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Biomedical subjects

A M Sullivan

Publications and source records attributed to A M Sullivan.

At least 19 recordsLinked to original sources
PubMed2004

Heparin-binding epidermal growth factor-like growth factor: a component in chromaffin granules which promotes the survival of nigrostriatal dopaminergic neurones in vitro and in vivo.

Chromaffin cells can restore function to the damaged nigrostriatal dopaminergic system in animal models of Parkinson's disease. It has been reported that a protein which is released from chromaffin granules can promote the survival of dopaminergic neurones in vitro and protect them against N-methylpyridinium ion toxicity. This neurotrophic effect has been found to be mediated by astroglial cells and blocked by inhibitors of the epidermal growth factor (EGF) receptor signal transduction pathway. Here we report the identification of bovine heparin-binding EGF-like growth factor (HB-EGF) in chromaffin granules and the cloning of the respective cDNA from bovine-derived adrenal gland. Protein extracts from bovine chromaffin granules were found to promote the survival of embryonic dopaminergic neurones in culture, to the same extent as recombinant human HB-EGF. Furthermore, the neurotrophic action of the chromaffin granule extract could be abolished by antiserum to recombinant human HB-EGF. We also show that intracerebral injection of recombinant human HB-EGF protected the nigrostriatal dopaminergic system in an in vivo adult rat model of Parkinson's disease. Intracerebral administration of this protein at the same time as a 6-hydroxydopamine lesion of the medial forebrain bundle was found to spare dopamine levels in the striatum and tyrosine hydroxylase-immunopositive neurones in the midbrain. This study has found that the main component in chromaffin granules responsible for their neurotrophic effect on dopaminergic neurones is HB-EGF. Furthermore, HB-EGF has significant protective effects on nigrostriatal dopaminergic neurones in vivo, making it a potential candidate for use in the treatment of Parkinson's disease.

Amino Acid Sequence↗
PubMed2003

Viability of dopaminergic neurones is influenced by serum and astroglial cells in vitro.

Transplantation of embryonic nigral grafts into the striatum of Parkinson's disease patients is not optimal, mainly due to low survival of grafted neurones. Current strategies focus on enhancing neuronal survival by transplanting enriched neuronal cell populations. There is growing evidence for the importance of astroglia in neuronal survival.To characterise the effects of glial cells on dopaminergic neurones, 5-fluoro-2'-deoxyuridine was added to embryonic rat ventral mesencephalic cultures in the presence or absence of serum. The survival and morphology of glial fibrillary acidic protein immunopositive astroglia and tyrosine hydroxylase immunopositive dopaminergic neurones was examined. In serum-containing medium, astroglial cells predominated and 5-fluoro-2'-deoxyuridine had no significant effect on either astroglia or dopaminergic neurone survival. In serum-free medium, astroglial growth was attenuated and numbers were significantly lower in 5-fluoro-2'-deoxyuridine treated compared with untreated cultures. There was no significant difference in the numbers of dopaminergic neurones between 5-fluoro-2'-deoxyuridine treated and untreated cultures. However, by the eighth day in vitro, there were differences in the morphology of these neurones between treated and untreated cultures. This study shows that the use of 5-fluoro-2'-deoxyuridine and serum-free medium can produce a neurone-enriched culture. However, the dopaminergic neurone population present in these cultures appeared to be morphologically dissimilar to those found in control cultures as neurites were retracted and the cell somas of these cells appeared enlarged. These results provide information on the effects of astrocytes on dopaminergic neurones in ventral mesencephalic cultures and thus have implications for transplantation in Parkinson's disease.

Animals↗
PubMed2001

The effect of medical education on primary care orientation: results of two national surveys of students' and residents' perspectives.

PURPOSE: To examine changes among a nationally representative sample of students and residents in their orientations toward primary care as reflected in their attitudes toward the psychosocial and technical aspects of medicine and their perceptions of the academic environment for primary care. METHOD: Confidential telephone interviews of stratified national probability samples of first- and fourth-year medical students and residents were conducted in 1994 and 1997. The 1997 survey included 219 students and 241 residents who had also been interviewed in 1994. Participants were asked about their attitudes toward addressing psychosocial issues in medicine and their perceptions of faculty and peer attitudes toward primary care. Responses were compared over time and across groups. RESULTS: Between the first and fourth years of medical school, there was a decline over time in students' reported orientations to socioemotional aspects of patient care (61.6% versus 42.7%, p =.001) and their perceptions that working with psychosocial issues of patients made primary care more attractive (56.3% versus 43.5%, p =.01). This pattern continued for 1997 residents (PGY-3), who were even less likely to say that addressing psychosocial issues made primary care more attractive (26.9%). For fourth-year students in 1994 who became PGY-3 residents in 1997, there was an increased perception that non-primary-care house officers and specialty faculty had positive attitudes toward primary care (20.8% versus 33.0%, p =.005; 28.3% versus 45.7%, p <.0001; respectively). CONCLUSIONS: Between 1994 and 1997 students and residents perceived a positive shift in the attitudes of peers and faculty toward primary care. During the course of their education and training, however, the students experienced an erosion of their orientations to primary care as they progressed through medical school into residency.

Adult↗
PubMed2000

Profile of a comprehensive psychiatric emergency program in a New York City municipal hospital.

This paper profiles the services provided, and the patient population treated, in a busy inner city Comprehensive Psychiatric Emergency Program (CPEP) located in Elmhurst, Queens, New York City. For each CPEP component, including the emergency room, extended observation unit and crisis services two years of data are reviewed. A diagnostic profile of patients seen, description of services, patient referrals and dispositions are presented. The children and adolescents treated in the CPEP are described in more detail, focusing on the high frequency of violence to self or others seen in their presenting problems. The CPEP's role in providing comprehensive community based services is discussed.

Adolescent↗
PubMed1999

Views of managed care--a survey of students, residents, faculty, and deans at medical schools in the United States.

BACKGROUND AND METHODS: Views of managed care among academic physicians and medical students in the United States are not well known. In 1997, we conducted a telephone survey of a national sample of medical students (506 respondents), residents (494), faculty members (728), department chairs (186), directors of residency training in internal medicine and pediatrics (143), and deans (105) at U.S. medical schools to determine their experiences in and perspectives on managed care. The overall rate of response was 80.1 percent. RESULTS: Respondents rated their attitudes toward managed care on a 0-to-10 scale, with 0 defined as "as negative as possible" and 10 as "as positive as possible." The expressed attitudes toward managed care were negative, ranging from a low mean (+/-SD) score of 3.9+/-1.7 for residents to a high of 5.0+/-1.3 for deans. When asked about specific aspects of care, fee-for-service medicine was rated better than managed care in terms of access (by 80.2 percent of respondents), minimizing ethical conflicts (74.8 percent), and the quality of the doctor-patient relationship (70.6 percent). With respect to the continuity of care, 52.0 percent of respondents preferred fee-for-service medicine, and 29.3 percent preferred managed care. For care at the end of life, 49.1 percent preferred fee-for-service medicine, and 20.5 percent preferred managed care. With respect to care for patients with chronic illness, 41.8 percent preferred fee-for-service care, and 30.8 percent preferred managed care. Faculty members, residency-training directors, and department chairs responded that managed care had reduced the time they had available for research (63.1 percent agreed) and teaching (58.9 percent) and had reduced their income (55.8 percent). Overall, 46.6 percent of faculty members, 26.7 percent of residency-training directors, and 42.7 percent of department chairs reported that the message they delivered to students about managed care was negative. CONCLUSIONS: Negative views of managed care are widespread among medical students, residents, faculty members, and medical school deans.

Administrative Personnel↗
PubMed1999

Incidence of coagulase positive Staphylococcus on beef carcasses in three Australian abattoirs.

The contamination of beef carcasses with coagulase-positive staphylococci (CPS) was studied at three beef abattoirs (A, B and C). The incidence and the number of CPS were determined on cattle hides immediately after slaughter and on three carcass sites (brisket, flank and round) at different points during processing along the slaughter line. The incidence of CPS on cattle hides ranged from 20 to 68.6%. At abattoir A, 6.5% of the carcasses sampled before evisceration were contaminated with CPS, compared to 40% of the carcasses after evisceration. The incidence on carcasses changed little during further processing; however, after chilling for 72 h, the incidence increased to 83%. After evisceration, the brisket and flank areas were more often contaminated than the round. A similar pattern of contamination was observed at abattoir B. At abattoir C, 26.7% of the samples collected before evisceration were contaminated and this fell to 16.7% after evisceration. After chilling for 72 h, the incidence of carcass contamination with CPS increased to 46.7%. The average number of CPS on contaminated carcasses prior to and after overnight chilling was less than 50 colony-forming units (cfu)/cm2 and, after weekend chilling, increased to 64 and 112 cfu/cm2 in abattoirs A and B, respectively. Of the isolates tested, 71.4% produced staphylococcal enterotoxin and 21% could not be classified phenotypically. The hands of workers and environmental sites associated with the evisceration process were examined for CPS at abattoir A. Hands were heavily contaminated and were the likely source of CPS contamination at this abattoir.

Abattoirs↗
PubMed1999

Neuroprotective effects of growth/differentiation factor 5 depend on the site of administration.

Growth/differentiation factor 5 (GDF5) is a neurotrophin which protects the rat nigrostriatal dopaminergic pathway from 6-hydroxydopamine-induced damage. Here we used amphetamine-induced rotational testing, high-performance liquid chromatography and immunocytochemistry to investigate the minimum effective dose of GDF5. We also compared the effectiveness of injecting GDF5 into either the substantia nigra pars compacta (SNpc), the lateral ventricle (LV) or the striatum (or combinations of these sites).

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Long-term protection of the rat nigrostriatal dopaminergic system by glial cell line-derived neurotrophic factor against 6-hydroxydopamine in vivo.

Glial cell-line-derived neurotrophic factor (GDNF) has been shown to enhance the survival of dopaminergic neurones both in vitro and in vivo, and to protect the rodent dopaminergic system from neurotoxic damage. However, most previous studies have only examined the short-term protective effects of GDNF. We have investigated the long-term effects of GDNF on a 6-hydroxydopamine (6-OHDA)-induced lesion of the rat medial forebrain bundle (MFB), which results in complete and irreversible destruction of the nigrostriatal pathway, and is a robust model of Parkinson's disease. GDNF was administered ipsilaterally above the substantia nigra and into the lateral ventricle immediately before a unilateral 6-OHDA injection into the MFB. The effects of GDNF were examined in vivo by behavioural testing and positron emission tomography (PET) at weekly intervals, for 12 weeks. GDNF prevented the development of amphetamine-induced rotations at all time-points. PET studies, using [11C]-RTI-121 as a tracer for the dopamine transporter, indicated that GDNF prevented 6-OHDA-induced reduction of dopamine reuptake sites in the ipsilateral striatum. Post-mortem neurochemical analysis at 13 weeks after surgery found that GDNF significantly inhibited 6-OHDA-induced loss of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the ipsilateral striatum. Immunocytochemistry showed that GDNF reduced 6-OHDA-induced loss of tyrosine hydroxylase-positive neurones in both the substantia nigra pars compacta and ventral tegmental area. We have shown that a single treatment with GDNF can confer long-term protective effects against a 6-OHDA lesion, which suggests that this factor may be useful for the treatment of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease.

Growth/differentiation factor 5 is a member of the transforming growth factor beta superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [11C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.

Animals↗
PubMed1998

Phage types of Australian isolates of Salmonella enterica subsp. enterica serovar Virchow.

Australian isolates (79) of Salmonella enterica subsp. enterica serovar Virchow (Salmonella Virchow) were characterized by phage typing. Thirteen phage types were identified, of which phage type (PT) 8, representing 54 of 79 isolates, was predominant, as it had been in England and Wales up to 1994 when it was replaced by PT26. Other phage types identified in Australia were distinct from those observed in England and Wales. This suggests that PT8 may be a global phage type, while others may be distinct to particular geographical regions.

Animals↗
PubMed1998

Attitudes about end-of-life care: a national cross-sectional study.

BACKGROUND: Major concerns have been expressed about the preparation of physicians to provide end-of-life care. Little is known about how well academic health centers prepare students and residents to care for patients at the end-of-life and about the values about end-of-life care transmitted by faculty. METHODS: In 1997, we conducted a telephone survey of a nationally representative sample of first-year medical students (n = 287), fourth-year medical students (n = 173), residents (n = 473), clinical faculty (n = 728), internal medicine residency training directors (n = 143), department chairs (n = 186), and medical school deans (n = 101) within U.S. academic health centers (response rate = 80.2%). RESULTS: U.S. medical students, residents and faculty evaluate themselves as inadequately prepared to provide end-of-life care. Academic health center constituents perceive that providing care at the end of life requires medium to high levels of expertise. Academic health center constituents are divided about whether responsibility for providing care at the end of life rests with generalists or with specialists and view managed care as nearly equivalent to the fee-for-service sector in its capacity to provide excellent end-of-life care. CONCLUSIONS: Academic leaders and faculty, as well as their students, lack confidence in their own skills in providing end-of-life care. They also question the ability of the current and evolving health care delivery system to provide excellent end-of-life care.

Journal Article↗
PubMed1998

Back-up bone marrow is frequently ineffective in patients with poor peripheral-blood stem-cell mobilization.

PURPOSE: To assess hematologic recovery and procedure-related mortality in patients who received high-dose therapy with stem-cell support, in whom the peripheral-blood stem-cell (PBSC) collection fails (CD34+ cells < 1 x 10(6)/kg). The predictive value of granulocyte-monocyte colony-forming cell (GM-CFC) measurements and the value of bone marrow obtained after PBSC collection failure was assessed. PATIENTS AND METHODS: The study group comprised 324 consecutive patients mobilized with granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide (273 patients), G-CSF with other chemotherapy (37 patients), and G-CSF alone (14 patients). Between one and four aphereses were performed. RESULTS: In 51 of 324 patients, there was failure to obtain 1 x 10(6)/kg CD34+ cells. Twenty-three patients had greater than 1 x 10(5)/kg GM-CFC; 22 patients proceeded to high-dose therapy. Neutrophil recovery occurred within 21 days, but platelet independence was delayed (> 28 days) in eight patients. Of 28 patients with less than 1 x 10(5)/kg GM-CFC, six received high-dose therapy with PBSC alone and five had delayed engraftment. Twelve patients with less than 1 x 10(5)/kg GM-CFC received high-dose therapy supported by bone marrow collected after PBSC collection failure. Eleven patients were assessable for engraftment; four patients had slow (> 21 days) or delayed (> 28 days) neutrophil recovery and eight patients had delayed platelet recovery. In the group of patients who received less than 1 x 10(5)/kg GM-CFC, there were five procedure-related deaths. CONCLUSION: This study shows that delayed hematologic recovery is frequent if less than 1 x 10(6)/kg CD34+ cells are infused after high-dose therapy, particularly with GM-CFC less than 1 x 10(5)/kg. The procedure-related mortality in this latter group is high. In most patients whose PBSC collection contains less than 1 x 10(5)/kg GM-CFC, the use of bone marrow cells does not improve engraftment, which suggests that poor PBSC mobilization usually indicates poor marrow function.

Adolescent↗
PubMed1997

Growth/differentiation factor 5 protects nigrostriatal dopaminergic neurones in a rat model of Parkinson's disease.

Growth/differentiation factor 5 (GDF5), a novel member of the transforming growth factor beta superfamily, promotes the survival of dopaminergic neurones in vitro. We present here the first evidence for a neuroprotective action of GDF5 in vivo. We investigated the effects of intracerebral administration of GDF5 on a rat model of Parkinson's disease. GDF5 was administered just above the substantia nigra and into the lateral ventricle immediately before ipsilateral injection of 6-hydroxydopamine into the medial forebrain bundle. GDF5 prevented the development of amphetamine-induced rotations and preserved the integrity of striatal dopaminergic nerve terminals, as measured by positron emission tomography. Post-mortem studies showed that GDF5 spared dopamine levels in the striatum and tyrosine hydroxylase positive neurones in the midbrain. This study suggests that GDF5 has potential for the treatment of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Evaluation of clinical scale CD34+ cell purification: experience of 71 immunoaffinity column procedures.

Seventy-one mobilised PBSC collections were subject to CD34+ cell purification using the CEPRATE SC stem cell concentration system. The overall median purity of CD34+ cells was 69% (6-93%). CD34+ cell, and GM-CFC recoveries were 52% (8-107%) and 36% (3-118%). Purity was logarithmically related to the input percentage of CD34+ cells and starting requirements were established of 1% CD34 cell content for optimal purity and a minimum of 2 x 10(6)/kg CD34+ cells to ensure recovery of our minimum engraftment threshold of 1 x 10(6)/kg CD34+ cells. Reduction of the washing steps reduced non-specific cell losses and shortened the procedure but did not affect progenitor cell recovery. Purified CD34+ cells were reinfused following high-dose therapy in 35 patients. The median time to neutrophil recovery of 0.5 x 10(9)/l was 12 (10-23) days and to the attainment of platelet independence was 13 (7-100) days. The risks of delayed platelet recovery were related to the CD34+ cell dose infused and were identical to the risks when non-purified PBSC collections were used. In conclusion, purification of CD34+ cells using the CEPRATE device is reliable and the purified product results in prompt engraftment. The cell losses that occur do however restrict its use in many patients.

Adult↗
PubMed1997

Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor: an analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma.

PURPOSE: To define parameters that predict for rapid engraftment after peripheral-blood stem-cell (PBSC) transplantation, progenitor thresholds, the proportion of patients who achieve these thresholds with a standardized mobilization regimen, and the factors that predict for mobilization efficiency. PATIENTS AND METHODS: One hundred and one patients with pretreated lymphoma were mobilized with cyclophosphamide 1.5 g/m2 and granulocyte colony-stimulating factor (G-CSF), with the first apheresis performed when the recovery WBC count was > or = 5.0 x 10(9)/L. The relationship between the number of progenitor cells collected and patient age, sex, diagnosis, prior radiotherapy, and time since last chemotherapy was determined by multivariate analysis. The relationship between these factors, progenitor numbers returned, post-PBSC G-CSF, and hematologic recovery was performed in 81 patients following chemotherapy with carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM protocol). RESULTS: No BEAM recipients had delayed neutrophil recovery beyond 28 days. Delayed platelet recovery occurred in 7.4% and minimum and optimum thresholds of 1 x 10(6) and 3.5 x 10(6) CD34+ cells/kg and 1 x 10(5) and 3.5 x 10(5) granulocyte-macrophage colony-forming cells (GM-CFC)/kg were established. Hematologic recovery was adversely affected by prior treatment with mini-BEAM, and neutrophil recovery was accelerated by post-PBSC G-CSF. The minimum GM-CFC threshold was achieved with a single apheresis in 83% of patients and in 90% with two aphereses. The optimal threshold was achieved with two leukaphereses in 69% of patients. Prior radiotherapy adversely affected mobilization. CONCLUSION: Hematopoietic recovery following PBSC is dependent on progenitor-cell number infused and affect of previous chemotherapy on progenitor quality. Progenitor-cell mobilization is adversely affected by prior radiotherapy. The minimum threshold of GM-CFC required is achieved in most patients with a single apheresis, but an optimal collection usually requires at least two harvests.

Adolescent↗
PubMed1996

Cortical induction of c-fos by intrastriatal endothelin-1 is mediated via NMDA receptors.

Endothelin (ET) is a potent vasoconstrictor which has also been proposed to act as a neuromodulator. We have investigated the action of ET-1 on neurones in vivo, using c-fos as a marker of neuronal activation. Intrastriatal injection of ET-1 caused seizures and barrel rolling which were prevented by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and attenuated by the nitric-oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA). In association with these behaviours, a dramatic increase in c-fos mRNA expression was seen in the cerebral cortex. This increase was blocked by both MK-801 and L-NNA. We suggest that ET-1 modulates the activity of cortical afferents to the striatum, and causes seizures via an NMDA receptor-dependent mechanism.

Animals↗