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Biomedical subjects

M J Farrell

Publications and source records attributed to M J Farrell.

At least 19 recordsLinked to original sources
PubMed2001

Cell biology of cardiac development.

Building a vertebrate heart is a complex task and involves several tissues, including the myocardium, endocardium, neural crest, and epicardium. Interactions between these tissues result in the changes in function and morphology (and also in the extracellular matrix, which serves as a substrate for morphological change) that are requisite for development of the heart. Some of the signaling pathways that mediate these changes have now been identified and several investigators are now filling in the missing pieces in these pathways in hopes of ultimately understanding the molecular mechanisms that govern healthy heart development. In addition, transcription factors that regulate various aspects of heart development have been identified. Transcription factors of the GATA and Nkx2 families are of particular importance for early specification of the heart field and for regulating expression of genes that encode proteins of the contractile apparatus. This chapter highlights some of the most significant discoveries made in the rapidly expanding field of heart development.

Animals↗
PubMed2001

FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation.

Cardiac neural crest ablation results in depressed myocardial calcium transients and elevated proliferation in myocardium at a stage when cardiac neural crest cells are not in contact with the myocardium. To test the hypothesis that cardiac neural crest-derived cells, which migrate into the caudal, ventral pharynx at stage 14, block a signal from the ventral pharynx, we cultured stage 12 chick heart tube or myocardial strips in the presence or absence of ventral pharynx. We found that myocardium cultured with ventral pharynx that had not yet contacted neural crest cells had significantly reduced calcium transients and an increased rate of proliferation. Ventral pharynx from intact embryos at a stage when neural crest-derived cells had reached the pharynx had no effect on myocardial calcium transients. Ventral pharynx from neural crest-ablated embryos continued to suppress myocardial calcium transients at this later stage. Myocardium cultured with FGF-2 also showed a significant reduction in calcium transients. An FGF-2-neutralizing Ab reversed the deleterious effect of the ventral pharynx on myocardial calcium transients and proliferation. We therefore examined the expression of FGF-2 and similar FGFs in the ventral pharynx. Only FGF-8 was expressed in a temporospatial pattern that made it a viable candidate for altering the myocardial calcium transient during stages 14-18. In explant cultures, neutralizing Ab for FGF-8 rescued development of the myocardial calcium transient in neural crest-ablated chick embryos.

Animals↗
PubMed2000

Double-stranded RNA injection produces null phenotypes in zebrafish.

Zebrafish is a simple vertebrate that has many attributes that make it ideal for the study of developmental genetics. One feature that has been lacking in this model system is the ability to disable specifically targeted genes. Recently, double-stranded RNA has been used to silence gene expression in the nematode Caenorhabditis elegans. We have found that expression of the green fluorescent protein (GFP) from a microinjected plasmid vector can be suppressed in zebrafish embryos by the coinjection of a double-stranded RNA that is specifically targeted to GFP. To determine that double-stranded RNA can attenuate endogenous gene expression, single-cell zebrafish embryos were injected with double-stranded RNA specifically targeted to Zf-T and Pax6.1. We found that microinjection of double-stranded Zf-T RNA resulted in a high incidence of a phenotype similar to that of ntl. Furthermore, Zf-T gene expression could not be detected by in situ hybridization and the message was decreased by 75% by semiquantitative RT-PCR in 12-h embryos that had been injected with the double-stranded RNA. Expression of the zebrafish genes sonic hedgehog and floating head was altered in the embryos microinjected with the Zf-T double-stranded RNA in a manner that is remarkably similar to the zebrafish no-tail mutant. Microinjection of double-stranded RNA targeted to Pax6.1 was associated with depressed expression of Pax6. 1 and resulted in absent or greatly reduced eye and forebrain development, similar to the phenotype seen in mouse mutants. Simultaneous injection of Pax6.1 and Zf-T resulted in embryos lacking notochords, eyes, and brain structures.

Animals↗
PubMed2000

The automatic updating of egocentric spatial relationships and its impairment due to right posterior cortical lesions.

The non-visual updating of body-centred spatial relationships was investigated in an experiment in which blindfolded patients had to point to previously seen targets after a body rotation in the absence of vision. Patients with lesions to the right dorsal (RD) area were impaired at updating their positions relative to non-RD patients and normal subjects: they tended to underestimate systematically the angle through which they had turned. The results are interpreted in terms of impoverished locomotor input and/or systematically biased processing or locomotor proprioception in the RD patients, which prevented accurate tracking of changes in egocentric spatial relationships.

Adult↗
PubMed2000

Increased movement pain in osteoarthritis of the hands is associated with A beta-mediated cutaneous mechanical sensitivity.

The relationship between joint pain and hyperalgesia has been explored in animal models of articular inflammation, but is yet to be shown in the most common rheumatologic condition: osteoarthritis. In this study, cutaneous thermal and mechanical pain thresholds were measured over the thumb of patients with osteoarthritis of the hands. In symptomatic patients, pain was manipulated through resisted active movement of the thumb. Provocation of movement pain (MP) was associated with a sustained fall in mechanical pain thresholds. Thermal pain thresholds remained stable during increases in joint pain. Increased mechanical sensitivity after exacerbation of MP was alleviated by A beta fiber blockade. It appears that superficial tenderness over the osteoarthritic thumb fluctuates with pain arising from movement of the joint. It is concluded that dorsal horn mechanisms contribute to MP-related hyperalgesia in osteoarthritis of the hands.

Journal Article↗
PubMed1999

HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation.

DiGeorge syndrome (DGS) is a congenital disease characterized by defects in organs and tissues that depend on contributions by cell populations derived from neural crest for proper development. A number of candidate genes that lie within the q11 region of chromosome 22 commonly deleted in DGS patients have been identified. Orthologues of the DGS candidate gene HIRA are expressed in the neural crest and in neural crest-derived tissues in both chick and mouse embryos. By exposing a portion of the premigratory chick neural crest to phosphorothioate end-protected antisense oligonucleotides, ex ovo, followed by orthotopic backtransplantation to the untreated embryos, we have shown that the functional attenuation of cHIRA in the chick cardiac neural crest results in a significantly increased incidence of persistent truncus arteriosus, a phenotypic change characteristic of DGS, but does not affect the repatterning aortic arch arteries, the ventricular function, or the alignment of the outflow tract.

Animals↗
PubMed1998

Automatic spatial updating during locomotion without vision.

People can update their spatial relationships relative to the environment while walking without vision. The hypothesis that such updating is automatic was tested in a locomotor task in which the subjects were asked to refrain from updating their positions. Subjects walked without vision to one of four previously seen targets via a second location. In one condition--the updating condition--the subjects were asked to walk to the real position of the target relative to the second location; in another--the ignoring condition--they were asked to imagine that they had not moved from the starting point and to walk from the second location as if walking to the target from the initial location. When the subjects were asked to start walking to the target as soon as it was named by the experimenter, they performed better in the updating condition than in the ignoring condition. When the subjects were allowed more time to respond, the difference in performance between these two conditions disappeared. The results suggest that the subjects automatically updated their positions as they moved, but that, given enough time, they could override this updating retrospectively using more deliberate cognitive processing.

Automatism↗
PubMed1998

National palliative care education and training needs analysis.

This purpose of this research study was to conduct a needs analysis for the education and training of palliative care providers. The research methodology was a descriptive survey of the education and training needs of palliative care providers. A total of 1848 questionnaires was distributed to the palliative care providers throughout Australia and a return rate of 34 per cent (627) was attained. The responses from Australia metropolitan areas totalled 51.7 per cent and those from Australian rural and remote areas totalled 48.3 per cent (302). The results showed that the specific education and training needs, as identified by the palliative care providers, included pain management, loss and grief, drug therapies, education updates and other needs. Deficiencies of current education and training programs in palliative care included cost as most postgraduate courses are not HECs funded but are offered as full fee-paying courses. Travel and distance were reported as the most prohibitive aspect to attending a palliative care course. The content in existing palliative care programs predominantly focused on providing care in a palliative care unit or a respite setting. More emphasis needs to be placed on caring for patients in their home; a shift from death in the hospital to death in the home.

Adolescent↗
PubMed1997

Promoter analysis in living zebrafish embryos identifies a cis-acting motif required for neuronal expression of GATA-2.

We have used zebrafish embryos to dissect the promoter activity of a gene with a complex expression pattern during embryogenesis. GATA-2 is a transcription factor required for hematopoiesis and is dynamically expressed in hematopoietic tissues and in the central nervous system. Using constructs containing zebrafish GATA-2 genomic flanking sequences and the green fluorescent protein (GFP) reporter gene, we demonstrate that distinct regulatory domains are required for hematopoietic, enveloping layer (EVL), and neuronal expression of GATA-2. During gastrulation, GFP expression is confined to the ventral ectoderm and lateral mesoderm and is lacking in the dorsal shield. Cells derived from the regions expressing GFP give rise to hematopoietic progenitors, EVL cells, and neurons. Deletion analysis of the 7.3-kb GATA-2 promoter region revealed that a 1.1-kb DNA sequence is critical for expression of GATA-2 in neurons. Fine mapping revealed that a 31-bp region is required for neuron enhancer activity, and mutagenesis showed that the DNA motif CCCTCCT is essential for GATA-2 promoter activity in the central nervous system of zebrafish. Our use of zebrafish embryos can be exploited as a whole animal system for the dissection of any developmentally regulated vertebrate promoter.

Animals↗
PubMed1997

The classification of patients with chronic pain: age as a contributing factor.

OBJECTIVE: To explore the influence of age on the empirical classification of patients with chronic pain. DESIGN: Cluster analyses of two cohorts defined by age. SETTING: Two outpatient pain management clinics for young and older people. SAMPLE: The sample consisted of 340 patients between the ages of 17 and 93 years, who were consecutively assessed on admission to the multidisciplinary pain clinics. The subjects were allocated to two groups according to age; either 17 to 65 years or 66 years and older. MEASUREMENTS: Clustering was carried out using standardised scores from measures of pain (McGill Pain Questionnaire), depression (Zung or Geriatric Depression Scales), and impact of pain (Sickness Impact Profile adapted for pain). RESULTS: Previous classifications of younger adults were replicated in the clusters of: "Good Pain Control," "Positive Adaption to Pain," and "Chronic Pain Syndrome." A fourth cluster, "High Impact," was identified in the older group and subsequently replicated in the combined sample. This group consisted of subjects with high levels of impact of pain and depression and low levels of pain. CONCLUSION: Age differences are present in the clinical presentation of chronic pain patients. Some older patients with chronic pain present with a unique constellation of clinical symptoms, and the classic patient profile of high pain, high impact, and high mood disturbance (i.e., Chronic Pain Syndrome) identified in younger to middle-aged adults does not occur as frequently in older patients. A number of explanations are presented to account for these differences, including comorbidity as well as other medical, psychological, and social factors.

Adolescent↗
PubMed1997

GATA-1 expression pattern can be recapitulated in living transgenic zebrafish using GFP reporter gene.

In this study, DNA constructs containing the putative zebrafish promoter sequences of GATA-1, an erythroid-specific transcription factor, and the green fluorescent protein reporter gene, were microinjected into single-cell zebrafish embryos. Erythroid-specific activity of the GATA-1 promoter was observed in living embryos during early development. Fluorescent circulating blood cells were detected in microinjected embryos 24 hours after fertilization and were still present in 2-month-old fish. Germline transgenic fish obtained from the injected founders continued to express green fluorescent protein in erythroid cells in the F1 and F2 generations. The green fluorescent protein expression patterns in transgenic fish were consistent with the pattern of GATA-1 mRNA expression detected by RNA in situ hybridization. These transgenic fish have allowed us to isolate, by fluorescence-activated cell sorting, the earliest erythroid progenitor cells from developing embryos for in vitro studies. By generating transgenic fish using constructs containing other zebrafish promoters and green fluorescent protein reporter gene, it should be possible to visualize the origin and migration of any lineage-specific progenitor cells in a living embryo.

Animals↗
PubMed1996

Measuring the activity of older people with chronic pain.

OBJECTIVE: A variety of instruments have been applied to the measurement of activity, yet few, if any, have been validated specifically for older people with chronic pain. This study has sought to examine the utility of the Human Activity Profile (HAP) for describing activity in a sample drawn from a pain clinic for older people. DESIGN: The HAP was administered to 193 older pain clinic patients, 72 of whom completed the profile on a second occasion. A further 55 responses were collected from a group of community-dwelling volunteers. The factor structure of the HAP was tested using these 320 responses. The factors subsequently derived were compared with the Sickness Impact Profile (SIP) and the Barthel Index (BI). The discriminant validity of the HAP was examined by comparing factor scores for groups determined by gender, diagnosis, and status in the pain clinic. RESULTS: The 94 items of the HAP loaded onto 10 factors, which explained 63.7% of the variance. These factors demonstrated moderate associations with the BI and the subscales of the SIP. The factors discriminated between men and women (F[12.180] = 9.85. p < 0.000). Differences were also present between subjects with a musculoskeletal pain problem, postherpetic neuralgia, and pain-free volunteers (F[24.340] = 4.7. p < 0.000). Factor scores increased between pre- and postclinic assessments (F[12.60] = 4.79. p < 0.000). CONCLUSIONS: The HAP has demonstrated qualities which favor its adoption as an activity measure for older pain clinic patients.

Aged↗
PubMed1995

The effect of medical status on the activity level of older pain clinic patients.

OBJECTIVE: This project sought to assess the effect of disease status on the activity level of older people suffering from chronic pain. DESIGN: A retrospective comparison of groups defined by disease attributes. SETTING: Outpatient pain management clinic for older people. SAMPLE: The sample consisted of 115 patients, of a possible 144, aged between 52 and 91 years, who were assessed upon admission to a multidisciplinary pain management clinic. Subjects were allocated to groups for comparison on the basis of the diagnosis of their pain problem and the extent of coexistent medical problems. MEASUREMENTS: Groups were compared on scores of activity level using the Human Activity Profile, with and without pain (McGill Pain Questionnaire) and depressive symptom (Geriatric Depression Scale) scores as covariates. MAIN RESULTS: Both pain diagnosis and number of additional medical problems characterized groups that were distinguishable by level of activity. A musculoskeletal disorder was associated with greater impact on activity than either postherpetic neuralgia or pain associated with a psychiatric diagnosis. Less activity was also evident among the subjects with several additional medical problems. However, this effect did not operate independently of depressive symptoms. CONCLUSIONS: Disease status is a factor that rarely explains variations in the pain experience of young adult patients with chronic pain. The results from this study suggest that disease state does influence self-reported activity level in older people with chronic pain. The influence of medical status should be acknowledged as an important factor when assessing and managing the older patient with chronic pain.

Activities of Daily Living↗
PubMed1994

Effect of the transcription start region of the herpes simplex virus type 1 latency-associated transcript promoter on expression of productively infected neurons in vivo.

It has been previously reported that the latency-associated transcript (LAT) promoter contains a DNA sequence at the LAT transcription start site which resembles the ICP4 consensus DNA binding site and that this site allows ICP4-mediated downregulation of the LAT promoter in transient assays (A. H. Batchelor and P. O'Hare, J. Virol. 64:3269-3279, 1990). We have confirmed these data by showing that an ICP4-expressing plasmid will downregulate lacZ expression from a plasmid containing the LAT promoter and transcription start site (pJA1) and does not downregulate lacZ expression from a plasmid in which the start site has been mutagenized (pWAG15). To determine the role of the LAT transcription start site in regulating LAT promoter activity in the context of the virus, two recombinant viruses, KOS-1 and KOS-15, were studied. KOS-1 contains an 863-bp portion of the LAT promoter, including the LAT cap site, fused to the lacZ gene and inserted into the gC locus (T.P. Margolis, F. Sedarati, A.T. Dobson, L.T. Feldman, and J.G. Stevens, Virology 189:150-160, 1992). The second virus (KOS-15) was constructed in identical fashion, using plasmid pWAG-15, which is not downregulated by ICP4. Vero cells productively infected with KOS-15 produce 10-fold more beta-galactosidase than do those infected with KOS-1. In murine dorsal root ganglia acutely infected with KOS-1, only 1.2% of dorsal root ganglion neurons that expressed viral antigen also expressed beta-galactosidase. In contrast, in KOS-15-infected mice, beta-galactosidase was detected in 18% of viral antigen-positive neurons. Similar findings were observed in trigeminal ganglia acutely infected with KOS-1 and KOS-15. Thus, the region encompassing the LAT transcription start site appears to play an important role in repression of the LAT promoter activity not only in vitro but also in acutely infected neurons in vivo. These results suggest that during productive infection with HSV-1, LAT expression is tightly regulated.

Base Sequence↗
PubMed1993

The herpes simplex virus type 1 reactivation function lies outside the latency-associated transcript open reading frame ORF-2.

The latency-associated transcription unit has been shown to be important for in vivo reactivation of herpes simplex virus from the latent state. A recombinant virus was constructed to alter the largest open reading frame in this region. This virus had a wild-type reactivation phenotype, suggesting that herpes simplex virus does not require a protein function from this reading frame for efficient reactivation from latency.

DNA, Recombinant↗
PubMed1991

Herpes simplex virus latency-associated transcript is a stable intron.

The latency-associated transcript (LAT) is the major viral transcript detected by in situ hybridization of mouse and human sensory ganglia latently infected with herpes simplex virus type 1. The last 750 bases of LAT are complementary to infected-cell polypeptide 0, a herpes simplex virus type 1 immediate-early gene that encodes a transactivating protein that may facilitate re-activation of the virus from the latent state. Several laboratories have shown that LAT accumulates in the nucleus and is not polyadenylylated. Recently, we showed that the promoter for LAT lies 688 bases upstream from its 5' end. We report here that LAT is actually a uniquely stable intron. Furthermore, LAT effectively inhibits transactivation of gene expression by infected-cell polypeptide 0 in transient transfection assays.

Animals↗
PubMed1989

Identification of the latency-associated transcript promoter by expression of rabbit beta-globin mRNA in mouse sensory nerve ganglia latently infected with a recombinant herpes simplex virus.

The herpes simplex virus type 1 latency-associated transcript (LAT) is expressed as a major species in latently infected mouse neurons. Previous sequence analysis revealed no obvious promoter elements near the 5' end of the LAT, but a TATA box and other potential promoter elements were found 700 base pairs upstream. A recombinant virus in which the rabbit beta-globin gene was inserted immediately downstream of the TATA box expressed globin mRNA and did not express the LAT. A second recombinant virus, in which this TATA box was removed, was negative for LAT expression in a latent infection. The location of the LAT promoter suggested that RNA upstream of the LAT was synthesized and degraded during latent-phase transcription. Low levels of this RNA were observed by in situ hybridization. In other experiments, RNA from a productive infection was used to detect a transcript extending from the LAT promoter to a polyadenylation signal approximately 8.5 kilobase downstream. These data suggest that the LAT may be processed from a larger transcription unit which begins distal to the TATA box 700 base pairs upstream of the LAT and extends to a polyadenylation signal almost 5 kilobases downstream of the 3' end of the LAT.

Animals↗