Biomedical subjects

D Hill

Publications and source records attributed to D Hill.

At least 19 recordsLinked to original sources

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

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↗

PubMed1996

Opening doors: improving access to hospice and specialist palliative care services by members of the black and minority ethnic communities. Commentary on palliative care.

To put Council's project on improving access to hospice and specialist palliative care services by members of the black and minority ethnic communities into context, palliative care will be defined, and the scope of palliative care services currently available in the UK outlined. Palliative care is the active total care of patients whose disease no longer responds to curative treatment. It is provided through a network of home-care, day-care, hospital support and hospital or hospice based in-patient services. These services are accessed mainly through GPs or hospital consultants and the extent to which people are referred depends on the knowledge of hospital consultants and GPs, and their perception of the value of the palliative care service to their patients. Council's project on improving access was supported by Cancer Relief Macmillan Fund and Help the Hospices as well as receiving a grant from the NHS Ethnic Minorities Unit. The report describes how the specialist palliative care services are currently provided in three areas with high minority ethnic populations and contains a series of recommendations around ethnic monitoring, equal opportunities strategies, staff training, communications and the provision of a more culturally sensitive service provision.

Black or African American↗

PubMed1995

Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice.

Megakaryocyte growth and development factor (MGDF) has recently been identified as a ligand for the c-mpl receptor. Using retroviral-mediated gene transfer, MGDF has been overexpressed in mice to evaluate the systematic effects due to chronic exposure to this growth factor. MGDF overexpressing mice had more rapid platelet recovery than control mice after transplantation. Following this recovery, the platelet levels continued increasing to fourfold to eightfold above normal baseline levels and remained elevated (five-fold above control mice) in these animals, which are alive and well at more than 4 months posttransplantation. Increased megakaryocyte numbers were detected in a number of organs in these mice including bone marrow, spleen, liver, and lymph nodes. Prolonged overexpression of MGDF led to decreased marrow hematopoiesis, especially erythropoiesis, with a shift to extramedullary hematopoiesis in the spleen and liver. All the MGDF overexpressing mice analyzed to date developed myelofibrosis and osteosclerosis, possibly induced by megakaryocyte and platelet produced cytokines. No significant effect on other hematopoietic lineages was seen in the MGDF overexpressing mice, showing that the stimulatory effect of MGDF in vivo is restricted to the megakaryocyte lineage.

Animals↗

PubMed1995

Effects of cell cycle, wild-type p53 and DNA damage on p21CIP1/Waf1 expression in human breast epithelial cells.

In this study we examine the relationship between p21CIP1/Waf1 (CIP1), a 21 kDa protein that binds to and modulates the activity of several cyclin dependent kinases and expression of wild-type (WT) p53 in human breast epithelial cells. Basal CIP1 protein, but not CIP1 mRNA levels correlated well with expression of WT p53 in human breast epithelial cells. To obtain more direct evidence that WT p53 regulated the level of CIP1 protein, the Human Papilloma Virus (HPV) E6 protein was introduced into immortalized 184B5 breast cells. Residual WT p53 levels correlated well with CIP1 protein but not CIP1 mRNA levels in isolated clones of transfected cells. CIP1 protein was increased at early times after growth factor arrested cells were stimulated to proliferate. The rise in CIP1 protein was due to a concomitant increase in CIP1 mRNA levels in MCF10, but not in normal mammary epithelial cells. DNA damage induced by ionizing radiation resulted in a transient increase in WT p53 levels but a prolonged induction of CIP1 protein. The sustained increase in CIP1 protein 24 h after radiation could not be attributed to a concomitant increase in CIP1 mRNA levels. Although the half-life of the CIP1 protein was not altered following irradiation, a fourfold increase in the amount of radioactivity incorporated into CIP1 protein was detected. When considered together these data suggest that wild-type p53 affects CIP1 protein accumulation at a posttranscriptional level in human breast epithelial cells under different physiologic and stress conditions.

Breast↗

PubMed1995

Chromosome X numerical abnormalities in patients with non-Hodgkin's lymphoma. A study of 59 patients using fluorescence in situ hybridization.

Chromosome X numerical abnormalities are frequently observed in non-Hodgkin's lymphoma (NHL), with an incidence of 3% to 14% for chromosomal loss and 7% to 33% for chromosomal gain. Because sex chromosome numerical abnormalities are thought to be due to aging, little information is known about their relation to gender, therapy, and prognosis. Therefore, to determine the incidence and clinical relevance of this abnormality in NHL, we studied specimens from 59 NHL patients (31 men and 28 women) by fluorescence in situ hybridization (FISH) using a directly conjugated centromeric probe for chromosome X. The median age for the entire group was 52 years (range, 31-88 years). All specimens were obtained by fine-needle aspiration of diseased lymph nodes. Sex-matched lymphocytes from benign hyperplastic lymph nodes were used as controls. The overall incidence of chromosome X numerical abnormalities was 49.2%. Female patients had a higher overall incidence than males (76% vs. 24%; p < 0.001). The median percentage of cells involved in this abnormality in each specimen was 5.2%. There was no statistically significant difference in the incidence in previously treated than untreated patients (53.1% vs. 44.4%; p < 0.75) and in intermediate-grade NHL than low-grade NHL (61.1% vs. 50%; p < 0.75). There was a trend towards a higher incidence of chromosome X loss in older patients. While the difference in the incidence of chromosome X abnormalities observed between women and men may be due to the difference in the normal copy numbers of this chromosome in each sex group, this abnormality remained higher than any other autosomal chromosome abnormality in NHL previously evaluated by FISH. We conclude that, although FISH detected a high incidence of chromosome X numerical abnormalities and that females had a higher incidence than males, only a small percentage of the cells were involved, suggesting that this abnormality is most likely a secondary genetic defect that is not important in the pathogenesis of NHL.

Adult↗

PubMed1995

Application of computer graphics for assessment of spinal deformities.

A graphical portrayal system to assess spinal deformities is described. The system is based on software to display and manipulate three-dimensional images of the spine and trunk surface. Qualitative measurements of internal spinal alignment and trunk appearance are provided. The graphics display is developed using graPHIGS routines in conjunction with the C programming language and the UNIX operating system. This software provides clinicians with a computer-aided measurement tool that rapidly conveys clear and concise information about the deformities associated with abnormal spinal curvatures.

Computer Graphics↗

PubMed1995

Bridging the professions: an integrated and interdisciplinary approach to teaching health care ethics.

In 1993, the authors introduced an interdisciplinary course in health care ethics at the University of British Columbia. They were motivated by two convictions: (1) an interdisciplinary approach to health care decision making is best; and (2) every significant health care decision has an ethical component. They wanted to encourage students from the various health care disciplines to participate in interdisciplinary decision making in their future practices by giving them an opportunity to study health care ethics together during their training. The authors give detailed descriptions of the objectives, format, curriculum, and evaluation of this innovative course in the hope that other educators who may want to develop similar courses can learn from their experience.

British Columbia↗

PubMed1995

Carmalt splinter forceps: a useful instrument.

Most dermatologic surgeons have favourite instruments that they like to use. One of mine is the Carmalt splinter forceps. These forceps are short (about 10 cm in length) and have triangular pointed tips with serrations that are kept in alignment by a small pin at the broadest area of the tip.

Dermatology↗

PubMed1995

Outcome of patients with neurotrauma: the effect of a regionalized trauma system.

A system of regionalized trauma care was introduced to Sydney in early 1992. This study was carried out to assess the effect of regionalization on the outcome of patients suffering major head injury within the central Sydney area. A prospective before and after study extending over 3 years and centred on the time of designation of Royal Prince Alfred Hospital (RPAH) as a trauma centre, was the methodology used. The study group consisted of all patients admitted with head injury (Glasgow Coma Score < 9; admission systolic blood pressure > 90 mmHg; Injury Severity Score > 15) to RPAH from the central Sydney area. Outcome criteria include survival rates, transfer numbers, and time to definitive neurosurgical care. Fifty patients were entered during the first 18 months of the study, and 38 during the second 18 months. Fifteen in the first group required evacuation of intracranial mass lesions, as did nine in the second group. The overall mortality fell from 42 to 26% (P = 0.13). During the study period there were 77 primary retrievals and 20 required evacuation of mass lesions. The median time from injury to commencement of operation in these patients was 2 h 13 min (range 1 h 3 min-5 h 35 min). There were 11 transfers, four requiring craniotomy. The median time from injury to surgery was 7 h 24 min (range 3 h 2 min-10 h 25 min; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1995

Prevalence of cigarette smoking among Australian secondary school students in 1993.

The prevalence of cigarette smoking in Australian secondary school students in 1993 was estimated from a survey of 22 696 12- to 17-year-old students from 332 secondary schools (and feeder schools) in all states and the Northern Territory. Self-administered questionnaires were answered anonymously by groups of up to 20 students selected randomly from school rolls, a method that replicated previous surveys in 1984, 1987 and 1990. Current smoking (smoking at least one cigarette in the week preceding the survey) at 12 years of age was 8 per cent in boys and 7 per cent in girls, but in those 17 years of age the prevalence was much higher (28 per cent of boys, 31 per cent of girls). Age was also associated with the mean number of cigarettes smoked per week by current smokers (8.6 in boys and 7.0 in girls at age 12 and 43.8 in boys and 32.0 in girls at age 17). After controlling for sex, age, school type and state of residence, the percentage of 12- to 15-year-olds who were current smokers rose from 15.7 per cent to 17.5 per cent between 1990 and 1993, an effect that was more pronounced in boys. On the other hand, the mean number of cigarettes smoked by 12- to 15-year-old current smokers dropped from 23 per week to 19.5, and the reduced consumption was greatest in boys. Furthermore, there was no increase in the proportion of students who smoked on three or more days per week, which suggests the increase was limited to occasional, casual or social smoking.

Adolescent↗

PubMed1995

Effects of carbohydrate supplementation during intense training on dietary patterns, psychological status, and performance.

The purpose of this study was to determine the effects of carbohydrate supplementation during intense training on dietary patterns, psychological status, and markers of anaerobic and aerobic performance. Seven members of the U.S. National Field Hockey Team were matched to 7 team counterparts (N = 14). One group was blindly administered a carbohydrate drink containing 1 g.kg-1 of carbohydrate four times daily, while the remaining group blindly ingested a flavored placebo during 7 days of intense training. Subjects underwent pre- and posttraining aerobic and anaerobic assessments, recorded daily diet intake, and were administered the Profile of Mood States (POMS) psychological inventory prior to and following each practice. Results revealed that the carbohydrate-supplemented group had a greater (p < .05) total energy intake, carbohydrate intake, and change (pre vs. post) in time to maximal exhaustion following training while reporting less postpractice psychological fatigue. However, no significant differences were observed in remaining psychological, physiological, or performance-related variables.

Adult↗

PubMed1995

Public understanding of medical screening.

AIM: To estimate the extent of public understanding of mass screening for disease and of the benefits and limitations of screening. METHODS: Telephone interviews were conducted with a national sample of 835 Australians. RESULTS: Of total respondents, 68% claimed to have heard of screening tests, but only 21% correctly understood that screening tests are for asymptomatic people. This understanding was related to education. The most frequently named tests were mammography (51%) and Pap tests (33%), and for all age groups these were mentioned by more women than men. Around 27% of respondents thought that the Pap test would detect 95% or more of case, 45% thought the test would detect 90% or more, while 60% of respondents thought the test would detect 80% or more of cases. Around 29% of respondents thought that mammography would detect 95% or more of cases, 49% thought the test would detect 90% or more, while 65% of respondents thought the test would detect 80% or more of cases. Of all respondents, 33% favoured compensation when cases were "missed" by screening provided people were warned beforehand, 58% were not in favour, and 9% were unsure. CONCLUSIONS: There are misconceptions among the public concerning the purpose of screening and the accuracy of screening tests. However, most people accept that some cases of disease will be missed by screening and that if people are adequately informed beforehand compensation should not automatically follow for those whose disease is missed.

Adolescent↗