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Biomedical subjects

D Hill

Publications and source records attributed to D Hill.

At least 19 recordsLinked to original sources
PubMed1997

Chronic expression of murine flt3 ligand in mice results in increased circulating white blood cell levels and abnormal cellular infiltrates associated with splenic fibrosis.

The effect of chronic expression of flt3 ligand (FL) on in vivo hematopoiesis was studied. Retroviral vector-mediated gene transfer was used in a mouse model of bone marrow transplantation to enforce expression of mouse FL cDNA in hematopoietic tissues. As early as 2 weeks posttransplantation, peripheral blood white blood cell counts in FL-overexpressing recipients were significantly elevated compared with controls. With the exception of eosinophils, all nucleated cell lineages studied were similarly affected in these animals. Experimental animals also exhibited severe anemia and progressive loss of marrow-derived erythropoiesis. All of the FL-overexpressing animals, but none of the controls, died between 10 and 13 weeks posttransplantation. Upon histological examination, severe splenomegaly was noted, with progressive fibrosis and infiltration by abnormal lymphoreticular cells. Abnormal cell infiltration also occurred in other organ systems, including bone marrow and liver. In situ immunocytochemistry on liver sections showed that the cellular infiltrate was CD3+/NLDC145+/CD11c+, but B220- and F4/80-, suggestive of a mixed infiltrate of dendritic cells and activated T lymphocytes. Infiltration of splenic blood vessel perivascular spaces resulted in vascular compression and eventual occlusion, leading to splenic necrosis consistent with infarction. These results show that FL can affect both myeloid and lymphoid cell lineages in vivo and further demonstrate the potential toxicity of in vivo treatment with FL.

Animals↗
PubMed1997

Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.

A novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity.

Amino Acid Sequence↗
PubMed1997

Competency-based learning in traumatology.

BACKGROUND: A multidisciplinary, competency-based trauma teaching program was introduced for final year medical students (n = 67) at Royal Prince Alfred Hospital (RPAH) in 1994 to complement the surgical clerkship. METHODS: The method involved small groups rotating through a series of teaching stations each structured to address a predetermined competency. Four 3-hour sessions were held on the subject areas of resuscitation, plastic, orthopedic, and neurotrauma. Performance in the trauma section of a summative Objective Structured Clinical Examination (OSCE), 6 months after the teaching, was compared with that of a control group (n = 127) from other campuses where trauma was taught by a series of discipline-based lectures. Three trauma OSCE stations were designed to test psychomotor skills while five addressed aspects of the cognitive domain. Checklists were used to ensure standardization of scoring in a range of questions asked for skills tested at each station. RESULTS: The marks of the RPAH students (mean 78% +/- SD 9%) were significantly higher (P < 0.0005) than the controls (mean 70% +/- SD 9%) in the 8 trauma questions. There was no significant difference (P = 0.8) in marks obtained by the study group (mean 61% +/- SD 8%) and controls (mean 63% +/- SD 7%) in 22 questions sampling a wide spectrum of nontrauma subject areas. The study group performed significantly better in one of the three skills stations and three of the five problem-solving stations when compared with the control group. CONCLUSION: The innovation has the potential to fulfill a need for an integrated trauma program in the undergraduate core curriculum.

Australia↗
PubMed1997

The effect of intravenous ketorolac given intraoperatively versus postoperatively on outcome from gynecologic abdominal surgery.

STUDY OBJECTIVES: To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total abdominal hysterectomy (TAH) and myomectomy. DESIGN: Prospective, randomized, placebo-controlled study. PATIENTS: 248 ASA physical status I and II adult female patients scheduled for elective hysterectomy or myomectomy. INTERVENTIONS: General anesthesia was administered that consisted of thiopental sodium for induction, enflurane or isoflurane in nitrous oxide-oxygen for maintenance, and small doses of fentanyl and midazolam. Patients were randomized into three groups to receive toradol/placebo on a dosing schedule of dose 1 given one-half hour prior to expected end of surgery, dose 2 given on awakening in the postanesthesia care unit, and doses 3, 4, and 5 given at 6, 12, and 18 hours, respectively, after dose 2; Group 1 patients received placebo (saline) for dose 1, ketorolac 60 mg i.v. for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 2 patients received ketorolac 60 mg i.v. for dose 1, placebo for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 3 patients received placebo for all doses. All patients were given i.v. morphine PCA postoperatively, and morphine usages, visual analog pain intensity (VAS) scores, as well as adverse events and median times to recovery milestones were recorded. MEASUREMENTS AND MAIN RESULTS: VAS scores (mean) before dose 2 were significantly lower in Group 2 than Group 1, as were at-rest evaluations at 15 minutes and one hour. Group 2 patients also had decreased morphine requirements as compared to placebo. Both ketorolac groups (Groups 1 and 2) had significantly higher values for patient and observer overall ratings, case of nursing care, and tolerability as compared to placebo (Group 3). There were no significant differences among groups in adverse events or median times to recovery milestones. CONCLUSIONS: Although it is possible to demonstrate an improvement in early postoperative pain scores with intraoperative ketorolac and better overall ratings of ketorolac both intraoperatively and postoperatively as compared with placebo, the lack of clinically significant differences in analgesic efficacy in the two active study groups indicates the need for a careful consideration by the clinician of the risks versus benefits involved in the administration of antiplatelet medication in the perioperative period.

Adult↗
PubMed1997

Paclitaxel as a radiosensitizer combined with fractionated stereotactic radiotherapy in the treatment of recurrent medulloblastoma.

This report describes the treatment of a 39-year-old man with recurrent medulloblastoma previously treated with extensive chemotherapy and radiation therapy. A novel treatment technique combining paclitaxel (275 mg IV bolus) and fractionated stereotactic radiotherapy (30 Gy in six fractions over 3 weeks) was given to palliate the patient's significant neurologic symptoms. The patient experienced a significant improvement both radiographically and in the quality of his life at follow-up 5 months after completion of treatment. No toxicity has been observed. The treatment of medulloblastoma with paclitaxel and fractionated stereotactic radiotherapy, either alone or in combination, merits further investigation.

Adult↗
PubMed1997

Predictors of returning for second round screening at a population based mammographic screening programme in Melbourne, Australia.

OBJECTIVE: To examine factors associated with returning for second round mammography screening. SETTING: This was a population based mammographic screening programme in Melbourne, Australia. DESIGN: A cohort design was used whereby 668 women were interviewed before the screening programme began and attendance for both first and second round screening was ascertained from programme records. The cohort sample was drawn from two regions of a defined area (close to and distant from the screening centre). MAIN RESULTS: Of the 315 women who attended for first round screening, 75% from the proximal sample and 70% from the distal sample returned for second round screening. Attendance at the second round was predicted by the following: the method of recruitment for first round screening, with women who required a letter of invitation and a reminder being less likely to reattend than those who initially attended in response to a community campaign (OR = 0.34; CI 0.19, 0.61); mammographic history before the initial screen, with women who reported previous diagnostic mammography being more likely to reattend than those who did not (OR = 2.97; CI 1.01, 8.9); stated intention of attending for the initial screen, with those with weakest intention of attending for their first round being less likely to attend for second round (OR = 0.44; CI 0.23, 0.85); and increasing scores on a scale that measured preventive orientation to health (OR = 1.24; CI 1.02, 1.50). CONCLUSION: Our findings corroborate other findings of reduced long term attendance for screening from people who are "reluctant participants" initially.

Aged↗
PubMed1996

Characterization of novel peptoid agonists for the CCK-A receptor.

The successful design of peptoid CCK-B receptor antagonists using rational approaches suggested that it might be feasible to develop similar non-peptide small molecule agonists with potential therapeutic applications. We now report the characterization of such a compound with full agonist activity at CCK-A receptors on rat exocrine pancreatic acinar cells. The compound, PD149164, stimulated a similar maximal response to CCK8 from the exocrine pancreas in anaesthetized rats in vivo, and from isolated pancreatic acini in vitro it also generated intracellular Ca2+ oscillations similar to those evoked by CCK8. These effects were inhibited by the CCK-A antagonist L-364,718. Interestingly, the enantiomer of PD149164, PD151932, was a CCK-A antagonist and blocked PD149164 stimulated effects on the exocrine pancreas. The data indicate that it is possible to develop both agonist and antagonist activities in enantiomers of small non-peptide molecules.

Adamantane↗
PubMed1996

A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation.

We have previously shown that mice induced to overexpress thrombopoietin (TPO) by retroviral-mediated gene transfer into bone marrow (BM) cells develop myelofibrosis and osteosclerosis. It was speculated that these effects were secondary to TPO, resulting from high levels of megakaryocytes and platelets. Also, it was proposed that these mice represent a model for myelofibrosis and osteosclerosis. In this report, we show that levels of both transforming growth factor-beta 1 and platelet-derived growth factor are increased twofold to fivefold in the platelet-poor plasma of TPO overexpressing mice compared with control mice. These data suggest that the increased megakaryocytes produce elevated levels of these cytokines that lead to the pathogenesis of disease. Further, we retransplanted TPO overexpressing mice, at 40 to 42 weeks after primary transplantation, with normal BM cells. After the secondary transplantation, megakaryocytes and platelets returned to normal levels and the myelofibrosis and osteosclerosis were completely corrected. These data extend our initial studies of the effects of overexpression of TPO and show the potential use of this model to explore the underlying cause of myelofibrosis and osteosclerosis and potential treatments for these diseases.

Animals↗
PubMed1996

Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues.

Hereditary nonpolyposis colorectal cancer is caused by inherited mutations of mismatch repair genes. We developed monoclonal antibodies to the prototype human mismatch repair gene hMSH2 and used them to detect an immunoreactive protein of M(r) 100,000 in mismatch-proficient cell lines. In addition, a M(r) 150,000 protein coimmunoprecipitated with the hMSH2 gene product in cell lines expressing hMSH2. Immunohistochemistry demonstrated that the hMSH2 protein was exclusively nuclear. Whereas the hMSH2 protein was expressed in a variety of tissues, the most striking pattern was observed in esophageal and intestinal epithelia, where expression was limited to the replicating compartment. Neoplastic cells within benign and malignant mismatch repair-proficient tumors expressed the protein, but no hMSH2 immunoreactivity was observed in the colorectal tumors of patients with germline hMSH2 mutation. These results have implications for tumorigenic mechanisms and, potentially, for diagnosis.

Animals↗
PubMed1996

Cholecystokinin B antagonists. Synthesis and quantitative structure-activity relationships of a series of C-terminal analogues of CI-988.

A study of structure-activity relationships of a series of 'dipeptoid' CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-alpha-methyl-R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum pi near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.

Animals↗
PubMed1996

Novel beta-methoxyacrylates of the 9-methoxystrobilurin and oudesmansin classes produced by the basidiomycete Favolaschia pustulosa.

Submerged liquid cultures of the basidiomycete Favolaschia pustulosa (Xenova culture collection no. X27732) afforded the novel 9-methoxystrobilurin derivatives, 9-methoxystrobilurin L (1) and 9-methoxystrobilurin E (2), and the related oudemansin derivative, oudemansin L (3). Their structures were established by 2D NMR experiments. Compounds 1 and 3 possess a novel arrangement of two isoprenoid units fused to the aromatic nucleus. Both 1 and 2 have the EEE-configuration in the pentadienyl side chain as reported previously for 9-methoxystrobilurins. Compound 1 was cytotoxic to cells of the human B lymphoblastoid cell line (Jijoye), with an IC50 of 1.8 nM. This cytotoxicity was observed in a 5- day assay only and was not apparent after 2 days. Compound 1 showed some antibacterial activity against Bacillus subtilis (MIC = 0.9 microM) and antifungal activity against Candida albicans (MIC = 6 microM).

Acrylates↗
PubMed1996

Ataxia-telangiectasia: founder effect among north African Jews.

The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency and cancer predisposition. A-T carriers were reported to be moderately cancer-prone. A wide variety of A-T mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays. However, a single mutation was observed in 32/33 defective ATM alleles in Jewish A-T families of North African origin, coming from various regions of Morocco and Tunisia. This mutation, 103C-->T, results in a stop codon at position 35 of the ATM protein. In keeping with the nature of this mutation, various antibodies directed against the ATM protein failed to defect this protein in patient cells. A rapid carrier detection assay detected this mutation in three out of 488 ATM alleles of Jewish Moroccan or Tunisian origin. This founder effect provides a unique opportunity for population-based screening for A-T carriers in a large Jewish community.

Africa, Northern↗
PubMed1996

Absence of continuous epitopes in the house dust mite major allergens Der p I from Dermatophagoides pteronyssinus and Der f I from Dermatophagoides farinae.

BACKGROUND: The house dust mite has been shown to be an important source of domestic allergens associated with immediate hypersensitivities. The Group I mite allergens Der p I from Dermatophagoides pteronyssinus and Der f I from D. farinae display extensive amino acid sequence homology and have similarities with cysteine protease enzymes. OBJECTIVE: The availability of the complete amino acid sequences for these allergens allowed us to search for the allergic determinants within these molecules. The aim of the present investigation was to identify any continuous IgE-binding epitopes within these amino acid sequences. We also sought to test the validity of previously reported Der p I peptide epitope sequences. METHODS: In order to identify any continuous IgE epitopes, the amino acid sequences of Der p I and Der f I were synthesized as decapeptides overlapping in sequence and coupled to plastic pins. The specific IgE-binding capacity of these peptides was assayed using an enzyme-linked biotin-streptavidin procedure and sera from patients known to be sensitive to these allergens. Previously reported Der p I peptide epitopes were synthesized as free peptides and tested for their ability to inhibit specific IgE binding to allergen extract discs. RESULTS: None of the pin-coupled Der p I or Der f I peptides was found by the continuous epitope mapping procedure to bind significantly to specific IgE in the sera of hypersensitive patients. The previously reported Der p I peptide epitopes did not inhibit specific IgE binding to mite extract discs. CONCLUSION: The specific IgE binding epitopes of the house dust mite allergens Der p I and Der f I are discontinuous in nature.

Allergens↗
PubMed1996

A quiet revolution: a surgical approach to skin cancers of the forehead.

Dermatologists are performing increasing numbers of procedures for skin cancers with specialized training in a number of treatment modalities. As an example, repairs of surgical defects of the forehead are presented including rotation flaps, O to T closures and Burow's triangle flap.

Forehead↗