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Biomedical subjects

R Davis

Publications and source records attributed to R Davis.

At least 73 records · Page 4Linked to original sources
PubMed2000

Therapy for patients with high grade astrocytoma using intraarterial chemotherapy and radiation therapy.

BACKGROUND: High grade astrocytomas account for approximately 40% of all primary brain tumors. The median survival is approximately 8-10 months for patients with glioblastoma multiforme and 36 months for patients with anaplastic astrocytoma. The results of systemic chemotherapy in the treatment of brain tumors have been reported to be less than satisfactory, mainly because of the blood-brain barrier impermeability for chemotherapeutic drugs. Intraarterial chemotherapy has been an attractive alternative with which to overcome this problem. METHODS: Eighty-three patients with high grade astrocytoma (glioblastoma multiforme [63 patients] and anaplastic astrocytoma--[20 patients]) were treated with intraarterial (intracarotid and/or intravertebral) chemotherapy and radiation therapy between 1987 and 1997. Patients received cisplatin, 60 mg/m2, and etoposide, 40 mg/m2. Radiation therapy was delivered either after completion of the chemotherapy or concomitantly with the chemotherapy. RESULTS: Thirty-four of 71 evaluable patients with high grade astrocytoma (48%) responded to the chemotherapy. The median survival for patients with glioblastoma multiforme who received chemotherapy prior to radiation therapy was 20 months versus 7 months for those patients who underwent concomitant chemotherapy/radiation therapy. Patients with anaplastic astrocytoma who received chemotherapy prior to radiation therapy had a median survival of 45 months compared with 12 months for patients who received concomitant chemotherapy/ radiation therapy. The toxicity profile has been reported to be mild and well tolerated. CONCLUSIONS: Intraarterial chemotherapy for patients with glioblastoma multiforme, delivered prior to radiation therapy, appears to result in a median survival three times longer than that achieved with concomitant chemotherapy/radiation therapy. In addition, patients appear to survive substantially longer than they do after radiation therapy with the addition of systemic chemotherapy. Side effects are reported to be acceptable.

Adult↗
PubMed2000

Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme.

Many membrane-bound proteins, including cytokines, receptors, and growth factors, are proteolytically cleaved to release a soluble form of their extracellular domain. The tumor necrosis factor (TNF)-alpha converting enzyme (TACE/ADAM-17) is a transmembrane metalloproteinase responsible for the proteolytic release or "shedding" of several cell-surface proteins, including TNF and p75 TNFR. We established a TACE-reconstitution system using TACE-deficient cells co-transfected with TACE and substrate cDNAs to study TACE function and regulation. Using the TACE-reconstitution system, we identified two additional substrates of TACE, interleukin (IL)-1R-II and p55 TNFR. Using truncations and chimeric constructs of TACE and another ADAM family member, ADAM-10, we studied the function of the different domains of TACE in three shedding activities. We found that TACE must be expressed with its membrane-anchoring domain for phorbol ester-stimulated shedding of TNF, p75 TNFR, and IL-1R-II, but that the cytoplasmic domain is not required for the shedding of these substrates. The catalytic domain of ADAM-10 could not be functionally substituted for that of TACE. IL-1R-II shedding required the cysteine-rich domain of TACE as well as the catalytic domain, whereas TNF and p75 TNFR shedding required only the tethered TACE catalytic domain.

ADAM Proteins↗
PubMed2000

Search for the decay &Bmacr;(0)-->D(*0)gamma

We report results of a search for the rare radiative decay &Bmacr;(0)-->D(*0)gamma. Using 9.66x10(6) B&Bmacr; meson pairs collected with the CLEO detector at the Cornell Electron Storage Ring, we set an upper limit on the branching ratio for this decay of 5.0x10(-5) at 90% C.L. This provides evidence that the anomalous enhancement is absent in W-exchange processes and that weak radiative B decays are dominated by the short-distance b-->sgamma mechanism in the standard model.

Journal Article↗
PubMed2000

The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).

Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function.

Amino Acid Sequence↗
PubMed2000

Abundant tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes.

The role of the cellular immune response in human T-cell leukemia virus type I (HTLV-I) infection is not fully understood. A persistently activated cytotoxic T lymphocyte (CTL) response to HTLV-I is found in the majority of infected individuals. However, it remains unclear whether this CTL response is protective or causes tissue damage. In addition, several observations paradoxically suggest that HTLV-I is transcriptionally silent in most infected cells and, therefore, not detectable by virus-specific CTLs. With the use of a new flow cytometric procedure, we show here that a high proportion of naturally infected CD4+ peripheral blood mononuclear cells (PBMC) (between 10% and 80%) are capable of expressing Tax, the immunodominant target antigen recognized by virus-specific CTLs. Furthermore, we provide direct evidence that autologous CD8+ T cells rapidly kill CD4+ cells naturally infected with HTLV-I and expressing Tax in vitro by a perforin-dependent mechanism. Consistent with these observations, we observed a significant negative correlation between the frequency of Tax(11-19)-specific CD8+ T cells and the percentage of CD4+ T cells in peripheral blood of patients infected with HTLV-I. Those results are in accordance with the view that virus-specific CTLs participate in a highly efficient immune surveillance mechanism that persistently destroys Tax-expressing HTLV-I-infected CD4+ T cells in vivo. (Blood. 2000;95:1386-1392)

Anti-Bacterial Agents↗
PubMed2000

The discovery of potent cRaf1 kinase inhibitors.

A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway.

Enzyme Inhibitors↗
PubMed2000

TR3 death receptor expression in the normal and ischaemic brain.

Members of the death receptor family may play a prominent role in developmental and pathological neuronal cell death. We report the expression of the TR3 and TR7 death receptors in the adult human and rat central nervous system. Whereas expression of TR3 appears to be high in the human cerebellum, with lower levels in other brain regions, robust expression is observed in many regions of the rat brain. We also analyzed modulation of death receptor expression in an in vivo rat model of acute stroke. In contrast to tumor necrosis factor receptor 1, Fas and p75(NGFR), which all show up-regulation specifically in lesioned cortex of the permanent middle cerebral artery occlusion model of stroke. TR3 shows a rapid global increase in both lesioned and unlesioned brain. In comparison, the recently described death receptor TR7 shows no change in this model. These data indicate that the death receptors show clear differences in patterns of expression in response to ischemic injury. ¿ 2000 IBRO. Published by Elsevier Science Ltd.

Amino Acid Sequence↗
PubMed2000

A community pseudo-outbreak of invasive Staphylococcus aureus infection.

Outbreaks of invasive infection caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus occur in hospitals, long term care institutions, and in patients discharged from these settings. In contrast, epidemic S. aureus infection has not been reported in well persons in the community. Here, we describe a group of healthy young adults who resided in the same neighborhood and participated together in school sports, and who developed serious S. aureus infections within 3 weeks of each other, suggesting a true community outbreak. Timely use of molecular epidemiological tools, however, demonstrated that their illnesses were caused by unrelated bacterial strains.

Adolescent↗
PubMed2000

Childhood sexual abuse and affective symptoms in women: a general population study.

BACKGROUND: Child sexual abuse (CSA) is associated, after controlling for other adversities, with a range of non-psychotic disorders in adult life. There is a need to clarify whether CSA contributes to risk of disorder in the absence of such adversities, and given that associations may be accounted for by genetic mechanisms, whether they are seen where the perpetrator of CSA is not a biological relative, and where there has been only one incident. METHODS: A questionnaire-based study of a socio-economically representative sample of women age 25-36 (N = 862) was carried out. Parental care and control were assessed using the Parental Bonding Instrument, and CSA using a previously validated questionnaire. Current affective symptoms were assessed from the depression scale of the GHQ-28. RESULTS: Low maternal and paternal care were associated with risk of abuse by a biologically unrelated perpetrator before the age of 11, but not during early adolescence. Low maternal care and CSA each made independent contributions to the prediction of affective symptoms. CSA by a non-relative was strongly associated with GHQ depression, as was CSA by a non-relative that had occurred only once. CONCLUSIONS: Quality of parental care probably influences risk of CSA by unrelated abusers in younger children, while there may be a combination of genetic and parental influences on the risk of abuse by a relative. The strong association of affective symptoms in adult life with CSA by a non-relative suggests an environmental effect. Studies, utilizing genetic designs, of the role of childhood trauma in relation to adult affective symptoms are needed.

Adult↗
PubMed2000

Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children.

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.

Adolescent↗
PubMed2000

Tissue-specific expression of a type I adenylyl cyclase rescues the rutabaga mutant memory defect: in search of the engram.

Most attempts to localize physical correlates of memory in the central nervous system (CNS) rely on ablation techniques. This approach has the limitation of defining just one of an unknown number of structures necessary for memory formation. We have used the Drosophila rutabaga type I Ca(2+)/CaM-dependent adenylyl cyclase (AC) gene to determine in which CNS region AC expression is sufficient for memory formation. Using pan-neural and restricted CNS expression with the GAL4 binary transcription activation system, we have rescued the memory defect of the rutabaga mutant in a fast robust spatial learning paradigm. The ventral ganglion, antennal lobes, and median bundle are likely the CNS structures sufficient for rutabaga AC- dependent spatial learning.

Adenylyl Cyclases↗
PubMed2000

Aligned microcontact printing of micrometer-scale poly-L-lysine structures for controlled growth of cultured neurons on planar microelectrode arrays.

We describe a method for producing high-resolution chemical patterns on surfaces to control the attachment and growth of cultured neurons. Microcontact printing has been extended to allow the printing of micron-scale protein lines aligned to an underlying pattern of planar microelectrodes. Poly-L-lysine (PL) lines have been printed on the electrode array for electrical studies on cultured neural networks. Rat hippocampal neurons showed a high degree of attachment selectivity to the PL and produced neurites that faithfully grew onto the electrode recording sites.

Animals↗
PubMed2000

Quiet pride: the experience of chronic illness by rural older adults.

PURPOSES: To explore how chronic illness is experienced and managed by rural Hispanic and non-Hispanic older adults and their families, and to identify how the health care system and community facilitate or inhibit the ability to manage chronic illness in a changing health care environment. DESIGN: Descriptive ethnography with purposive sampling. METHODS: Data-generation methods included audiotaped interviews from 42 Hispanic and White, non-Hispanic participants, participant observations, examination of documents and artifacts, and photography in rural Colorado. Interpretive ethnographic methods were used to identify an overarching cultural theme. FINDINGS: Living with chronic illness was a proactive, reciprocal learning process shaped by interrelationships in the context of multiple, diverse communities. Participants expressed living with chronic illness as a quiet pride on the journey toward living a meaningful life. CONCLUSIONS: Findings provide an understanding of the webs of relationships that constitute the experience of elders living with chronic illness in rural communities. Viewing life as meaningful in the context of a broader understanding of health and well-being is important for nursing practice and future models of care.

Aged↗
PubMed2000

Interaction of Shigella flexneri IpaC with model membranes correlates with effects on cultured cells.

Invasion of enterocytes by Shigella flexneri requires the properly timed release of IpaB and IpaC at the host-pathogen interface; however, only IpaC has been found to possess quantifiable activities in vitro. We demonstrate here that when added to cultured cells, purified IpaC elicits cytoskeletal changes similar to those that occur during Shigella invasion. This IpaC effect may correlate with its ability to interact with model membranes at physiological pH and to promote entry by an ipaC mutant of S. flexneri.

Antigens, Bacterial↗
PubMed2000

Probing structure-function relationships of the DNA polymerase alpha-associated zinc-finger protein using computational approaches.

We present the application of a method for protein structure prediction to aid the determination of structure-function relationships by experiment. The structure prediction method was rigourously tested by making blind predictions at the third meeting on the Critical Assessment of Protein Structure methods (CASP3). The method is a combined hierarchical approach involving exhaustive enumeration of all possible folds of a small protein sequence on a tetrahedral lattice. A set of filters, primarily in the form of discriminatory functions, are applied to these conformations. As the filters are applied, greater detail is added to the models resulting in a handful of all-atom "final" conformations. Encouraged by the results at CASP3, we used our approach to help solve a practical biological problem: the prediction of the structure and function of the 67-residue C-terminal zinc-finger region of the DNA polymerase alpha-associated zinc-finger (PAZ) protein. We discuss how the prediction points to a novel function relative to the sequence homologs, in conjunction with evidence from experiment, and how the predicted structure is guiding further experimental studies. This work represents a move from the theoretical realm to actual application of structure prediction methods for gaining unique insight to guide experimental biologists.

Amino Acid Sequence↗
PubMed2000

Comparison of family therapy and family group psychoeducation in adolescents with anorexia nervosa.

OBJECTIVE: To compare the effects of 4 months of 2 family-oriented treatments, family therapy and family psychoeducation, on female adolescents with newly diagnosed restrictive eating disorders. METHOD: Twenty-five female adolescents requiring hospitalization were randomized into either family therapy or family group psychoeducation. Outcome measures included medical (body weight) and psychosocial (specific and nonspecific eating disorder psychopathology) variables at baseline and after 4 months of treatments every 2 weeks. RESULTS: A significant time effect was found in both treatment groups for the restoration of body weight (percentage of ideal body weight, P < 0.00001). The group averages ranged from 75% to 77% ideal body weight before treatment to 91% to 96% after it. A time effect was also seen on the Family Assessment Measure (P < 0.018), in that the patients of both groups acknowledged more family psychopathology at the end of treatment. No significant group differences were found on any of the self-report measures of specific and nonspecific eating disorder pathology. CONCLUSIONS: Weight restoration was achieved following the 4-month period of treatment in both the family therapy and family psychoeducation groups, but no significant change was reported in psychological functioning by either adolescents or parents. Family group psychoeducation, the less expensive form of treatment, is an equally effective method of providing family-oriented treatment to newly diagnosed, medically compromised anorexia nervosa patients and their families.

Adolescent↗