Biomedical subjects
T Davis
Publications and source records attributed to T Davis.
Usefulness of intravenous magnesium for multifocal atrial tachycardia in patients with chronic obstructive pulmonary disease.
Intravenous magnesium is an effective drug for rate control in multifocal atrial tachycardia. In addition, magnesium may be helpful in restoring sinus rhythm.
Repressive and defensive coping styles predict resting plasma endorphin levels in the elderly.
Jamner, L.D., Schwartz, G.E., 1986, Psychosom. Med. 48, 211-223, have proposed that repressive and defensive coping are associated with greater central endogenous opioid activity. They reasoned that high-defensive (HD) participants' attenuated distress, increased pain tolerances, attenuated somatic symptomatology, and accentuated reports of positive emotions are consistent with actions of centrally active opioid peptides. The present study assessed plasma beta-endorphin (END) levels, Marlowe Crowne Social Desirability Scale (MCSD), and Taylor Manifest Anxiety Scale (TMAS) scores in men (n = 6) and women (n = 20) between the ages of 59 and 79. Contrary to predictions, HD had lower plasma endorphin levels than did low-defensive (LD) participants. Raw MCSD scores correlated negatively with endorphin levels. Findings were significant for women only, which may have been due to the small sample of men. The results are discussed as they related to the hypothesis that defensiveness involves alteration of central opioid systems.
Oxygen permeability of a new type of high Dk soft contact lens material.
Lotrafilcon A is a biphasic block-copolymer, comprising a highly permeable siloxane-based polymeric phase, coupled with a water phase (hydrogel phase). The high oxygen permeability of this material, and the fact that it is a hydrogel, places it outside the applicability of both the polarographic ISO standard and coulometric ISO draft standards for contact lens Dk determination. The oxygen permeability (Dk) and transmissibility (Dk/t) of lotrafilcon A lenses were determined by an adaptation of the standard coulometric method. Lenses with a thickness (t) range from 30 microns to over 300 microns were measured in a liquid-to-gas and a gas-to-gas configuration in an effort to combine features of the ISO (draft) standards to yield a valid measurement of the intrinsic material's oxygen transmission characteristics. The following results, for lotrafilcon A, are the mean values and SE for the oxygen permeability coefficient (Dk) determined at 34 degrees C: 140 +/- 2 barrer with water overlay (liquid-to-gas) at 2100 rpm stirring speed, 150 +/- 5 barrer with water overlay (liquid-to-gas) at "infinite" stirring speed, and 170 +/- 2 barrer without water overlay (gas-to-gas), where barrer = 10(-11) (mlO2.cm)/(sec.cm2.mm Hg). Clinical lenses produced from this material are expected to be in the 60 to 90 microns thickness range, with an average center thickness of 80 microns. Given that the Dkmaterial is greater than or equal to 140 barrers, for this material, a parallel sided lens of 80 microns central thickness would exhibit a lens transmissibility (Dk/t) of at least 170 x 10(-9) mlO2/(sec.cm2.mm Hg) at 34 degrees C. This transmissibility is well in excess of the 87 x 10(-9) mlO2/(sec.cm2.mm Hg) value postulated to be sufficient to prevent overnight lens-induced corneal swelling and places it in the hyper-permeable material category.
Neuromuscular stimulation for upper extremity motor and functional recovery in acute hemiplegia.
BACKGROUND AND PURPOSE: The purpose of this study was to assess the efficacy of neuromuscular stimulation in enhancing the upper extremity motor and functional recovery of acute stroke survivors. METHODS: Forty-six stroke survivors admitted to an inpatient rehabilitation unit were randomly assigned to receive either neuromuscular stimulation or placebo. Twenty-eight subjects completed the study. The treatment group received surface neuromuscular stimulation to produce wrist and finger extension exercises. The control group received placebo stimulation over the paretic forearm. All subjects were treated 1 hour per day, for a total of 15 sessions. Outcomes were assessed in a blinded manner with the upper extremity component of the Fugl-Meyer Motor Assessment and the self-care component of the Functional Independence Measure at pretreatment, after treatment, and at 4 and 12 weeks after treatment. RESULTS: The treatment subjects and control subjects had comparable baseline characteristics. Parametric analyses revealed significantly greater gains in Fugl-Meyer scores for the treatment group after treatment (13.1 versus 6.5; P=0.05), at 4 weeks after treatment (17.9 versus 9.7; P=0.05), and at 12 weeks after treatment (20.6 versus 11.2; P=0.06). Functional Independence Measure scores were not different between groups at any of the time periods (P>0.10). CONCLUSIONS: Data suggest that neuromuscular stimulation enhances the upper extremity motor recovery of acute stroke survivors. However, the sample size in this study was too small to detect any significant effect of neuromuscular stimulation on self-care function.
Protein phosphatase 4 is an essential enzyme required for organisation of microtubules at centrosomes in Drosophila embryos.
The protein serine/threonine phosphatase 4 (PP4), which localises to centrosomes/spindle pole bodies in human cells, is shown to exhibit a similar localisation in Drosophila cells and embryos and possess a highly conserved (91% identical) amino acid sequence from humans to invertebrates. A homozygous Drosophila melanogaster strain mutant in the PP4 gene at 19C1-2 has been produced using P element mutagenesis. This strain, termed centrosomes minus microtubules (cmm), has reduced amounts of PP4 mRNA, approximately 25% of normal PP4 protein in early embryos and exhibits a semi-lethal phenotype with only 10% viability in certain conditions. Reversion mutagenesis shows that the phenotype is due to the presence of the P element in the PP4 mRNA. In early cmm embryos, nuclear divisions become asynchronous and large regions containing centrosomes with no well defined radiating microtubules are visible. In such areas, most nuclei arrest during mitosis with condensed DNA, and mitotic spindle microtubules are either absent, or aberrant and unconnected to the centrosome. A reduction in the staining of gamma-tubulin at centrosomes in cmm embryos suggests a conformational change or relocation of this protein, which is known to be essential for initiation of microtubule growth. These findings indicate that PP4 is required for nucleation, growth and/or stabilisation of microtubules at centrosomes/spindle pole bodies.
Short report: Decrease in seroprevalence of antibodies to hantavirus in rodents from 1993-1994 hantavirus pulmonary syndrome case sites.
Rodent trapping was conducted at seven hantavirus pulmonary syndrome (HPS) case sites from June 1993 to March 1994 during the HPS outbreak in the southwestern United States. To determine if there were changes in the rodent population or the hantavirus seroprevalence in rodents since the HPS outbreak, rodents were trapped at the same sites three years later using the same trapping protocol. The trap success decreased from the numbers trapped during the outbreak, however, the number of Peromyscus, as a percentage of the total rodents captured, did not noticeably decrease. In addition, the seroprevalence of hantavirus antibodies in Peromyscus decreased significantly (P < 0.0001).
Clinical trials referral resource. Clinical trials using monoclonal antibodies.
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Evidence-based nursing practice.
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Research rounds. Evidence-based nursing practice.
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MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines.
A candidate tumor suppressor gene, MMAC1/PTEN, located in human chromosome band 10q23, was recently identified based on sequence alterations observed in several glioma, breast, prostate, and kidney tumor specimens or cell lines. To further investigate the mutational profile of this gene in human cancers, we examined a large set of human tumor specimens and cancer cell lines of many types for 10q23 allelic losses and MMAC1 sequence alterations. Loss of heterozygosity (LOH) at the MMAC1 locus was observed in approximately one-half of the samples examined, consistent with the high frequency of 10q allelic loss reported for many cancers. Of 124 tumor specimens exhibiting LOH that have been screened for MMAC1 alterations to date, we have detected variants in 13 (approximately 10%) of these primary tumors; the highest frequency of variants was found in glioblastoma specimens (approximately 23%). Novel alterations identified in this gene include a missense variant in a melanoma sample and a splicing variant and a nonsense mutation in pediatric glioblastomas. Of 76 tumor cell lines prescreened for probable LOH, microsequence alterations of MMAC1 were detected in 12 (approximately 16%) of the lines, including those derived from astrocytoma, leukemia, and melanoma tumors, as well as bladder, breast, lung, prostate, submaxillary gland, and testis carcinomas. In addition, in this set of tumor cell lines, we detected 11 (approximately 14%) homozygous deletions that eliminated coding portions of MMAC1, a class of abnormality not detected by our methods in primary tumors. These data support the occurrence of inactivating MMAC1 alterations in multiple human cancer types. In addition, we report the discovery of a putative pseudogene of MMAC1 localized on chromosome 9.
Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor.
Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase. This mitogen-activated protein kinase pathway has been implicated in the signal transduction of cytokine- and stress-induced apoptosis in a variety of cell types. Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 human cancer cell lines prescreened for loss of heterozygosity, we detected two nonsense and three missense sequence variants of MKK4 in cancer cell lines derived from human pancreatic, breast, colon, and testis cells. In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase. Thus, the incidence of coding mutations of MKK4 in the set of cell lines is 6 of 213 (approximately 3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.
IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma.
IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell-specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.
Localization of SMAD5 and its evaluation as a candidate myeloid tumor suppressor.
Acquired interstitial or complete losses of chromosome 5 are recurring anomalies associated with preleukemic myelodysplasia and acute myelogenous leukemia with a poor prognosis. Previous studies have delineated a potential myeloid tumor suppressor locus to a <2.4-Mb interval between the genes for IL9 and EGR1 on 5q31. In this report, we have localized the SMAD5 gene, a homologue of the tumor suppressor genes SMAD4/DPC-4 and SMAD2/JV18.1, to the minimal myeloid tumor suppressor locus and characterized its open reading frame and genomic organization. SMAD5 transcripts are readily detectable in hematolymphoid tissues and leukemic blasts. Absence of intragenic mutations in the remaining SMAD5 allele of leukemic patients and multiple solid tumor cell lines prescreened for loss of heterozygosity suggests that SMAD5 may not be a common target of somatic inactivation in malignancy.
Cycling Werner's syndrome fibroblasts display calcium-dependent potassium currents.
Werner's Syndrome (WS) fibroblasts undergo premature senescence. Two hypotheses have been proposed to explain this phenomenon: (i) the phenotype is due to the overexpression of senescence-specific proteins in every cell in the population. Such proteins are known to suppress calcium-dependent potassium currents. (ii) The WS mutation greatly increases the proportion of cells that stop cycling at each generation and become senescent. If hypothesis (i) is correct, such currents should be suppressed in all WS fibroblasts; whereas hypothesis (ii) predicts that they will be retained in the cycling fraction of the population. To distinguish between these hypotheses whole-cell patch-clamp currents were recorded from cycling cells. Slowly activating outward calcium-dependent potassium currents were detected in both cycling WS and control fibroblasts. These findings support hypothesis (ii): the premature senescence of WS fibroblasts is due to an increased rate of transition from cycling to senescence in the total cell population.
Purification, characterisation, and molecular cloning of a chicken erythroblast mono(ADP-ribosyl)transferase.
We have purified an arginine-specific mono(ADP-ribosyl)transferase from chicken erythrocytes. The purified transferase was free from poly (ADP-ribose) polymerase activity. The molecular weight of the purified enzyme was estimated to be 27.5 kDa by gel filtration through Sephadex G-75 in a non-denaturing solvent. Activity gel experiments indicate that the active enzyme has an apparent molecular weight in SDS gels of about 28 kDa. The optimum pH of the reaction is about 8.0. The K(m) value for NAD+ of the purified enzyme is about 130 microM. Small molecular weight inhibitors of poly (ADP-ribose) polymerase have no significant effect on the mono ADP-ribosyl transferase enzyme activity. A number of inhibitors of the arginine-specific mono(ADP-ribosyl)transferase activity have been identified. Among the more effective inhibitors are 1,4 naphthoquinone, 5,8-dihydroxy-1,4-naphthoquinone, 4-amino-1-naphthol and 1,2-naphthoquinone. We have also cloned a mono(ADP-ribosyl)transferase from chicken erythroblasts. This gene has been expressed in E. coli and ADP-ribosylation activity has been demonstrated using histones as substrate. The activity is shown to be arginine-specific by the use of poly-L-arginine as substrate. Use of a specific inhibitor has shown that this enzyme is indeed a mono(ADP-ribosyl)transferase and not a NAD glycohydrolase activity. The sequence of this gene is very similar to several other mono(ADP-ribosyl)transferase genes. There are thus at least three different chicken mono(ADP-ribosyl)transferase genes in the blood system alone; this suggests that there is a quite large family of mono(ADP-ribosyl)transferase genes in animals. We have also isolated the promoter region of this chicken gene and are able to identify several standard motifs in this promoter.
Human COL6A1: genomic characterization of the globular domains, structural and evolutionary comparison with COL6A2.
The alpha1(VI) and alpha2(VI) chains of type VI collagen (nonfibrillar) are highly similar and are encoded by single-copy genes in close proximity on human Chromosome (Chr) 21q22.3, a gene-rich region that has proved refractory to cloning. For the alpha1(VI) chain, only the regions encoding the triple-helical and the promoter have been characterized hitherto.To facilitate our study of the role of this gene in the phenotype of Down syndrome, we have cloned and sequenced the amino- and carboxyl-terminal globular domains of COL6A1. The amino-terminal domain consists of seven exons and the carboxyl-terminal globular domain of nine exons. Together with the exons of the triple-helical domain, COL6A1 is encoded by a total of 36 exons spanning approximately 30 kb. Comparison of the genomic organization of COL6A1 and COL6A2 revealed that despite the similarity within their triple-helical domains, the intron-exon structures of their globular domains differ markedly. Conservation is limited to the exons encoding amino acids immediately adjacent to the triple-helical region, including the cysteine residues essential for the structure of mature collagen VI. The intron-exon structures of these two genes are highly similar to the collagen VI genes of chicken. These data suggest that COL6A1 and COL6A2 arose from a gene duplication before the divergence of the reptilian and mammalian lineages.
Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.
Deletions involving regions of chromosome 10 occur in the vast majority (> 90%) of human glioblastoma multiformes. A region at chromosome 10q23-24 was implicated to contain a tumour suppressor gene and the identification of homozygous deletions in four glioma cell lines further refined the location. We have identified a gene, designated MMAC1, that spans these deletions and encodes a widely expressed 5.5-kb mRNA. The predicted MMAC1 protein contains sequence motifs with significant homology to the catalytic domain of protein phosphatases and to the cytoskeletal proteins, tensin and auxilin. MMAC1 coding-region mutations were observed in a number of glioma, prostate, kidney and breast carcinoma cell lines or tumour specimens. Our results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.