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Biomedical subjects

M Gordon

Publications and source records attributed to M Gordon.

At least 37 records · Page 2Linked to original sources
PubMed1995

The cloning of Grb10 reveals a new family of SH2 domain proteins.

SH2 domains function to bind proteins containing phosphotyrosine and are components of proteins that are important signal transducers for tyrosine kinases. We have cloned SH2 domain proteins by screening bacterial expression libraries with the tyrosine phosphorylated carboxyterminus of the epidermal growth factor (EGF) receptor. Here we report the identification of a new SH2 domain protein, Grb10. Grb10 is highly related to Grb7, an SH2 domain protein that we have previously identified. In addition to an SH2 domain, Grb7 and Grb10 have a central domain with similarity to a putative C. elegans gene likely to be involved in neuronal migration. At least three forms of Grb10 exist in fibroblasts apparently due to alternate translational start sites. Grb10 undergoes serine but not tyrosine phosphorylation after EGF treatment resulting in a shift mobility in a large fraction of Grb10 molecules. However Grb10 appears to bind poorly to EGF-Receptor and the true binding partner for the Grb10 SH2 domain is unclear. Grb10 maps to mouse chromosome 11 very close to the EGF-Receptor which is remarkably similar to Grb7 that maps near the EGF-Receptor related HER2 receptor. The finding of multiple family members with evolutionarily conserved domains indicates that these SH2 domain proteins are likely to have an important, although as of yet, unidentified function.

3T3 Cells↗
PubMed1995

Identification of residues on CD40 and its ligand which are critical for the receptor-ligand interaction.

Interactions between gp39 (CD40L, TRAP, T-BAM) on activated T cells and CD40 on antigen-presenting cells play an important role in regulating antibody production by B cells, cytokine production by monocytes, and other immune responses which require T cell "help". Using structure-based sequence alignments, a molecular model of gp39, site-directed mutagenesis, and receptor-ligand binding assays, we have identified CD40 and gp39 surface residues which are important for receptor-ligand binding. Binding studies with CD40 or gp39 proteins containing single and double amino acid substitutions showed that CD40 residues Y82, D84, and N86 are involved in gp39 binding, while gp39 residues K143 and Y145 are important for CD40 binding. Analysis of the location of amino acid substitutions in the naturally occurring gp39 mutants expressed by the X-linked hyper-IgM (X-HIM) patients studied to date indicated the E129/G substitution found in the S128/R-E129/G double mutant affects a solvent-accessible residue which might participate in CD40/gp39 binding. Binding studies with E129/G and E129/A gp39 point mutants showed that this residue does not contribute directly to CD40/gp39 binding but that its substitution with a glycine disrupts the gp39 structure. Comparison of the gp39 and CD40 residues involved in receptor-ligand contacts with those previously identified as playing an important role in TNF-beta/TNFR binding suggests that some of the identified residues from contacts similar to those found in the TNF-beta/TNFR while others are unique to the CD40-gp39 interaction.

Amino Acid Sequence↗
PubMed1995

A randomized, prospective study of adjunctive ceftizoxime in preterm labor.

OBJECTIVE: Our purpose was to determine the effect of ceftizoxime in the prolongation of pregnancies receiving tocolysis for preterm labor. STUDY DESIGN: A prospective, randomized, double-blinded, placebo-controlled trial was conducted in patients with preterm labor between 24 and 35 weeks' gestation. A total of 545 patients with intact membranes and without chorioamnionitis who were receiving magnesium sulfate were screened. Exclusions were for advanced cervical dilatation, penicillin allergy, current antibiotic therapy, and failure to give informed consent. Of these, 117 consecutive, eligible, consenting patients were randomized to receive either 2 gm of ceftizoxime or a placebo every 8 hours. The primary end point was prolongation of gestation. Statistical comparisons were performed by use of unpaired two-tailed t tests and chi 2 analysis. RESULTS: Of the 58 ceftizoxime and 59 placebo patients, there was no difference in the interval to delivery (34.5 +/- 21.1 days vs 34.6 +/- 24.5 days, p = 0.99) and no difference in the rate of delivery before 37 weeks' gestation (60% in the ceftizoxime group vs 58% in the placebo group, p = 0.91). Subanalyses of 61 subjects who received nine or more doses and who were group B streptococci negative, 69 patients at < or = 32 weeks on presentation, and 22 sets of twins all showed no differences in delivery interval or rate of delivery at < 37 weeks. The sample size of this study was sufficient to detect a 9-day difference in prolongation of pregnancy (alpha = 0.05, beta = 0.2). CONCLUSIONS: Ceftizoxime had no effect on interval to delivery or duration of pregnancy in women treated for preterm labor.

Adolescent↗
PubMed1995

CPR instruction by videotape: results of a community project.

STUDY OBJECTIVE: To increase the rate of bystander CPR in a community by use of a free, mailed, 10-minute videotape of CPR instruction. DESIGN: Prospective, randomized intervention trial. One half of the households (8,659) received the free videotape (video-tape group) and were considered the intervention group, and one half (8,659) served as the control (no-videotape group). All households were followed from December 1991 to March 1993 to determine whether a cardiac arrest occurred and who initiated CPR. A telephone interview obtained additional information about circumstances of the arrest and whether members of the household viewed the videotape. SETTING: City of Everett and South Snohomish County, Washington. A commercial mailing list was used to identify 17,318 households with a head of the household who was more than 50 years old. PARTICIPANTS: A case was defined as a cardiac arrest in which CPR was initiated or continued by emergency medical services personnel. Only cardiac arrests due to presumed underlying heart disease were included. Arrests occurring after arrival of emergency medical services personnel were not included. INTERVENTIONS: The intervention was a free 10-minute videotape with CPR instructions mailed to the 8,659 intervention households. Paramedic run reports were reviewed and interviews were conducted with cardiac arrest bystanders to determine who initiated CPR and whether they had received and viewed the videotape. RESULTS: Sixty-five cardiac arrests occurred in the study households: 31 in households that received the videotape and 34 in households that did not review the videotape. The overall rate of bystander CPR was 47% in the videotape group and 53% in the no-videotape group (P = NS). In nine cardiac arrests, an individual was present who had watched the videotape; six of these nine cases (66%) had bystander CPR. CONCLUSION: Mass mailings of CPR instructional videos are likely to be ineffective in increasing the rate of bystander CPR in a community.

Aged↗
PubMed1995

Bacteremic pneumococcal pneumonia. A community hospital experience.

We reviewed our experience with bacteremic pneumococcal pneumonia (BPP) over a 1-year period at a 600-bed community teaching hospital; 26 cases were identified. The mean age was 57.5 years and there were 12 male and 14 female subjects. Cough, sputum production, fever, and mental status changes were the most frequent symptoms. Risk factors included drug abuse in 10, HIV in 4, current smoking in 7, diabetes in 3, and cancer in 3. The mean PaO2/FIo2 ratio was 274. Radiographic features included a consolidation pattern in 7, bronchopneumonia in 15, combined in 1, and an initial normal film in 3. Average length of stay (LOS) was 11 days with an overall mortality of 11.5%. Four patients required mechanical ventilation, two meeting the criteria for ARDS (if this group were eliminated, LOS would be 8.4 days). Three of these survived. Four patients had organisms resistant to penicillin and all survived. We conclude that (1) BPP remains a serious but treatable infection particularly when utilizing full supportive care; (2) the bronchopneumonia x-ray film pattern was associated with all the mortality; and (3) the occurrence of penicillin resistance did not contribute to the mortality, since early recognition and the use of appropriate antibiotics saved all of these patients.

Adult↗
PubMed1995

A pilot study of the biologic and therapeutic effects of granulocyte colony-stimulating factor (filgrastim) in patients with acute myelogenous leukemia.

In a carefully monitored pilot study, the in vivo biologic effects of filgrastim were investigated in eight patients with relapsed/refractory acute myelogenous leukemia. Within each patient, filgrastim was administered as a single agent prior to any chemotherapy in escalating doses of 0.12-6.0 micrograms/kg/day as a continuous intravenous infusion. The dose was increased every 14 days until an ANC of > or = 2500/mm3 had been achieved or there was evidence of proliferation of the leukemia. In patients who demonstrated growth of the leukemic clone, cytosine arabinoside was initiated at 200 mg/m2/day for 5 days. Through-out the course of therapy, the effects of filgrastim on maturation and proliferation were assessed by in vitro studies of bone marrow aspirates. Three patients demonstrated a sustained increase in ANC; one achieved a partial remission and remained on therapy for 31 weeks. Two of the three responding patients had hypocellular marrows at the time of initiating filgrastim and demonstrated a low but normal pattern of growth in CFU-GM assay early in the treatment course. This suggested that these two characteristics may define an environment in which filgrastim can induce a growth advantage for the normal residual hematopoietic elements. In this study of selected patients, filgrastim appeared safe.

Adult↗
PubMed1995

Lissencephaly gene (LIS1) expression in the CNS suggests a role in neuronal migration.

Miller-Dieker lissencephaly syndrome (MDS) is a human developmental brain malformation caused by neuronal migration defects resulting in abnormal layering of the cerebral cortex. LIS1, the gene defective in MDS, encodes a subunit of brain platelet-activating factor (PAF) acetylhydrolase which inactivates PAF, a neuroregulatory molecule. We have isolated murine cDNAs homologous to human LIS1 and mapped these to three different chromosomal loci (Lis1, Lis3, Lis4). The predicted sequences of murine Lis1 protein and its human homolog LIS1 are virtually identical. In the developing mouse and human, Lis1 and LIS1 genes were strongly expressed in the cortical plate. In the adult mouse Lis1 transcripts were abundant in cortex and hippocampus. The direct correlation between cortical defects in MDS patients and Lis1 expression in the murine cortex suggest that the mouse is a model system suitable to study the mechanistic basis of this intriguing genetic disease.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1995

Further clinical studies of curdlan sulfate (CRDS)--an anti-HIV agent.

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which inhibits the attachment of HIV to T-cells, and also has intracellular anti-HIV activity. In Phase I clinical trials, CRDS was found in 4 hr i.v. infusions, to be well tolerated up to 200 mg/70 kg and unexpectedly to produce marked, dose-related increases in CD4 lymphocytes in HIV-infected patients. Prolongation of bleeding time is expected to be the dose limiting toxicity, but no episodes of bleeding were seen. In one of the studies in this report, CRDS was administered i.v. daily for 7 days to HIV patients at doses of 40, 100, 140 and 180 mg/70 kg/day. At the higher doses, marked increases in CD4 and CD8 lymphocytes were observed. These increases mainly returned to baseline after 24 hr. To further delineate the pharmacokinetics of these changes in CD4 and CD8 lymphocytes, another Phase I study was done in which CRDS was infused i.v. over a 30 min period in HIV patients at single doses of 25, 50, 75, 100, 125, 150, 175 and 200 mg/70 kg/day. The drug was well tolerated in all cases and marked increases in CD4 lymphocytes were again seen at the higher doses, in some cases amounting to increases of 500 cells/mm3 after a single dose. The half-life of CRDS in man was found to be about two hours, as measured by activated partial thromboplastin time (APTT) and by plasma assays.

Antiviral Agents↗
PubMed1995

A phase II controlled study of a combination of the immune modulator, lentinan, with didanosine (ddI) in HIV patients with CD4 cells of 200-500/mm3.

This study was carried out to assess the safety and efficacy of a combination of lentinan, an immune modulator, and didanosine (ddI) in a controlled study in HIV positive patients with CD4 levels of 200-500 cells/mm3. Didanosine was administered to HIV patients at doses of 400 mg/day (po) for six weeks (bid), then 2 mg of lentinan i.v. was added per week for 24-80 weeks. A control group (20%) received ddI only. A total of 107 patients were enrolled at three sites, and 88 patients started the ddI/lentinan phase. The combination caused significant increases in CD4 levels up to 38 weeks, whereas ddI alone was significant at the 5% level at 14 weeks. Based on these data, lentinan qualifies as a participant in future multi-drug studies in HIV.

Adjuvants, Immunologic↗