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Biomedical subjects

M Gordon

Publications and source records attributed to M Gordon.

At least 73 records · Page 4Linked to original sources
PubMed1998

Temporal processing across frequency channels by FM selective auditory neurons can account for FM rate selectivity.

Auditory neurons tuned to the direction and rate of frequency modulations (FM) might underlie the encoding of frequency sweeps in animal vocalizations and formant transitions in human speech. We examined the relationship between FM direction and rate selectivity and the precise temporal interactions of excitatory and inhibitory sideband inputs. Extracellular single-unit recordings were made in the auditory midbrains of eight mustached bats. Up- and down-sweeping linear FM stimuli were presented at different modulation rates in order to determine FM selectivity. Brief tone pairs with varying interstimulus delays were presented in a forward masking paradigm to examine the relative timing of excitatory and inhibitory inputs. In the 33 units for which tone pair data were collected, a correspondence existed between FM rate selectivity and the time delays between paired tones. Moreover, FM directional selectivity was strongly linked to rate selectivity, because directional preferences were expressed only at certain rates and not others. We discuss how abnormalities in the relative timing of inputs could alter or abolish the selectivity of such neurons, and how such a mechanism could account for the perceptual deficits for formant transitions seen in certain children with phonological deficits.

Acoustic Stimulation↗
PubMed1998

Predicting hematological toxicity (myelosuppression) of cytotoxic drug therapy from in vitro tests.

Several clinical oncology units are studying the roles of in vitro hematotoxicology in phase I evaluations. At the same time, the European Center for the Validation of Alternative Methods (ECVAM) is supporting a validation study of the CFU-GM assay. It is important that these activities be coordinated so that high performance, optimized technical protocols are used for prospective and retrospective clinical evaluations. The EROTC, the NCI and ECVAM could provide support for these coordinated efforts. There is an opportunity for medical oncologists involved in early clinical trials to participate in the evaluation of in vitro tests and their clinical application . Fundamental to acceptance of these assays by oncologists and regulatory scientists, they must predict clinical outcome for myelosuppressive agents and then improve phase I design and performance. These achievements would justify more aggressive dose escalation schemes using guidance from in vitro studies without compromising patient safety. Success in predicting neutropenia might also stimulate the research required to understand how to predict other hematologic toxicities, such as a thrombocytopenia. The complexity of a validation study in hematotoxicology is that it seeks to predict the level of exposure that causes neutropenia, in contrast to other validation studies that have sought to classify a xenobiotic as toxic or not. It may be that the clinical relevance of a new assay is not just a yes-no answer. This important distinction came from the realization that the xenobiotic tolerance in other organ systems of the body must be the same or greater than marrow in order for myelosuppression to be a clinical consequence of exposure. Pharmacological principles of system exposure and toxicity that are integrated into the prediction model provide the links to clinical oncology. It is also important to anticipate future applications of in vitro hematotoxicology. If the maximum tolerated level of drug exposure for human hematopoietic cells can be predicted, then in vitro hematotoxicology could play an important role in new drug discovery. One concept involves screening for compounds that show efficacy at the IC level that predicts maximum tolerated exposure levels in the human. 'Therapeutic index based' drug discovery has been applied to the tallimustine family with some success.

Animals↗
PubMed1998

Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair.

Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer (HNPCC; refs 1-5). An important role for DNA replication errors in colorectal tumorigenesis has been suggested by the finding of frequent alterations in the length of specific mononucleotide tracts within genes controlling cell growth, including TGF-beta receptor type II (ref. 6), BAX (ref. 7) and APC (ref. 8). A broader role for MMR deficiency in human tumorigenesis is implicated by microsatellite instability in a fraction of sporadic tumours, including gastric, endometrial and colorectal malignancies. To better define the role of individual MMR genes in cancer susceptibility and MMR functions, we have generated mice deficient for the murine homologues of the human genes MLH1, PMS1 and PMS2. Surprisingly, we find that these mice show different tumour susceptibilities, most notably, to intestinal adenomas and adenocarcinomas, and different mutational spectra. Our results suggest that a general increase in replication errors may not be sufficient for intestinal tumour formation and that these genes share overlapping, but not identical functions.

Adaptor Proteins, Signal Transducing↗
PubMed1998

General practitioners' role in preventive medicine: scenario analysis using smoking as a case study.

AIM: It is the purpose of this paper to develop a model which may be used in conjunction with scenario analysis to evaluate strategies which are available to assist the general practitioner (GP) in reducing smoking behaviour among their patients. DESIGN: The scenario analysis uses a four-step procedure which involves identifying opportunities for detection, intervention and efficacy, and assigning probabilities to outcome to enable a range of prevention strategies to be examined in both isolation and in combination. SETTING AND PARTICIPANTS: This study deals specifically with Australian general practice and the model is derived by using information for a smoker visiting their GP within a 6-month period together with empirical evidence on the rates of detection, intervention and efficacy. MEASUREMENTS: The outcome measures, which are evaluated in terms of marginal effectiveness, include the number of smoking patients detected, the number of smoking patients offered an intervention, the number of smoker patients who quit as a result of the intervention and the additional years of life saved due to an intervention. FINDINGS. The most significant indicator for reducing smoking rates among patients is improving the efficacy of interventions. The results also suggest that although improvements in the rate of GP detection of patients' smoking status have a potentially greater effect on quit rates than increasing intervention levels, increasing both detection and intervention levels had a greater effect than each strategy alone. DISCUSSION: : General practitioners have an important role to play in preventive medicine. The knowledge, skill and attitude of practitioners toward smoking are significant, and they can be the prime motivators is persuading their patients to stop smoking. Detection, intervention and efficacious strategies are all key elements in achieving this result.

Family Practice↗
PubMed1998

Further characterization of the binding of human recombinant interleukin 2 to heparin and identification of putative binding sites.

We have previously provided compelling evidence that human recombinant interleukin 2 (IL-2) binds to the sulfated polysaccharides heparin, highly sulfated heparan sulfate and fucoidan. Here we show that IL-2 binding is dependent on heparin chain length, but with fragments as small as 15-mers retaining binding activity. The addition of exogenous heparin has no effect on the in vitro biological activity of IL-2. In addition soluble IL-2 receptor alpha and beta polypeptides do not compete with heparin for the binding of IL-2. IL-2 bound by heparin is still recognized by two IL-2 specific monoclonal antibodies, 3H9 and H2-8, whose epitopes lie in the amino terminal region. Murine IL-2 unlike its human counterpart fails to bind to heparin. Human IL-2 analogs with single amino acid substitutions at positions Lys43, Thr51, and Gln126 analogs no longer bind to heparin. By contrast the Arg38Ala analog retains heparin full heparin binding activity. These experimental findings together with molecular modeling studies suggest two putative heparin binding sites on human IL-2, one involving four basic residues, Lys48, Lys49, Lys54, and His55, and the other being a discontinuous site comprising Lys43, Lys64, Arg81, and Arg83. Neither of these two clusters is completely conserved in murine IL-2. Overall our data suggest that the binding of human IL-2 to heparin and heparan sulfate does not interfere with IL-2/IL-2 receptor interactions. Therefore, binding to glycosaminoglycan may be a mechanism for retaining the cytokine in an active form close to its site of secretion in the tissue, thus favoring a paracrine role for IL-2.

Animals↗
PubMed1998

Abbott AxSYM Vancomycin II assay: multicenter evaluation and interference studies.

The authors evaluated the performance characteristics of the Abbott AxSYM Vancomycin II immunoassay in sera of patients with (n = 93 samples) and without (n = 327 patients) renal dysfunction. Correlation of vancomycin measurements with the Abbott AxSYM Vancomycin, Abbott TDx/TDxFLx, Syva enzyme-multiplied immunoassay technique (EMIT), DuPont automated chemistry analyzer (ACA), and high-performance liquid chromatography methods showed acceptable correlation as indicated by: slope values >0.95, r-values >0.97, y-intercepts <1.7 microg/ml, and S(y/x) ranging from 9% to 15% of the average vancomycin value. The AxSYM Vancomycin II assay showed acceptable correlation with AxSYM vancomycin, TDx/TDxFLx, and high-performance liquid chromatography methods in 93 samples from patients with renal dysfunction. This monoclonal antibody-based assay showed no apparent interference from the presence of human antimouse antibody (HAMA) or the microbiologically inactive vancomycin crystalline degradation product (CDP). The authors conclude that the AxSYM Vancomycin II assay showed satisfactory agreement with other methods tested in this study.

Anti-Bacterial Agents↗
PubMed1998

Electromagnetic interference from a muscle stimulation device causing discharge of an implantable cardioverter defibrillator: epicardial bipolar and endocardial bipolar sensing circuits are compared.

This case report is about two patients with two different types of ICDs who underwent electrical muscle stimulation (EMS) therapy. In one patient with an ICD that has epicardial screw-in bipolar sensing leads, electromagnetic interference (EMI) from the EMS device caused the delivery of an inappropriate ICD discharge. In a second patient with an ICD with endocardial true bipolar sensing, there was no evidence of EMI during the EMS therapy despite all of our attempts to reproduce it. The sensing circuits in the two different ICDs are compared.

Aged↗
PubMed1998

Who are older adults? Demographics and major health problems.

The care of older patients is a challenging and often rewarding experience. Elderly people can be helped to fulfill their needs and realize their goals with a sensitive and comprehensive evaluation, a positive and supportive attitude and an emphasis on illness rather than disease. Health care providers can contribute greatly to improved function and enhanced quality of life through an understanding of and respect for the individual qualities and aspirations of their older patients.

Aged↗
PubMed1998

Histone- and protamine-DNA association: conservation of different patterns within the beta-globin domain in human sperm.

Most DNA in human sperm is bound to highly basic proteins called protamines, but a small proportion is complexed with histones similar to those found in active chromatin. This raises the intriguing possibility that histones in sperm are marking sets of genes that will be preferentially activated during early development. We have examined the chromatin structure of members of the beta-globin gene family, which are expressed at different times in development, and the protamine 2 gene, which is expressed in spermatids prior to the widespread displacement of histones by transition proteins. The genes coding for epsilon and gamma globin, which are active in the embryonic yolk sac, contain regions which are histone associated in the sperm. No histone-associated regions are present at the sites tested within the beta- and delta-globin genes which are silent in the embryonic yolk sac. The trends of histone or protamine association are consistent for samples from the same person, and no significant between-subject variations in these trends are found for 13 of the 15 fragments analyzed in the two donors. The results suggest that sperm chromatin structures are generally similar in different men but that the length of the histone-associated regions can vary. The association of sperm DNA with histones or protamines sometimes changes within as little as 400 bp of DNA, suggesting that there is fine control over the retention of histones.

Binding Sites↗
PubMed1998

Comparative magnetic resonance image-based evaluation of thalamotomy and pallidotomy lesion volumes.

Acute thalamotomy and pallidotomy lesion volumes based on magnetic resonance (MR) images were measured in 22 patients (11 thalamotomy and 11 pallidotomy patients). Thalamotomy inner lesion volumes (0.06 +/- 0.04 ml; thermocoagulative zone) were smaller than pallidotomy inner lesion volumes (0.14 +/- 0.08 ml) as determined using T(1)-weighted 3D-MPRAGE (1.5-mm slice spacing). Similar results were found using T(1)-weighted (6-mm slice spacing) image sets (0.09 +/- 0.05 ml, thalamotomy; 0.13 +/- 0.05 ml, pallidotomy). No differences were found when comparing thalamic or pallidal inner lesion volumes when the comparison was based on T(2) weighted images. Thalamotomy total lesion volumes (thermocoagulative and surrounding edematous zones) were less than pallidotomy total lesion volumes independent of the MR protocol. The difference in thalamotomy and pallidotomy lesion volumes is most likely based on the distance between each discrete lesion placed along the lesioning tracts. In 7 of 11 thalamotomies, this distance was 1 mm with the remaining having 2 mm between each discrete lesion. All pallidotomy discrete lesions were 2 mm apart. More overlap between discrete lesioning sites for thalamotomies is likely to produce reduced lesion volumes.

Adult↗
PubMed1998

Lesion volume and clinical outcome in stereotactic pallidotomy and thalamotomy.

Postoperative lesion volume and clinical outcome were assessed in 19 Parkinson's disease (PD) patients who received posteroventral pallidotomy, and in 14 essential tremor (ET) patients who received ventrolateral thalamotomy. Before and after surgery, PD patients were evaluated using the Unified PD Rating Scale (UPDRS), and ET patients were evaluated using the Fahn-Tolosa-Marin (FTM) tremor rating scale. Inner and total lesion volumes were determined with postoperative MR imaging and three-dimensional data segmentation. Lesion volumes were compared to percent improvement in UPDRS and FTM scores, using Spearman's rank-order correlation test. No rank-order correlations were found between lesion volume and clinical improvement in either the PD or the ET patients. In performing stereotactic surgery for movement disorders, any lesion volume within a prescribed range may be equally effective in relieving symptoms associated with PD or ET.

Aged↗
PubMed1998

Modifications of airway reconstruction in children.

We review our treatment experience of subglottic stenosis in 66 children. Sixty-one of these children required some form of airway expansion using cartilage grafts. Eight children had grade I (Cotton classification), 15 grade II, 28 grade III, and 15 grade IV stenosis. All patients with grade I and II lesions were decannulated. Ninety-three percent of grade III patients and 67% of grade IV patients were also ultimately decannulated. Laryngotracheal reconstruction with costal cartilage grafting has become widely accepted for treatment of severe laryngotracheal stenosis. Several modifications of this technique have been employed to treat our patients. Recently, we have used a modified single-stage technique with an endotracheal tube stent, externally secured for 1 week, to avoid postoperative intensive care unit admission for sedation and/or paralysis, and its related complications. Posterior graft design and placement without sutures was also performed in 20 cases. A two-surgeon technique that involves a simultaneous endoscopic control of incision of the stenotic area was employed. These modifications will be described in detail.

Adolescent↗
PubMed1998

Phytoremediation of trichloroethylene with hybrid poplars.

Axenic tumor cultures of poplar cells, clone H11-11, were grown in the presence of [14C]-trichloroethylene (TCE) (uniformly labeled). The cells were capable of metabolizing TCE to produce trichloroethanol, di- and trichloroacetic acid. Some of the carbon from TCE was found in insoluble, nonextractable cell residue, and small amounts were mineralized to [14C]CO2. Poplar cuttings grown in soil and exposed to TCE produced the same metabolites. In field trials, trees were planted in soil in test cells and exposed to TCE via underground water injection during the growing season. During the growing season, at least 95% of the TCE was removed from the influent water stream in cells containing trees. Mass balance studies conducted in the laboratory indicated that 70 to 90% of the TCE was transpired; however, greenhouse and field study results showed that less than 5% of the total TCE taken up by the plants is transpired. These results show that significant TCE uptake and degradation occur in poplars. Poplars appear to be useful for in situ remediation of TCE-contaminated sites under proper conditions.

Biodegradation, Environmental↗
PubMed1998

A placebo-controlled trial of the immune modulator, lentinan, in HIV-positive patients: a phase I/II trial.

Lentinan is a beta 1-->3 glucan isolated from Lentinus edodes (Shiitake mushroom) which has immune modulating properties. We have conducted two phase I/II placebo-controlled trials on a total of 98 patients. In one study at the San Francisco General Hospital (SFGH), ten patients each were administered 2, 5, or 10 mg of lentinan or placebo i.v. once a week for eight weeks. In the second study at the Community Research Initiative in New York (CRI), two groups of 20 patients each were administered 1 or 5 mg of lentinan i.v. twice a week for 12 weeks, and ten patients were administered placebo (vehicle containing mannitol plus dextran 40) i.v. twice a week. Entry criteria were an HIV positive test, CD4 levels of 200-500 cells, age 18-60 years, and without current opportunistic infections. This study confirms, in Caucasian subjects also, the good tolerability of lentinan observed in Japanese cancer patients. Side effects were mainly mild, especially when infusion was carried out over a 30-minute period. In the SFGH study, where administration was over a ten minute period, there were nine side effects severe enough to be reported to the FDA (one case each of anaphylactoid reaction, back pain, leg pain, depression, rigor, fever, chills, granulocytopenia and elevated liver enzymes) and there were four patients who discontinued therapy because of side effects. In the CRI study, where infusion was over a 30-minute period, there were no side effects reportable to the FDA and there were four dropouts due to side effects or personal preference. Most side effects resolved promptly after the discontinuation of medication, and all of them were relieved within 24 hours. Patients in the study have shown a trend toward increases in CD4 cells and in some patients neutrophil activity. Because of the small numbers, these values do not have statistical significance. Inasmuch as no side effects such as anemia, leukopenia, pancreatitis or neuropathy were seen, and in view of the positive effects of lentinan on certain surrogate markers (recognizing that these were small studies), we recommended a long-term clinical trial of lentinan in combination with didanosine (ddI) or zidovudine in HIV positive patients. Most patients in these trials did not have measurable p24 levels. In the CRI trials of ten patients with elevated p24 levels, eight on lentinan and two on placebo had decreased p24 levels. Of these decreases, those with lentinan and one with placebo were marked. These results were provocative and needed confirmation. Subsequent to this study, a trial of lentinan in combination with didanosine (ddI) showed a mean increase of 142 CD4 cells/mm3 over a twelve month period, in contrast to a decrease in CD4 cells in patients on ddI alone (Gordon et al. 1995).

Adjuvants, Immunologic↗