (gp) and human (hu) C3a receptors (C3aR) was analyzed using human rC4a, which exhibited C4a-specific activity on guinea pig platelets. A gpC3aR of 475 residues with a large second extracellular loop and a peptide sequence approximately 60% identical to the huC3aR was isolated from a genomic DNA library and found to be expressed in guinea pig heart, lung, and spleen. HEK-293 cells cotransfected with this clone, and a cDNA encoding G alpha-16 specifically bound (Kd = 1.6+/-0.7 nM) and responded functionally to C3a with an intracellular calcium mobilization (ED50 = 0.18+/-0.02 nM). Human rC4a weakly bound to both the hu- and gpC3aR (IC50 > 1 microM). However, only HEK-293 cells expressing the gpC3aR responded functionally to rC4a (ED50 = 8.7+/-0.52 nM), while cells expressing the huC3aR did not (c < or = 1 microM). Thus, through an interaction with the C3aR, huC4a may elicit anaphylatoxic effects in guinea pigs but not in man.

Amino Acid Sequence↗
PubMed1998

Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway.

Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin-proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr-Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin-proteasome pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Genomic organization of the human C3a receptor.

The human C3a receptor (C3aR) mediates the activation of cells by the potent proinflammatory chemoattractant C3a, an anaphylatoxin, generated in the early phase of an inflammatory reaction by proteolytic cleavage of the complement component C3. To understand the molecular mechanisms that regulate C3aR gene expression, we initiated studies to determine its genomic and mRNA organization. We now report the following novel findings: (1) The C3aR is a single-copy gene as shown by Southern hybridization of human genomic DNA. (2) Using PCR amplification of DNA from monochromosomal somatic cell hybrid and radiation hybrid panels, the C3aR locus was mapped to chromosome 12p13. (3) Genomic DNA clones encompassing the C3aR locus were isolated from a human genomic DNA library and characterized by restriction mapping, Southern blotting, PCR analysis and DNA sequencing. Comparison of the genomic with the known cDNA sequences revealed a single 6-kb intron sequence located 1 1 bp upstream of the ATG initiation codon. The open reading frame and the complete 3' untranslated region are encoded on a single exon.

Base Sequence↗
PubMed1998

An unusual presentation of simultaneous bilateral popliteal artery embolism--a case report.

We present what we believe is the first case in the literature of carcinoma of the lung presenting de novo as an intracardiac mass with bilateral, simultaneous popliteal artery embolization. Arterial thromboembolism of cardiac origin and in situ thrombosis of a preexisting atherosclerotic lesion or aneurysm account for the majority of cases of acute lower extremity ischemia. Less common causes include trauma, aortic dissection, venous ischemia, and foreign body or tissue embolization. Although the history, physical examination, and electrocardiographic findings may provide a likely explanation in many cases, noninvasive studies such as echocardiography may help further elucidate the embolic source.

Aged↗
PubMed1996

Expression cloning of the human C3a anaphylatoxin receptor (C3aR) from differentiated U-937 cells.

A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells which had been differentiated with dibutyryl cAMP to a macrophage-like phenotype. The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. Chinese hamster ovary cells co-transfected with this cDNA clone and a G-protein alpha subunit (G alpha-16) became functionally responsive to C3a and a C3a analog synthetic peptide, as measured by increased phosphoinositide hydrolysis. As inferred from the cDNA sequence, the clone encodes a 482-residue polypeptide with seven hydrophobic membrane-spanning helices and a high homology to the human C5a and formyl-Met-Leu-Phe receptors. Uniquely among the family of G-protein coupled receptors, the C3aR contains an exceptionally large second extracellular loop of approximately 175 residues. Northern hybridizations revealed an approximately 2.3-kb transcript as the major and an additional approximately 3.9 kb-transcript as a minor transcription product of the C3aR. The C3aR appears to be widely expressed in different lymphoid tissues, as shown by Northern hybridizations, providing evidence for a central role of the C3a anaphylatoxin in inflammatory processes.

Amino Acid Sequence↗
PubMed1996

Human gastric intrinsic factor expression is not restricted to parietal cells.

Gastric parietal cells have been accepted as the only site of intrinsic factor production in the human stomach. In animals, however, intrinsic factor has been localised to various other cell types of foregut origin, including chief and enteroendocrine cells in gastric mucosa, and duct cells from salivary glands and pancreas. The availability of recombinant human intrinsic factor has led to production of high titre, monospecific antiserum which was used to reexamine the distribution and subcellular localisation of intrinsic factor in the human stomach. Immunolight microscopy revealed that most positively stained cells were gastric parietal cells, but at the margins of the anatomical regions (e.g. cardia/fundus, body/antrum) clusters of gastric chief cells and individual enteroendocrine cells were found to contain intrinsic factor. Immunoelectron microscopy demonstrated the highest antigen density on endocytic and apical membranes of parietal cells. Exocrine secretory granules of a subpopulation of chief cells, the secretory granules of some enteroendocrine cells, and the plasma membranes and smooth vesicles of endothelial cells of the lamina propria capillaries underlying enteroendocrine cells were also positive for the antigen. Labelling in all cells was specific, as it was abolished by preabsorption of the antisera with purified recombinant human intrinsic factor. These findings demonstrate a potential for cellular expression of human intrinsic factor in nonparietal cells. Because such expression occurs normally at the margins of anatomical gastric regions, it suggests that local factors may influence expression of intrinsic factor.

Adult↗
PubMed1995

G alpha-16 complements the signal transduction cascade of chemotactic receptors for complement factor C5a (C5a-R) and N-formylated peptides (fMLF-R) in Xenopus laevis oocytes: G alpha-16 couples to chemotactic receptors in Xenopus oocytes.

The human leukocyte chemoattractant receptors for complement factor C5a (C5a-R) and N-formylated peptides (fMLF-R) are important members of the superfamily of G-protein coupled receptors (GPCR). Uniquely among the GPCR, these two receptors cannot be expressed in a functionally active form in the oocytes of the frog Xenopus laevis, but require substitution of total RNA of the myelomonocytic U-937 or HL-60 cell lines, respectively. Recently, it was reported that the C5a-R may couple to the alpha subunit of G-16. We have tested this G-protein for its ability to complement the signal transduction cascade of the C5a-R and fMLF-R in Xenopus oocytes. Injection of cRNA for the C5a-R in combination with G alpha-16 led to expression of a functional C5a-R as measured by ligand-induced whole cell current. In contrast to a previous report, the fMLF-R exhibited some residual functional activity when transiently expressed in Xenopus oocytes the extent of which could, however, substantially be increased by coexpression of G alpha-16. Thus, G alpha-16 complements the signal transduction cascade of both receptors in Xenopus laevis oocytes and is most likely the complementing factor present in the U-937 and HL-60 cell lines.

Animals↗
PubMed1995

An ATF/CREB-binding site is essential for cell-specific and inducible transcription of the murine MIP-1 beta cytokine gene.

The murine macrophage inflammatory protein 1 beta mRNA (MIP-1 beta) is rapidly and transiently induced in macrophages by lipopolysaccharide (LPS), serum or cycloheximide. Functional studies of the MIP-1 beta proximal promoter indicate that it is cell-specific, and serum- and LPS-responsive in macrophages. A 76-bp proximal promoter sequence (-51 to -127 bp) confers cell-specific and LPS-inducible activity when placed upstream from a heterologous promoter in both orientations. One essential cis-regulatory element within the enhancer-like sequence is an activating transcription factor/cAMP response element (CRE)-binding protein (ATF/CREB)-binding site, although the promoter is not cAMP responsive. Electrophoretic mobility shift assays and mutational analyses suggest that the promoter site is bound by nuclear protein complexes containing cAMP-independent members of the ATF/CREB family of proteins and c-Jun, and are functionally distinct from the AP1-related TPA-response element (TRE) binding activity.

Activating Transcription Factors↗
PubMed1993

Mosaic isochromosome 8p.

Findings in a patient with mosaic isochromosome 8p are compared with those of previously reported cases. There were no distinguishing findings on physical examination; all had cognitive delays, especially in speech and language development.

Abnormalities, Multiple↗