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Biomedical subjects

D Young

Publications and source records attributed to D Young.

At least 127 records · Page 7Linked to original sources
PubMed2000

Clomiphene citrate-induced perturbations during meiotic maturation and cytogenetic abnormalities in mouse oocytes in vivo and in vitro.

OBJECTIVE: To determine if clomiphene citrate induces temporal perturbations during meiotic maturation and aneuploidy in mouse oocytes. DESIGN: A controlled dose study involving mouse oocytes in vivo and in vitro. SETTING: Clinical and academic research setting in a university medical center. INTERVENTION(S): Oocytes were obtained after superovulation and from mature follicles. MAIN OUTCOME MEASURE(S): Cytogenetic analysis of oocytes for aneuploidy, premature centromere separation, premature anaphase, and single chromatids, and the frequencies of metaphase I and diploid oocytes. RESULT(S): Clomiphene citrate resulted in a decrease in the number of ovulated oocytes and a significant (P<.05) increase in hyperploidy at 100 mg/kg in vivo. In vitro, 5.0 microg/mL of clomiphene citrate significantly (P<.05) increased hyperploidy and reduced the proportion of metaphase I oocytes. CONCLUSION(S): These findings suggest that clomiphene citrate has the potential for inducing aneuploidy in mouse oocytes both in vivo and in vitro and that the rate of oocyte maturation is altered after clomiphene exposure in vitro. Additional data are needed to support the results of this study.

Aneuploidy↗
PubMed2000

The predictability of corneal flap thickness and tissue laser ablation in laser in situ keratomileusis.

OBJECTIVE: To evaluate the relationship between predicted flap thickness and actual flap thickness and between predicted tissue ablation and actual tissue ablation. DESIGN: Prospective, nonrandomized comparative (self-controlled) trial. PARTICIPANTS: A total of 60 patients (102 eyes) who underwent laser in situ keratomileusis (LASIK). MAIN OUTCOME MEASURES: Subtraction pachymetry was used to determine actual corneal flap thickness and corneal tissue ablation depth. Other measurements included flap diameter and keratometry readings. RESULTS: Actual flap thickness was significantly different (P < 0.0001) from predicted flap thickness. Fifteen eyes had a predicted flap thickness of 160 micrometer and a mean actual flap of 105 micrometer (standard deviation [SD], +/-24. 3 micrometer range, 48-141 micrometer). Sixty-four had a predicted flap of 180 micrometer with an actual flap mean of 125 micrometer (SD, +/-18.5 micrometer range, 82-155 micrometer). Seventeen eyes had a predicted flap of 200 micrometer, with an actual flap mean of 144 micrometer (SD, +/-19.3 micrometer range, 108-187 micrometer). In addition, we found that significantly more tissue (P < 0.0001) was ablated than predicted. Linear regression of the observed ablation on predicted ablation yielded the following relationship: actual ablation = 14.5 + 1.5 (predicted ablation). Neither flap diameter nor flap thickness were found to increase with respect to steeper corneal curvatures. CONCLUSIONS: Actual corneal flap thickness was consistently less than predicted regardless of the depth plate used; actual tissue ablation was consistently greater than predicted tissue ablation for the laser used in this study.

Cornea↗
PubMed2000

ATM-dependent phosphorylation of nibrin in response to radiation exposure.

Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition. Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs). There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS). The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1,2). This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (IR) and is observed in brightly staining nuclear foci after a longer period of time. The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway. Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR. This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein. We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation. Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS.

Ataxia Telangiectasia↗
PubMed2000

Dendritic cell-based cancer immunotherapy: potential for treatment of colorectal cancer?

Human tumours including those of the gastrointestinal tract express a number of specific antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DC) are rare leucocytes that are uniquely potent in their ability to capture, process and present antigens to T cells, and so selectively migrate through tissues to reach lymph nodes and spleen where initiation of immune responses takes place. Studies in murine tumour models have shown clearly that DC are capable of presenting tumour antigens to initiate tumour-specific cytotoxic T cell responses, and DC vaccination can induce anti-tumour activity against both primary tumours and pre-established tumour metastases. These findings together with the ability to culture sufficient numbers of DC from human bone marrow or blood progenitors have prompted the current major interest in their potential use in human tumour vaccination. Vaccine production involves harvesting autologous DC from cultured peripheral blood mononuclear cells in the presence of a cocktail of cytokines, ex vivo exposure of the DC to tumour antigens and return of pulsed DC to the patient to induce tumour immunity. Reports from Phase I/II clinical trials indicate that DC vaccines are safe with little or no side effect, and are capable of initiating antigen-specific T cell responses. Furthermore, defined tumour antigens are not necessarily required, which may make the process more applicable to human cancers, including many gastrointestinal cancers that lack well-characterized tumour-specific antigens. Additional trials of DC vaccination for a variety of human cancers including colorectal cancers are under way, and refinement of vaccine protocols and methods for targeting tumour antigens to DC in vivo are also being explored. There is reason to believe that DC-based vaccination could become an adjunct to current treatments for human cancers including colorectal cancer in the foreseeable future.

Clinical Trials as Topic↗
PubMed2000

Which is most pungent: isoflurane, sevoflurane or desflurane?

We compared the pungency and tolerability of three inhaled anaesthetics in a randomized, double-blind study. Eighty-one unpremedicated patients (n = 27, each group) inhaled 2 MAC of isoflurane (2.3%), desflurane (12%) or sevoflurane (4%) for 60 s from an anaesthetic breathing circuit via a mask. Two blinded observers recorded coughing, complaints of burning and irritation, and how long the inhalation was tolerated. One sevoflurane patient coughed, but completed the study period, whereas 11 isoflurane patients and 20 desflurane patients coughed, objected verbally or removed the mask forcefully. All sevoflurane, 20 isoflurane and seven desflurane patients completed the study period (average 60, 49 and 33 s, respectively, P < 0.05). The irritability grading was: desflurane > isoflurane > sevoflurane (P < 0.05). Sevoflurane is the least irritating agent for inhalation at 2 MAC concentration.

Anesthesia, Closed-Circuit↗
PubMed2000

Sensitivity of mouse oocytes to nicotine-induced perturbations during oocyte meiotic maturation and aneuploidy in vivo and in vitro.

Oocyte meiosis is sensitive to endogenous and exogenous perturbations that upset the temporal sequence of biochemical reactions during oocyte maturation (OM) and predispose oocytes to aneuploidy. Nicotine is an alkaloid that has been reported to disrupt the rate of OM, reduce ovulation and fertilization rates, and increase diploidy. The objective of this study was to test the hypothesis that nicotine perturbs the rate of OM and induces aneuploidy in mouse oocytes in vivo and in vitro. Female mice were given 7.5 IU pregnant mare's serum and either 0, 5.0, 7.5, or 10 mg/kg nicotine in vivo at -3, 0, and +3 h relative to a 5 IU injection of HCG. Oocytes were also cultured in vitro in the presence of 0, 1.0, 5.0, or 10.0 mmol/l nicotine. In vivo, significant (P < 0.05) differences in the proportions of oocytes with premature centromere separation and premature anaphase were found at 10.0 mg/kg nicotine suggesting that the rate of OM was advanced. Also, at this dose the proportion of ovulated oocytes was reduced by approximately 50% relative to controls. In vitro, only non-significant differences were found among the parameters measured. Although nicotine reduced the ovulation rate and perturbed the rate of OM in vivo, these data show that the rate of aneuploidy was not significantly elevated.

Aneuploidy↗
PubMed2000

Three yeast proteins related to the human candidate tumor suppressor p33(ING1) are associated with histone acetyltransferase activities.

Three Saccharomyces cerevisiae proteins (Yng1/YOR064c, Yng2/YHR090c, and Pho23) and two Schizosaccharomyces pombe proteins (Png1/CAA15917 and Png2/CAA21250) share significant sequence identity with the human candidate tumor suppressor p33(ING1) in their C-terminal regions. The homologous regions contain PHD finger domains which have been implicated in chromatin-mediated transcriptional regulation. We show that GFP-Yng2, like human Ing1, is localized in the nucleus. Deletion of YNG2 results in several phenotypes, including an abnormal multibudded morphology, an inability to utilize nonfermentable carbon sources, heat shock sensitivity, slow growth, temperature sensitivity, and sensitivity to caffeine. These phenotypes are suppressed by expression of either human Ing1 or S. pombe Png1, suggesting that the yeast and human proteins are functionally conserved. Yng1- and Pho23-deficient cells also share some of these phenotypes. We demonstrated by yeast two-hybrid and coimmunoprecipitation tests that Yng2 interacts with Tra1, a component of histone acetyltransferase (HAT) complexes. We further demonstrated by coimmunoprecipitation that HA-Yng1, HA-Yng2, HA-Pho23, and HA-Ing1 are associated with HAT activities in yeast. Genetic and biochemical evidence indicate that the Yng2-associated HAT is Esa1, suggesting that Yng2 is a component of the NuA4 HAT complex. These studies suggest that the yeast Ing1-related proteins are involved in chromatin remodeling. They further suggest that these functions may be conserved in mammals and provide a possible mechanism for the human Ing1 candidate tumor suppressor.

Acetyltransferases↗
PubMed2000

Wrestling with typology: penetrating the "black box" of managed care by focusing on health care system characteristics.

The health care system has undergone a fundamental transformation undermining the usefulness of the typology of the health maintenance organization, the independent practice association, the preferred provider organization, and so forth. The authors present a new approach to studying the health care system. In matrix form, they have identified a set of organizational and delivery characteristics with the potential to influence outcomes of interest, such as access to services, quality, health status and functioning, and cost. The matrix groups the characteristics by domain--financial features, structure, care delivery and management policies, and products--and by key roles in the health care system--sponsor, plan, provider intermediary organization, and direct services provider. The matrix is a tool for researchers, administrators, clinicians, data collectors, regulators, and other policy makers. It suggests a new set of players to be studied, emphasizes the relationships among the players, and provides a checklist of independent, control, and interactive variables to be included in analyses.

Data Collection↗
PubMed2000

Skh1, the MEK component of the mkh1 signaling pathway in Schizosaccharomyces pombe.

We previously reported the identification of Mkh1, a MEK kinase in Schizosaccharomyces pombe that is required for cell wall integrity, and we presented genetic evidence that Pmk1/Spm1, a MAP kinase, functions downstream from Mkh1 in the same pathway. Here, we report the identification of Skh1, a MEK (MAP kinase kinase) in S. pombe. The sequence of Skh1 is nearly identical to that of the recently reported Pek1 sequence. We present biochemical and genetic evidence that Skh1 is the MEK component of the Mkh1-Spm1 MAP kinase cascade. Our yeast two-hybrid results indicate that Mkh1, Skh1, and Spm1 physically interact to form a ternary complex. Deletion of mkh1, skh1 or spm1 results in identical phenotypes, including sensitivity to (beta)-glucanase treatment, growth inhibition on media containing KCl, and filamentous growth on medium containing caffeine. Double mutant strains exhibit phenotypes that are identical to the single mutant strains. Furthermore, expression of an activated HA-Skh1(DD )protein suppressed these defects in mkh1(delta) cells, and overexpression of Spm1 suppressed these defects in skh1(delta) cells. We also show that HA-Spm1 is hyper-phosphorylated on tyrosine residues in cells co-expressing the activated HA-Skh1(DD) protein. Furthermore, we found the phosphorylated/activated form of GFP-HA-Spm1 at detectable levels in wild-type cells, but not at appreciable levels in mkh1(delta) or skh1(delta) cells expressing this fusion protein. Together, our results indicate that Mkh1, Skh1 and Spm1 constitute a MAPK cascade in fission yeast.

Amino Acid Sequence↗
PubMed2000

A phase II study of 9-aminocamptothecin in patients with refractory breast cancer.

We evaluated 9-aminocamptothecin (9-AC) in patients with metastatic or locally recurrent breast cancer who were no longer responsive to standard therapy. Patients were treated with 9-AC with a 72-hr continuous infusion given at a dose of 45 micrograms/m2/hr every 2 weeks. Granulocyte colony-stimulating factor 5 micrograms/kg was given subcutaneously for 7-10 days after completion of the treatment. Eighteen patients were treated, with all patients assessable for toxicity and 15 patients assessable for response. There were two partial responses seen in the 15 patients lasting 3.5 and 5 months, respectively. The major toxicity seen was myelosuppression, with 12 patients having grade 3 or greater granulocytopenia with four episodes of significant infectious complications. In addition, significant thrombocytopenia was seen in 14 patients. The other complications commonly seen were nausea and vomiting and alopecia. 9-AC given as a 3-day continuous infusion has limited activity in previously treated metastatic and locally recurrent breast cancer.

Adenocarcinoma↗
PubMed1999

Improving the health behaviours of elderly people: randomised controlled trial of a general practice education programme.

OBJECTIVES: To establish the effect of an educational intervention for general practitioners on the health behaviours and wellbeing of elderly patients. DESIGN: Randomised controlled trial with 1 year follow up. SETTING: Metropolitan general practices in Melbourne, Australia. SUBJECTS: 42 general practitioners and 267 of their patients aged over 65 years. INTERVENTION: Educational and clinical practice audit programme for general practitioners on health promotion for elderly people. MAIN OUTCOME MEASURES: Patients' physical activity, functional status, self rated health, immunisation status, social contacts, psychological wellbeing, drug usage, and rate of influenza vaccination. Primary efficacy variables were changes in outcome measures over 1 year period. RESULTS: Patients in the intervention group had increased (a) walking by an average of 88 minutes per fortnight, (b) frequency of pleasurable activities, and (c) self rated health compared with the control group. No change was seen in drug usage, rate of influenza vaccination, functional status, or psychological wellbeing as a result of the intervention. Extrapolations of the known effect of these changes in behaviour suggest mortality could be reduced by 22% if activity was sustained for 5 years. CONCLUSIONS: Education of the general practitioners had a positive effect on health outcomes of their elderly patients. General practitioners may have considerable public health impact in promotion of health for elderly patients.

Aged↗
PubMed1999

Taxol-induced meiotic maturation delay, spindle defects, and aneuploidy in mouse oocytes and zygotes.

To increase our understanding about the potential risks of chemically-induced aneuploidy, more information about the various mechanisms of aneuploidy induction is needed, particularly in germ cells. Most chemicals that induce aneuploidy inhibit microtubule polymerization. However, taxol alters microtubule dynamics by enhancing polymerization and stabilizing the polymer fraction. We tested the hypothesis that taxol induces meiotic delay, spindle defects, and aneuploidy in mouse oocytes and zygotes. Super-ovulated ICR mice received 0 (control), 2.5, 5.0, and 7.5 mg/kg taxol intraperitoneally immediately after HCG. Females were paired (1:1) with males for 17 h after taxol treatment. Mated females were given colchicine 25 h after taxol and their one-cell zygotes were collected 16 h later. Ovulated oocytes from non-mated females were collected 17 h after taxol. Chromosomes were C-banded for cytogenetic analyses. Oocytes were also collected from another group of similarly treated females for in situ chromatin and microtubule analyses. Taxol significantly (p<0.01) enhanced the proportion of oocytes exhibiting parthenogenetic activation, chromosomes displaced from the meiotic spindle, and sister-chromatid separation. Moreover, 7.5 mg/kg taxol significantly (p<0.01) increased the proportions of metaphase I and diploid oocytes and polyploid zygotes. A significant (p<0.01) dose response for taxol-induced hyperploidy in oocytes and zygotes was found. These results support the hypothesis that taxol-induced meiotic delay and spindle defects contribute to aneuploid mouse oocytes and zygotes.

Aneuploidy↗
PubMed1999

Intensification regimen 2 for advanced head and neck squamous cell carcinomas.

OBJECTIVE: To determine the feasibility, toxicity, and compliance of an intense treatment regimen for patients with advanced, previously untreated, resectable head and neck squamous cell carcinomas. DESIGN: Prospective, nonrandomized, controlled (phase 1 or 2) clinical trial; median time at risk, 25 months (range, 7 days to 36 months). SETTING: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus. PATIENTS: Forty-three patients (median age, 59 years; range, 32-76 years) with resectable, previously untreated stage III or IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx or stage II squamous cell carcinomas of the hypopharynx (referred sample of patients). INTERVENTIONS: Days 1 to 4, perioperative, slightly accelerated, hyperfractionated radiotherapy (9.1 Gy) to off cord fields; days 1 to 3, cisplatin, 30 mg/m2 per day; day 4, surgical resection and intraoperative radiotherapy boost (7.5 Gy); days 45 to 52, postoperative radiotherapy (40 Gy to the primary site and upper neck and 45 Gy to the supraclavicular areas); days 24, 45, and 66, paclitaxel, 135 mg/m2 per 24 hours, with routine granulocyte colony-stimulating factor support; and days 25 and 46, cisplatin, 100 mg/m2. MAIN OUTCOME MEASURES: Toxicity, compliance, local control, and distant metastatic rates. RESULTS: Patient compliance was 91% (39 of 43 patients), but protocol compliance was only 58% (25 of 43 patients), reflecting increased toxicity of the systemic regimen (2 [5%] of the 43 patients experienced grade 5 hematologic toxicity due to the regimen; 16 [37%], grade 4; and 10 [23%], grade 3). Local-regional control was 92% (23 of 25 patients), and the distant metastatic rate was 8% (2 of 25) in patients completing treatment per protocol. One patient had surgical salvage of a second primary tumor. CONCLUSIONS: Local control and patient compliance were encouraging, but systemic toxicity was unacceptable. Thus, the paclitaxel was changed to a weekly regimen.

Adult↗