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Biomedical subjects

M Donnelly

Publications and source records attributed to M Donnelly.

At least 19 recordsLinked to original sources
PubMed1996

Altered insulin-like growth factor-II (IGF-II) level and IGF-binding protein-3 (IGFBP-3) protease activity in interstitial fluid taken from the skin lesion of psoriasis.

In the present study, we have investigated insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in serum and artificially raised blister fluid from uninvolved and involved areas of nine patients with psoriasis. Both levels of IGFs and IGFBP-3, and profiles of IGFBP in serum and fluid from the uninvolved areas of these patients were comparable to those seen in normal subjects. In fluid from the involved areas, the IGF-II but not IGF-I level was significantly elevated. Among five molecular forms of IGFBP, the density of 41.5- and 38.5-kDa forms of IGFBP-3 were apparently increased in fluid from the involved areas, shown by Western ligand blotting. Radioimmunoassay further showed that the IGFBP-3 concentration in the involved areas was significantly raised. Immunoblotting revealed that the predominant form of IGFBP-3 in fluid from the uninvolved areas was a 29-kDa proteolytically modified product. In contrast, intact doublet IGFBP-3 was the main form of IGFBP-3 in fluid from the involved areas. Fluid from the involved areas but not the matched serum concentration-dependently inhibited the degradation of 125I-labeled nonglycosylated IGFBP-3 (ngIGFBP-3) caused by fluid from the uninvolved areas, suggesting the presence of an IGFBP-3 protease inhibitor(s) in psoriatic skin lesion. These findings suggest that the alterations in IGF/IGFBP system may contribute to the pathogenesis of psoriasis.

Adult↗
PubMed1996

One and two year outcomes for adults with learning disabilities discharged to the community.

BACKGROUND: Long-stay patients with learning disabilities (n = 214) were assessed in hospital and 12 and 24 months after discharge in order to examine the effects of relocation. METHOD: Each resident acted as his/her own control in a prospective repeated-measures design. Skills and behavioural problems were assessed by keyworkers. Self-perceived quality of life was obtained during interviews with researchers who also completed an environmental checklist of the residents' accommodation. RESULTS: There was little or no change in people's low pre-discharge skill levels. Certain aspects of problem behaviour improved after 12 months, although socially unacceptable behaviour increased slightly. People were less depressed (P < or = 0.01) 12 months after discharge (N = 119) and were more satisfied (P < or = 0.05) with their new 'homes' (n = 108). There were few changes in the pattern of activities or the social networks of people 12 months later. Little or no further change in outcomes was reported 24 months after discharge. CONCLUSIONS: The implementation of the deinstitutionalisation policy in Northern Ireland has been limited by the predominance of residential and nursing homes and the lack of 'ordinary' accommodation. There is a need for purchasers and providers to give more attention to ways in which the principles of normalisation could be incorporated in the process of contracting and delivering services.

Activities of Daily Living↗
PubMed1995

Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood.

TEL is a new member of the ETS family of transcription factors which is rearranged in a number of hematologic malignancies with translocations involving chromosome band 12p13. In some cases, both TEL alleles are affected, resulting in loss of wild-type TEL function in the leukemic cells. In addition, 5% of children with acute lymphoblastic leukemia (ALL) have 12p12-p13 deletions, suggesting that a tumor suppressor gene resides on 12p. These observations led us to consider whether TEL loss of function may contribute to the pathogenesis of ALL. In this report we show that the TEL gene maps between the polymorphic markers D12S89 and D12S98, and we use these flanking markers to screen paired diagnosis and remission samples from 81 children with ALL for loss of heterozygosity (LOH) at the TEL gene locus. Fifteen percent of informative patients showed TEL LOH which was not evident on cytogenetic analysis. Detailed examination of patients with LOH at this locus showed that the critically deleted region included two candidate tumor suppressor genes: TEL and KIP1, the gene encoding the cyclin-dependent kinase inhibitor p27. These studies show that LOH at the TEL locus is a frequent finding in childhood ALL.

Adolescent↗
PubMed1995

Anaesthesia for thyroplasty.

The purpose of this report is to describe the anaesthetic considerations for layngoplastic procedures. Thyroplasty is a procedure which restores the voice in unilateral vocal cord paralysis. The procedure employs an external approach via a window cut at the appropriate level in the thyroid ala. A wedge of silastic is inserted against the inner perichondrium, thereby displacing the vocal cord medially and permitting voice production. Correct placement of the implant is assessed by asking the patient to phonate; patient cooperation is therefore necessary at certain times during the procedure. We describe our management of a patient undergoing thyroplasty. The use of a benzodiazepine agonist-antagonist combination provided both optimal operating conditions and patient comfort.

Anesthesia↗
PubMed1995

Engineering a domain-locking disulfide into a bacterial malate dehydrogenase produces a redox-sensitive enzyme.

Light-dependent reduction of cystine disulfide bonds results in activation of several of the enzymes of photosynthetic carbon metabolism within the chloroplast. We have modeled the tertiary structure of four of these light-activated enzymes, namely NADP-linked malate dehydrogenase, glyceraldehyde-3-P dehydrogenase, fructosebisphosphatase, and sedoheptulosebisphosphatase, and identified cysteines in each enzyme that be expected to form inactivating disulfide bonds (Li, D., F. J. Stevens, M. Schiffer, and L. E. Anderson, 1994. Biophys. J. 67:29-35). We have now converted two residues in the Escherichia coli NAD-linked malate dehydrogenase to cysteines and produced a redox-sensitive enzyme. Oxidation of domain-locking cysteine residues in the mutant enzyme clearly mimics dark inactivation of the redox-sensitive chloroplast dehydrogenase. This result is completely consistent with our proposed mechanism.

Base Sequence↗
PubMed1995

Insulin-like growth factors (IGFs) and IGF-binding proteins in human skin interstitial fluid.

Despite extensive investigation of the insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) system in the circulation and body fluids, there is no information on this in interstitial fluid. We have compared the IGF/IGFBP system in the circulation with that in fluid obtained from blisters artificially raised by negative pressure in 10 healthy volunteers. IGFBP-1, -2, -3, and -4 were all found in blister fluid, but in concentrations much lower than those in matched serum. The IGF-I, IGF-II, and IGFBP-3 levels measured by RIA were 18%, 14%, and 16% of those in serum, respectively. Fast protein liquid chromoatography showed that both IGF-I and IGFBP-3 in 150- and 50-kilodalton complexes were approximately 13% and 37%, respectively, of the corresponding peaks found in matched serum. Compared to that in serum, the IGFBP-3 in the blister fluid was predominantly in a modified 29-kilodalton form, and there was increased activity of an IGFBP-3 protease. Therefore, although IGF concentrations are much lower in interstitial fluid than in the circulation, a greater proportion of this IGF is in forms more readily available for interaction with tissue receptors. The blister fluid appears to represent physiological interstitial fluid and may provide a model for studying the physiology and pathophysiology of growth factors in the interstitial environment.

Blister↗
PubMed1995

Ingested ethanol and binocular rivalry.

PURPOSE: An early study claimed that ethanol ingestion can attenuate binocular rivalry and, in some cases, may produce the phenomenal fusion of normally rivalrous stimuli. The current study examined those claims in an experiment incorporating key controls that were lacking in the earlier study. METHODS: There were two conditions, one in which observers consumed ethanol and the other in which they consumed a placebo. Observers reported the course of binocular rivalry for several hours after drink consumption using two types of rivalry stimuli, one consisting of a continuously illuminated set of stimuli, the other consisting of dichoptic afterimages. RESULTS: Ingestion of ethanol resulted in a decrease in rivalry alternation rates, although there was no evidence of phenomenal fusion. Results were essentially identical for both stimulus types. CONCLUSION: It is suggested that this effect is not caused by ethanol-induced changes in oculomotor mechanisms but may be caused by ethanol-induced decreases in contrast sensitivity.

Adult↗
PubMed1995

Depression among adolescents in Northern Ireland.

This paper examines the nature and distribution of self-reported depression among a sample of 887 secondary school students. The findings indicate that 12% of the total sample scored higher than 17 on the depression scale, the cut-off point used for designating a "case." Approximately 4% of adolescents reported that they wanted to kill themselves. Significant sex or school form associations were not found, except in form four where a higher proportion of females than males (16% vs. 7%) scored above 17. This would tend to suggest that the sex difference in depression found consistently with adults may begin to emerge in middle adolescence. The findings are discussed with reference to previous research on the mental health of young people living in Northern Ireland.

Adolescent↗
PubMed1994

TGF-beta receptor regulation mediates the response to exogenous ligand but is independent of the degree of cellular differentiation in human oral keratinocytes.

This study examined the expression of TGF-beta cell-surface receptors, the response to exogenous TGF-beta 1 and the autocrine production of TGF-beta in normal and squamous cell carcinoma-derived human oral keratinocytes with variable degrees of cellular differentiation. TGF-beta receptor expression, the response to exogenous ligand and the autocrine production of TGF-beta appeared unrelated to cellular differentiation. Cells expressed variable proportions of type-I, -II and -III TGF-beta receptors. The expression of type-III receptors correlated inversely with the expression of type-I receptors, but there was no relationship between type-II and either type-I or type-III TGF-beta receptors. Normal cells and the majority (7 of 8) of tumour-derived keratinocytes were inhibited by exogenous TGF-beta 1 and the degree of inhibition correlated with the expression of type-I, but not type-II or type-III, TGF-beta receptors. One tumour-derived cell line was refractory to exogenous TGF-beta 1 although it expressed all 3 receptor types. Endogenous TGF-beta was produced by both normal and tumour-derived keratinocytes and correlated inversely to the expression of type-I, but not type-II, TGF-beta receptors. Further, cells that produced more autocrine TGF-beta had a diminished response to exogenous TGF-beta 1. The data indicate a complex interaction between the expression of TGF-beta cell-surface receptors, endogenous ligand production and the cellular response to exogenous TGF-beta 1.

3T3 Cells↗
PubMed1994

Use of standardized patients to identify deficits in student performance and curriculum effectiveness.

Much literature supports the value of performance-based tests for obtaining an overall assessment of clinical skills; however, these tests can also identify specific deficits in medical curriculum and student learning. This study, conducted over a period of 2.5 years, used standardized patients to identify deficiencies in medical students' evaluation of a patient with "hoarseness and cough." Each of 230 students performed a physical examination and took a medical history, and each was evaluated on 29 items according to predetermined criteria. We conclude the following: (1) When examining a patient complaining of hoarseness and cough, students frequently did not screen for hemoptysis, thyroid problems, and otalgia; (2) Overall test performance correlated positively with the time of year of the rotation, but screening for certain items (including hemoptysis, thyroid problems, and otalgia) appeared not to depend on rotation; (3) Several important items significantly differentiated the more knowledgeable student from the less knowledgeable student.

Clinical Clerkship↗
PubMed1994

Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01.

PURPOSE: The goals of this treatment program were as follows: to improve event-free survival (EFS) rates for high-risk (HR) patients by increasing the intensity of induction treatment; to improve EFS rates for infants by adding a special postinduction intensification; to treat the CNS using cranial irradiation doses that were lower than in our historic control group; and to confirm our previously obtained good results for children with T-cell disease. PATIENTS AND METHODS: Two hundred twenty children with acute lymphoblastic leukemia (ALL) from all risk groups, including infants and patients with T-cell disease, were treated between 1985 and 1987 with multiagent chemotherapy and cranial irradiation. RESULTS: The 7-year EFS rate (+/- SE) for all 220 patients was 78% +/- 3% at a median follow-up duration of 6.2 years, 89% +/- 4% for the 82 patients classified as standard risk (SR), and 72% +/- 4% for the remaining 138 patients classified as HR and very high risk (VHR). Eleven infants had an EFS rate of 55% +/- 15% that might be attributable to treatment with high doses of methotrexate and cytarabine (ara-c). Twenty children with T-cell disease had an EFS rate of 70% +/- 10%. CNS leukemia relapse (isolated or combined with bone marrow) occurred in four of 82 SR patients who received 18 Gy of cranial irradiation and four of 138 HR and VHR patients who received 24 Gy. CONCLUSION: This protocol, which featured early intensive treatment including asparaginase, doxorubicin, and cranial irradiation, provided good long-term disease control for children with ALL.

Adolescent↗
PubMed1993

Central nervous system treatment in childhood acute lymphoblastic leukemia. Long-term follow-up of patients diagnosed between 1973 and 1985.

BACKGROUND: Despite advances in the treatment of childhood acute lymphoblastic leukemia (ALL), optimal therapy of the central nervous system (CNS) remains controversial. METHODS: Between 1973 and 1985, 540 children with ALL (199 standard risk and 341 high risk) were treated on four protocols. RESULTS: The 7-year event-free survival rate (+/- standard error) was 62.1% (+/- 2.1) for the entire group: 71.8% (+/- 3.2) for standard-risk and 56.4% (+/- 2.7) for high-risk patients. Five hundred eighteen of the children entered complete remission and received cranial irradiation with intrathecal methotrexate for CNS treatment; 197 had standard-risk ALL and 321 had high-risk ALL. Thirty-one patients (5 standard risk and 26 high risk) had a CNS relapse with or without concurrent bone marrow relapse as an initial event, the latest of which was observed 49 months after complete remission. The cumulative incidence of CNS relapse was 6.0% (+/- 1.1) for the entire group: 2.5% (+/- 1.1) for standard-risk and 8.2% (+/- 1.5) for high-risk patients (P = 0.01). CNS recurrence of leukemia, whether as an "isolated" site or a "combined" site of relapse, was a major adverse event. Only 4 of 31 patients were alive for 25+, 28+, 54+, and 71+ months after a CNS relapse. The median survival time after CNS relapse was 22 months: 21 months for the 20 patients who had an isolated CNS relapse, and 23 months for the 11 patients who had a CNS relapse concurrent with a recurrence in other sites. CONCLUSIONS: Although attempts to diminish CNS treatment-related morbidity are warranted for standard-risk patients, the authors recommend that intensive CNS treatment be enhanced for the high-risk patients because CNS relapses continue to occur in this population. Furthermore, CNS relapse after cranial irradiation was associated with a very poor prognosis and needs to be treated as intensively as a bone marrow relapse.

Brain Neoplasms↗
PubMed1993

What causes acute otitis externa?

External otitis is an extremely common condition and can affect between five to twenty per cent of the patients attending ENT clinics (Hawke et al., 1984). Its precise pathogenesis remains unclear, despite several aetiological classifications in the literature. The aim of this study was to investigate the relationship between infection, water exposure and trauma and the development of acute otitis externa. The study comprised 100 patients with their first attack of otitis externa and 150 age and sex matched controls. In only 40 per cent of cases could a primary microbiological cause be found. There was no significant statistical difference found between the two groups regarding the use of agents capable of traumatizing the external canal. Regular swimming, showering and hair washing were significantly more common in patients with acute otitis externa. Allergic disorders were nearly three times more common in the external otitis group suggesting a possible immunological aetiology.

Acute Disease↗
PubMed1993

The effects of visual depth and eccentricity on manual bias, induced motion, and vection.

The relationship between the effects of visual-surround roll motion on compensatory manual tracking of a central display and the perceptual phenomena of induced motion and vection were investigated. To determine if manual-control biases generated in the direction of surround rotation compensate primarily for the perceived counterrotation of the central display ('induced motion') or the perceived counterrotation of the entire body ('vection'), the depth and eccentricity of the visual surround were varied. In the first experiment, twelve subjects attempted to keep an unstable central display level while viewing rotating visual surrounds in three depth planes: near (approximately 20 cm in front of the central display), coplanar, and far (approximately 21 cm behind the central display). In the second experiment, twelve additional subjects viewed a rotating surround that was presented either in the full visual field (0-110 deg) or in central and peripheral regions of similar width. Manual-control biases and induced motion were shown to be closely related to one another and strongly influenced both by central and by peripheral surround motion at or beyond the plane of fixation. Vection, on the other hand, was shown to be much more dependent on peripheral visual inputs.

Adolescent↗
PubMed1993

Geriatric psychiatry: training guidelines and their application. Section on Geriatric Psychiatry of the Canadian Psychiatric Association.

Geriatric psychiatry is now a mandatory part of psychiatric residency education in Canada. Educational requirements in geriatric psychiatry were updated by the Royal College of Physicians and Surgeons of Canada in 1988, and guidelines were developed in more detail in 1989 by the Section on Geriatric Psychiatry of the Canadian Psychiatric Association (CPA). These guidelines are presented here together with a survey, conducted in the fall of 1991, of all 16 Canadian psychiatry residency programs. Thirteen of the training centres now require residents to have a formal rotation in geriatric psychiatry, generally three months in length. Residents are exposed to elderly patients in other services, such as consultation/liaison, but these services may not include formal teaching in geriatric psychiatry. Most programs have a seminar series in geriatric psychiatry and have training guidelines similar to those of the CPA. However, it is not clear how closely these are being followed, since it was felt in almost one-third of all programs that there was an insufficient number of teachers to fulfill the training requirements. In addition, a number of training directors felt that the objectives were too comprehensive to be met in the three month period. Earlier studies in the field are reviewed, implications of the current findings are discussed, and suggestions are made for further research.

Canada↗
PubMed1993

Pediatric histiocytosis. Characterization, prognosis, and oral involvement.

PURPOSE: Forty-five children with histiocytosis were reviewed to characterize such a group and to establish the prevalence of oral involvement. In addition, patients with and without oral disease were compared for severity of disease, response to treatment, and incidence of recurrent disease. PATIENTS AND METHODS: There were more boys (62.2%) than girls (37.8%) among the patients studied. About half (53.3%) were < 2 years of age. Approximately half of all patients had two or fewer affected organ systems at diagnosis. The average length of treatment was 46 weeks. RESULTS: A total 75.6% of patients were alive without disease at the completion of data collection, 15.6% died from the disease, 4.4% were alive with active disease, and 4.4% were alive with unknown status. Of the patients, 55.6% had long-term sequelae, and oral sequelae were present in 22.2% of the sample. In all, 28.8% of the patients exhibited oral symptoms at diagnosis, while 44.4% had oral involvement at some point during the course of the disease. Patients with oral symptoms were treated significantly longer and had more systemic therapy when compared with those without oral disease.

Child, Preschool↗
PubMed1992

Progressive abrogation of TGF-beta 1 and EGF growth control is associated with tumour progression in ras-transfected human keratinocytes.

This study examined the response of human keratinocytes in different stages of transformation to exogenous TGF-beta 1 and EGF as well as their receptor and growth-factor expression. Cells of the spontaneously immortalized HaCaT cell line and c-Ha-ras transfected clones (I-6, I-7, II-3, II-4) exhibited different tumorigenic potentials when transplanted to athymic mice. HaCaT- and I-6 cells were non-tumorigenic, I-7 cells formed persisting epidermal cysts (benign tumours) and II-3 and II-4 cells developed into invasive squamous-cell carcinomas. TGF-beta 1 inhibited thymidine uptake in a dose-dependent manner, a progressive decrease in response being associated with an increasing malignant potential (HaCaT greater than I-6 greater than I-7 = II-4). HaCaT-cells and ras-clones expressed TGF-beta 1 mRNA at similar levels, but cells of increasing malignant potential secreted markedly less receptor-binding TGF-beta (HaCaT greater than I-6 = I-7 greater than II-3 greater than II-4) into the culture medium. Whilst ras-transfected cells expressed fewer TGF-beta receptors than HaCaT cells, there was little difference between TGF-beta receptor number or affinity between the 4 transfected cell clones. The same was true for the TGF-beta receptor types, but Type-II receptors were expressed at lower levels by the malignant clones II-3 and II-4. When HaCaT and ras-transfected cells were investigated for their response to exogenous EGF, cells were refractory (I-7, II-4), partially stimulated (I-6) or fully stimulated (HaCaT). Cells with increasing malignant potential produced increasing amounts of endogenous TGF-alpha (II-4 = II-3 greater than I-7 = I-6 greater than HaCaT). All tumorigenic ras clones expressed higher mRNA levels than HaCaT-cells. Ras-transfected clones expressed fewer high- and low-affinity EGF receptors than HaCaT cells with a tendency toward increased numbers of high-affinity EGF receptors associated with increasing malignant potential (II-4 = II-3 greater than I-7 greater than I-6) but these changes were associated with a progressive decrease in receptor affinity. The results indicate that tumour progression in human epidermal keratinocytes transfected with c-Ha-ras is associated with a progressive abrogation of TGF-beta 1 and EGF growth control. They suggest that the increased autonomous growth potential associated with advanced stages of epithelial tumour progression can be defined more closely using a cellular profile of TGF-beta and EGF.

Cell Division↗