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Biomedical subjects

D Johnson

Publications and source records attributed to D Johnson.

At least 181 records · Page 10Linked to original sources
PubMed1999

Paclitaxel, UFT, and calcium folinate in metastatic breast cancer.

This is a phase I dose-escalation study of uracil and tegafur (in a molar ratio of 4:1 [UFT]) administered in combination with calcium folinate and paclitaxel in metastatic breast cancer. This trial was initiated to 1) determine the maximum tolerated dose and dose-limiting toxicities of UFT plus calcium folinate (Orzel) administered three times per day for 21 days in combination with paclitaxel; and 2) define the appropriate dose for phase II testing. Thus far, 14 patients have been accrued to three dose levels. Two patients developed dose-limiting toxicities at dose level 3. One patient experienced grade 3 hypotension. A second patient experienced grade 3 vomiting, grade 4 diarrhea, and severe hand-foot syndrome. Two partial responses and one complete response have been observed. Early trends suggest that this regimen is active in metastatic breast cancer and is well tolerated. Completion of this study is anticipated in 1999.

Adult↗
PubMed1999

Effects of position of chest drainage tube on volume drained and pressure.

BACKGROUND: The nursing practice of avoiding dependent loops in the tubing of chest drainage systems because such loops may impede drainage and alter the intrapleural pressure is not research based. OBJECTIVES: To determine if the volume of fluid drained and pressure vary when the chest drainage tubing is straight, coiled, has a dependent loop, or has a dependent loop that is periodically lifted and drained. METHODS: A repeated-measures design was used. For each tubing position, 500 mL of fluid was infused into the pleural space of 8 adult pigs during 45 minutes. The volume of fluid drained and the pressure at 2 locations within the drainage tubing were measured for 1 hour. RESULTS: After 60 minutes, significantly less fluid (least significant difference test, P = .03) was drained with the dependent-loop tubing position (65 mL) than with the other 3 positions. However, the amount of fluid drained was not significantly different among the lift and drain (250 mL), coiled (301 mL), or straight (337 mL) tubing positions. Throughout the entire study, pressure at the connection between the chest tube and the drainage tube was significantly higher (least significant difference test, P = .003) for the dependent loop with and without periodic lifting and draining. CONCLUSIONS: Straight and coiled tube positions are optimal for draining fluid from the pleural space. If a dependent loop cannot be avoided, lifting and draining it every 15 minutes will maintain adequate drainage.

Animals↗
PubMed1999

The role of radiation, with or without chemotherapy, in the management of NSCLC.

Lung cancer is the leading cause of cancer death in the United States. Surgery is the treatment of choice for early stage patients. Despite radical surgery, patients with early stage lung cancer remain at risk for recurrence. The role of adjuvant therapy remains to be clearly defined. Locally advanced non-small-cell lung cancer is too extensive for surgical resection, yet does not show evidence of metastatic disease. Historically, these patients were treated with radiation alone. More recent studies have provided the rationale for combining radiation with chemotherapy for patients with good performance status who have locally advanced disease. For patients with marginally resectable tumors, treatment is often given preoperatively (neoadjuvant) as a means of shrinking the tumor to make it resectable. In patients with clearly unresectable disease, radiation with chemotherapy has been established as better than either modality alone. Palliative radiation alone can be used for patients who cannot tolerate this aggressive approach. The optimal sequencing, as well as the best chemotherapeutic agent to use, remains under investigation. Some of the newer agents showing promise in the treatment of non-small-cell lung cancer include paclitaxel (Taxol) and carboplatin (Paraplatin). Other agents that are currently under investigation include topotecan, gemcitabine, and vinorelbine (Navelbine).

Antineoplastic Agents↗
PubMed1999

Case-based explanation of non-case-based learning methods.

We show how to generate case-based explanations for non-case-based learning methods such as artificial neural nets or decision trees. The method uses the trained model (e.g., the neural net or the decision tree) as a distance metric to determine which cases in the training set are most similar to the case that needs to be explained. This approach is well suited to medical domains, where it is important to understand predictions made by complex machine learning models, and where training and clinical practice makes users adept at case interpretation.

Artificial Intelligence↗
PubMed1999

Process models for telehealth: an industrial approach to quality management of distant medical practice.

Process modeling is explored as an approach for prospectively managing the quality of a telemedicine/telehealth service. This kind of prospective quality management is more appropriate for dynamic health care environments compared to traditional quality assurance programs. A vector model approach has also been developed to match a process model to the needs of a particular site.

Humans↗
PubMed1999

Building barriers to HIV.

The AIDS epidemic has an increasingly female face, and the need for women to use effective contraceptive and infection prevention methods has taken on a new urgency. Consistent, proper condom use is the most effective method of preventing sexually transmitted disease. Research shows that condom breakage most commonly results from latex deterioration or incorrect use. Spermicidal cream or gel containing nonoxynol 9 is effective in preventing sexually transmitted diseases that cause genital ulcers and cervicitis. Spermicides cause genital tract irritation in some people, however, increasing their risk of STD infection. Diaphragms can protect against pregnancy, but since the devices only protect the cervix and a small area of the vagina, HIV or STD transmission may still occur. Oral contraceptives do not protect against STDs, nor do injectable and implantable contraceptives.

Adult↗
PubMed1998

Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children. National Institutes of Health-sponsored Pediatric AIDS Clinical Trials Group (ACTG-218).

Study objectives were to evaluate the safety and immunogenicity of three HIV recombinant glycoproteins in HIV-infected infants and children between 1 month and 18 years of age with asymptomatic (P-1) infection. Using Chiron rgp 120 (SF-2) 15 or 50 microg; MicroGeneSys rgp 160 (IIIB) 40 or 320 microg; Genentech rgp120 (MN) 75 or 300 microg; or adjuvant control (Alum or MF-59), children were randomized to a double-blind, placebo-controlled, dose-escalating study of vaccine administered intramuscularly at entry and 1, 2, 3, 4, and 6 months later. No adverse events were attributed to study vaccines. Between 30% and 56% of volunteers exhibited a lymphoproliferative response as defined in terms of stimulation index (SI) to vaccine antigens; 65% of vaccinees but none of placebo recipients exhibited moderate or strong responses after enzyme immunoassay to HIV specific antigens. CD4 cell counts and quantitative HIV culture did not differ significantly among vaccine and control groups, nor were differences found among groups in HIV disease progression. The rgp160 and gp120 subunit vaccines were safe and immunogenic in this population.

AIDS Vaccines↗
PubMed1998

Characterization of the neuropeptide Y5 receptor in the human hypothalamus: a lack of correlation between Y5 mRNA levels and binding sites.

Neuropeptide Y (NPY) is a 36-amino-acid peptide that appears to play a central role in the control of feeding behavior. Recently, a cDNA encoding a novel NPY receptor subtype (Y5) was cloned from the rat and human hypothalamus, and shown to have a pharmacology consistent with NPY-induced feeding. We have subsequently cloned this cDNA from human hypothalamus and stably expressed it in CHO cells. Consistent with earlier reports, hY5 has a high affinity for NPY, [Leu31, Pro34]NPY, and NPY(3-36), but low affinity for larger C-terminal deletions of NPY and BIBP3226. High levels of hY5 mRNA were found in the human testis, brain, spleen and pancreas, with lower levels in several other tissues. In the human brain, hY5 mRNA levels were typically higher than hY2, but lower in comparison to hY1 receptor mRNA. To quantify the relative amounts of hY1, hY2 and hY5 mRNA in the human hypothalamus, we employed competitive RT-PCR. Interestingly, the relative amount of hY5 mRNA was substantially higher than either hY1 or hY2. However, pharmacological characterization of NPY binding sites in human hypothalamus membranes revealed predominantly the hY2 subtype. These data establish that while hY5 mRNA levels are very high in the human hypothalamus, conventional radioligand binding techniques do not detect hY5-like binding site. Whether hY5-like binding sites exist in the other human tissues that express hY5 mRNA (and what function hY5 has in those tissues) awaits future investigation.

Animals↗
PubMed1998

The major myosin phosphatase in skeletal muscle is a complex between the beta-isoform of protein phosphatase 1 and the MYPT2 gene product.

Myosin is dephosphorylated by distinct forms of protein phosphatase 1 (PP1) in smooth muscle and skeletal muscle that are composed of PP1 complexed to different regulatory subunits. The smooth muscle myosin phosphatase (smPP1M) has been characterised previously and is composed of PP1beta complexed to M110 and M21 subunits that enhance the dephosphorylation of smooth muscle myosin, but not skeletal muscle myosin. In contrast, the regulatory subunit(s) of skeletal muscle myosin phosphatase (skPP1M) greatly enhance(s) the dephosphorylation of skeletal muscle myosin. Here we identify a regulatory subunit of skPP1M as the product of the MYPT2 gene, a protein whose sequence is 61% identical to the M110 subunit of smPP1M. Surprisingly, the M21 subunit of smPP1M appears to be produced from the same gene that encodes MYPT2.

Amino Acid Sequence↗
PubMed1998

Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization.

Duplications of chromosome region 15q11q13 often occur as a supernumerary chromosome 15. Less frequently they occur as interstitial duplications [dup(15)]. We describe the clinical and molecular characteristics of three patients with de novo dup(15). The patients, two males and one female (ages 3-21 years), had nonspecific findings that included autistic behavior, hypotonia, and variable degrees of mental retardation. The extent, orientation, and parental origin of the duplications were assessed by fluorescent in situ hybridization, microsatellite analyses, and methylation status at D15S63. Two patients had large direct duplications of 15q11q13 [dir dup(15)(q11q13)] that extended through the entire Angelman syndrome/Prader-Willi syndrome (AS/PWS) chromosomal region. Their proximal and distal breaks, at D15S541 or D15S9 and between D15S12 and D15S24, respectively, were comparable to those found in the common AS/PWS deletions. This suggests that duplications and deletions may be the reciprocal product of an unequal recombination event. These two duplications were maternally derived, but the origin of the chromatids involved in the unequal crossing over in meiosis differs. In one patient, the duplication originated from two different maternal chromosomes, while in the other patient it arose from the same maternal chromosome. The third patient had a much smaller duplication that involved only D15S11 and parental origin could not be determined. There was no obvious correlation between phenotype and extent of the duplication in these patients.

Adult↗
PubMed1998

Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation.

The relationship between mitochondrial genotype and clinical phenotype is complicated in most instances by the heteroplasmic nature of pathogenic mitochondrial mutations. We have previously shown that maternally inherited hearing loss in a large Arab-Israeli kindred is due to the homoplasmic A1555G mutation in the mitochondrial 12S ribosomal RNA gene [Prezant et al., 1993: Nat Genet 4:289-294]. Family members with this mutation have phenotypes ranging from profound hearing loss to completely normal hearing, and we have shown that there is genetic and biochemical evidence for nuclear gene involvement in this family [Bu et al., 1993: Genet Epidemiol 9:27-44; Guan et al., 1996: Hum Mol Genet 5:963-971]. To identify such a nuclear locus, two candidate genes were excluded through linkage analysis and sequencing, and a genome-wide linkage search in family members who all have the identical homoplasmic mitochondrial mutation, but differ in their hearing status, was performed. In two stages a total of 560 polymorphic genetic markers was genotyped, and the data were analyzed under model-dependent and model-free assumptions. No chromosomal region was identified as a major contributor to the phenotypic expression of the mitochondrial mutation. Thus, in this simplified paradigm of a homoplasmic mitochondrial mutation in a single kindred who all live in the similar environment of a small village, the penetrance of the mitochondrial mutation appears to depend on the interaction of multiple nuclear genes.

Chromosome Mapping↗
PubMed1998

Expression of the v-Src oncoprotein in fibroblasts disrupts normal regulation of the CDK inhibitor p27 and inhibits quiescence.

To determine how an oncogenic tyrosine kinase disturbs cell cycle control we examined expression of cell cycle proteins and growth of fibroblasts reversibly transformed by a temperature sensitive mutant of v-Src (ts LA 29). ts LA 29 Rat-1 cells and normal Rat-1 cells had similar growth rates but the transformed cells traversed the G1 phase of the cell cycle more rapidly and failed to exit cycle efficiently in response to serum starvation and cell confluence. Cyclin D1 and cyclin E levels were not elevated in growing ts LA 29 Rat-1 cells and the abbreviated G1 was further accelerated by overexpression of cyclin E. A fall in cyclin E and cyclin A dependent kinase activities in Rat-1 cells in response to inhibitory growth conditions was abrogated in ts LA 29 Rat-1 cells and correlated with lack of p27 accumulation or cyclin A down regulation, the latter due to sustained cyclin A promoter activity. The expression of p27 mRNA was lower in ts LA 29 Rat-1 cells than Rat-1 cells and was elevated following v-Src inactivation concurrent with an increase in p27 promoter activity and temporary cell cycle exit. The suppression of mRNA or transcription is a novel way an oncoprotein can induce down regulation of p27 and contributes to the G1 shortening and perturbed cell cycle regulation of the v-Src transformed cells.

Animals↗
PubMed1998

Characterization and cloning of the gene encoding the vacuolar membrane protein EXP-2 from Plasmodium falciparum.

As a contribution to the characterization of the parasitophorous vacuolar membrane from Plasmodium falciparum we have begun the identification of vacuolar membrane proteins. Exported protein-2 (EXP-2) is a vacuolar membrane protein exposed into the vacuolar space. To further characterize EXP-2, it was purified, and the 45 N-terminal amino acids were determined by micro-sequencing. Based on this information, partial cDNA and genomic fragments were amplified by PCR and used as probes for the isolation of complete cDNA and genomic DNA clones. The single copy gene is located on chromosome 14, and is transcribed during the ring stage of parasite development. The open reading frame encodes an N-terminal signal sequence which is cleaved from the mature protein. The amino acid composition of EXP-2 is characterized by charged amino acids, with a high abundance of aspartate residues in the C-terminal portion of the protein. In contrast to EXP-1, an integral protein of the vacuolar membrane, EXP-2 lacks a typical hydrophobic transmembrane domain. We suggest that EXP-2 may associate with the vacuolar membrane via an amphipathic helix located in the N-terminal half of the protein.

Amino Acid Sequence↗
PubMed1998

Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells.

Expression of the trabecular meshwork inducible glucocorticoid response (TIGR) gene progressively increases from barely detectable levels to greater than 2% of total cellular mRNA over 10 days exposure of trabecular meshwork (TM) cells to dexamethasone. Cycloheximide blocked most of the TIGR mRNA induction, suggesting a requirement for ongoing protein synthesis. The genomic structure of TIGR (approximately 20 kilobases) consists of 3 exons, and a 5-kilobase promoter region that contains 13 predicted hormone response elements, including several glucocorticoid regulatory elements, and other potentially important regulatory motifs. TIGR cDNA encodes an olfactomedin-related glycoprotein of 504 amino acids with motifs for N- and O-linked glycosylation, glycosaminoglycan initiation, hyaluronic acid binding, and leucine zippers. Recombinant TIGR (rTIGR) showed oligomerization and specific binding to TM cells. Anti-rTIGR antibody detected multiple translational/post-translational forms of TIGR produced by the cells (including secreted 66 kDa/55 kDa glycoproteins/proteins in the media and 55 kDa cellular proteins), whereas Northern blot showed a single mRNA species. The findings suggest potential mechanisms by which TIGR could obstruct the aqueous humor fluid flow and participate in the pathogenesis of glaucoma.

Amino Acid Sequence↗
PubMed1998

Aminopyrimidines with high affinity for both serotonin and dopamine receptors.

A series of [4-[2(4-arylpiperazin-1-yl)alkyl]cyclohexyl]pyrimidin-2-ylamine s was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.

Animals↗