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Biomedical subjects

S Flanagan

Publications and source records attributed to S Flanagan.

At least 19 recordsLinked to original sources
PubMed2001

Premature calvarial synostosis and epidermal hyperplasia (Beare-Stevenson syndrome-like anomalies) resulting from a P250R missense mutation in the gene encoding fibroblast growth factor receptor 3.

We report on a patient with a severe premature calvarial synostosis and epidermal hyperplasia. The phenotype was consistent with that of a mild presentation of Beare-Stevenson syndrome but molecular analysis of the IgIII-transmembrane linker region and the transmembrane domain of the gene encoding the FGFR2 receptor, revealed wild-type sequence only. Subsequently, molecular analysis of the FGFR3 receptor gene identified a heterozygous P250R missense mutation in both the proposita and her mildly affected father. This communication extends the clinical spectrum of the FGFR3 P250R mutation to encompass epidermal hyperplasia and documents the phenomenon of activated FGFR receptors stimulating common downstream developmental pathways, resulting in overlapping clinical outcomes.

Amino Acid Substitution↗
PubMed2001

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy): an Australian perspective.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was determined clinically and by neuroimaging. Those suspected of having CADASIL had sequencing of exons 3 and 4 of the Notch3 gene. Eight patients, two of whom were siblings, were suspected of having CADASIL. Five patients (including the siblings) had mutations. Because of strong clustering of Notch3 mutations in CADASIL, this has potential as a reliable test for the disease in Australian patients.

Aged↗
PubMed2001

Histopathological analysis of Leri-Weill dyschondrosteosis: disordered growth plate.

Leri-Weill syndrome (LWS) is a dominant (pseudoautosomal) skeletal dysplasia with mesomelic short stature and bilateral Madelung deformity, due to dyschondrosteosis of the distal radius. It results from the loss of one copy of the Short Stature Homeobox Gene (SHOX) from the tip of the short arm of the X or Y chromosome. SHOX molecular testing enabled us to evaluate the histopathology of the radial physis in LWS patients with a documented SHOX abnormality. A widespread disorganisation of physeal anatomy was revealed with disruption of the normal parallel columnar arrangement of chondrocytes. Tandem stacking of maturing chondrocytes within columns was replaced by a side-by-side arrangement. The presence of hypertrophic osteoid with micro-enchondromata in the radial metaphysis suggests abnormal endochondral ossification. The Vickers' ligament was confirmed to blend with the triangular fibrocartilage complex (TFCC). This histopathological study demonstrates that the zone of dyschondrosteosis in LWS is characterised by marked disruption of normal physeal chondrocyte processes and that a generalised physeal abnormality is present.

Adolescent↗
PubMed2000

Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature.

We report on a patient with the skeletal findings of Jackson-Weiss syndrome, who manifests only mild craniofacial anomalies. Molecular analysis of her fibroblast growth factor receptor 1 gene (FGFR1) identified a heterozygous P252R missense mutation, previously only reported with FGFR1-Pfeiffer syndrome like manifestations. Mutations in the immunoglobulin-like, II-III (IgII-III) linker region of FGFR1 and FGFR3 molecules may present as a skeletal dysplasia affecting the appendicular skeleton including, brachydactyly, short broad middle phalanges, phalangeal epiphyseal coning and broad halluces. This communication is a further example of the phenomenon of an activated FGFR molecule resulting in overlapping manifestations in FGFR syndromes.

Abnormalities, Multiple↗
PubMed2000

Human Dermo-1 has attributes similar to twist in early bone development.

Basic helix-loop-helix (bHLH) transcription factors are implicated in cell lineage determination and differentiation. Dermo-1 encodes a bHLH transcription factor that shares extensive homology with another bHLH transcription factor, Twist. We have cloned and characterized human Dermo-1 from two different bone cytoplasmic DNA (cDNA) libraries. Dermo-1 mRNA and protein expression were examined in human embryo and adult tissue sections. Dermo-1 is expressed in a subset of mesodermally and ectodermally derived tissues. We further examined expression of Dermo-1/Twist in human tissues and cell lines. In addition, we observed Dermo-1 expression in response to basic fibroblast growth factor in osteoblastic cell lines. To evaluate the functionality of the human Dermo-1 transcription factor in osteoblast metabolism, we made stable osteoblastic cell lines that over- and underexpress human Dermo-1. These cell lines were analyzed and compared with previously published data of similar cell lines transfected with Twist. Our results demonstrate that Dermo-1 caused changes similar to Twist in the osteogenic properties of osteoblastic cells, such as morphology, bone marker gene expression, and biochemical response to cytokines. However, Dermo-1 expression also has unique effects in regulating the mechanism of proliferation, on alkaline phosphatase enzyme activity, and in temporal expression patterns. We speculate that expression of Twist and Dermo-1 maintains cells in an osteoprogenitor or preosteoblast-like state, respectively, and prevents premature or ectopic osteoblast differentiation. Therefore, Twist and Dermo-1 must be sequentially downregulated in order to initiate the cascade of events responsible for osteogenic cell differentiation. These results indicate that, during osteoblast development, Dermo-1 may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype by utilizing mechanisms similar but not identical to those utilized by Twist.

Amino Acid Sequence↗
PubMed2000

The backpack run test: a model for a fair and occupationally relevant military fitness test.

Our purpose in this investigation was to develop and validate a theoretical model for a backpack run test based on how fast one can run 2 miles while wearing a backpack. Using actual unloaded (no backpack) 2-mile-run test data from 59 male service academy cadets, we calculated the average oxygen cost during the run, the equivalent cost if wearing additional weight, and the corresponding estimated run time with the backpack. The correlations between body weight and loaded (backpack weight = 30 kg) run times (r = 0.55 [p < 0.05] and r = 0.12 [p > 0.05], respectively) demonstrate that the bias against heavier runners is eliminated with the backpack run. Given that the backpack run test requires only standard-issue equipment, demonstrates clear occupational and health-related fitness relevance, predicts no apparent body-size bias, and measures work- and health-related components of fitness, we recommend that the military services consider the present data when developing or modifying tests of physical fitness.

Adult↗
PubMed1999

The Palliative Care Education Group for Gloucestershire (PEGG): an integrated model of multidisciplinary education in palliative care.

Multidisciplinary teamwork is an essential part of palliative care. Traditionally, in the UK, education of health care professionals has been carried out within single professional disciplines. The Palliative Care Education Group (PEGG) for Gloucestershire, a county in the south-west region of England, UK, is a multidisciplinary group, which promotes and integrates palliative care education across the county. This report describes the evolution of the group, its aims and objectives and the methods used to evaluate its impact on clinical practice. PEGG is a practical model of multidisciplinary education, which could be adopted in other areas.

Attitude of Health Personnel↗
PubMed1999

Subjective and external assessments of quality of life in schizophrenia: relationship to insight.

OBJECTIVE: This study assessed the manner in which insight influenced schizophrenic patients' evaluation of their objective life conditions and the concurrent validity between patients' and clinicians' assessments of patients' global quality of life. METHOD: Forty out-patients who fulfilled DSM-III-R criteria for schizophrenia were independently interviewed using the Lancashire Quality of Life Profile and the Standard of Living Interview. Insight was assessed using a self-report questionnaire, the Insight Scale. RESULTS: For insightful patients there was a significant but modest correlation between objective and subjective indicators of quality of life. Likewise, a significant correlation between subjective and external evaluations of global quality of life was limited to those individuals who had good insight. CONCLUSION: Diminished insight may limit the usefulness of the self-report methodology for assessing quality of life for some individuals with schizophrenia.

Adolescent↗
PubMed1999

Physiatric management of mild traumatic brain injury.

Mild traumatic brain injury (MTBI) is a common condition, afflicting as many as 1.5 million Americans yearly. Most individuals sustain MTBI as a result of motor vehicle collisions, but it may also occur as a result of falls, physical assault or sporting accidents. Problems related to MTBI include various pain syndromes, cognitive impairments, disorders of affect, cranial nerve dysfunction, and vertigo, arising from injury to the brain, head, or cervical spine. Symptoms are usually transient, although a small percentage of afflicted individuals develop long-lasting problems, often preventing them from leading productive lives. Recognition of these problems as arising from MTBI is difficult due to the frequent lack of abnormal findings on diagnostic tests and failure to identify a history of head trauma. The American Congress of Rehabilitation Medicine has defined MTBI, an important first step in identifying individuals who need treatment. Diagnosis is usually made by directed questions regarding trauma history and careful procurement and interpretation of appropriate tests. Once a diagnosis is made, proper care can be prescribed in order to lead patients toward more productive lives.

Brain Injuries↗
PubMed1997

Parathyroid hormone suppression in spinal cord injury patients is associated with the degree of neurologic impairment and not the level of injury.

OBJECTIVE: To demonstrate that after spinal cord injury (SCI) suppression of the parathyroid-vitamin D axis is associated with the degree of neurologic impairment and not the level of injury. DESIGN: A retrospective analysis of clinical and biochemical data obtained from hospital records of patients with SCI compared to a control group of patients with traumatic brain injury (TBI). SETTING: The inpatient rehabilitation unit of a tertiary care hospital. SUBJECTS: The medical records of 82 consecutive admissions to the rehabilitation unit with a diagnosis of SCI or TBI were reviewed. Patients with SCI were classified by the American Spinal Injury Association (ASIA) impairment scale and then grouped based on the completeness and level of injury. MAIN OUTCOME MEASURE: Comparisons of serum parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25-D) were planned. Multiple comparisons were performed for total and ionized serum calcium levels, serum phosphorus levels, and 24-hour urinary calcium excretion rates to reflect changes in mineral homeostasis. Multiple comparisons were also performed for serum albumin, prolactin, thyroid function tests, and AM cortisol levels, as well as 24-hour urinary urea nitrogen and cortisol excretion rates to reflect metabolic responses to stress. RESULTS: Patients with SCI had significant suppression in PTH (p < .000009) and 1,25-D (p < .02) levels with elevated phosphorus (p < 0.03) and prolactin (p < .03) levels compared to patients with TBI. Also, more patients with SCI were hypoalbuminemic (p < .003) than patients with TBI. Patients with complete SCI (ASIA A) had more suppressed PTH (p < .03) and higher urinary urea nitrogen (p < .05) levels than SCI patients with incomplete injuries (ASIA B-D). Patients with complete, but not incomplete, SCI had lower albumin levels than patients with TBI (p < .05). These differences were not found between patients with tetraplegic and paraplegic SCI. ASIA motor scores did not correlate with any of the measured parameters but when used as a covariate did abolish differences in PTH and 1,25-D among the study groups by ANOVA. CONCLUSION: In patients with SCI, the degree of neurologic impairment, and not the level of injury, is associated with PTH suppression and markers of metabolic stress.

Activities of Daily Living↗
PubMed1994

Blunted growth hormone response to intravenous arginine in subjects with a spinal cord injury.

The influence of the activities of daily living on human growth hormone (hGH) release and plasma insulin-like growth factor (IGF-I) levels is not known. Individuals with spinal cord injury (SCI) and paralysis generally have reduced levels of activity compared with ambulatory subjects. We studied sixteen subjects with SCI and sixteen nonSCI subjects matched for age, gender and body mass index (BMI) as controls. After an intravenous infusion of arginine hydrochloride (30 g/subject over 30 minutes), mean plasma hGH values at 30 and 60 minutes were significantly lower in the group with SCI compared with the control group (3.4 +/- 0.7 versus 10.7 +/- 2.5 ng/ml, p < 0.01; and 5.2 +/- 1.5 versus 12.5 +/- 2.7 ng/ml, p < 0.05). Also, peak and sum hGH responses were significantly lower in the group with SCI than in the control group (5.8 +/- 1.5 versus 14.1 +/- 2.8 ng/ml, p < 0.01; and 15.2 +/- 3.1 versus 34.8 +/- 7.2 ng/ml, p < 0.02). Controlling for age and BMI, the results remained significant. However, the mean plasma IGF-I level was significantly lower in SCI subjects younger than 45 years old than in the similar subgroup of age-restricted controls (202 +/- 19 versus 324 +/- 27 ng/ml, p < 0.05), whereas, a comparison of subgroups of subjects 45 years or older did not reveal a significant difference. These findings support the hypothesis that decreased daily physical activity results in depression of the hGH/IGF-I axis in younger individuals with SCI and may be considered to be a state of premature aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Disease-activated transcription factor: allergic reactions in human skin cause nuclear translocation of STAT-91 and induce synthesis of keratin K17.

Epidermal keratinocytes have important immunologic functions, which is apparent during wound healing, in psoriasis, and in allergic and inflammatory reactions. In these processes, keratinocytes not only produce cytokines and growth factors that attract and affect lymphocytes but also respond to the polypeptide factors produced by the lymphocytes. Gamma interferon (IFN-gamma) is one such signaling polypeptide. Its primary molecular effect is activation of specific transcription factors that regulate gene expression in target cells. In this work, we present a molecular mechanism of lymphocyte-keratinocyte signaling in the epidermis. We have induced cutaneous delayed-type hypersensitivity reactions that are associated with an accumulation of lymphocytes. These resulted in activation and nuclear translocation of STAT-91, the IFN-gamma-activated transcription factor, in keratinocytes in vivo and subsequent induction of transcription of keratin K17. Within the promoter of the K17 keratin gene, we have identified and characterized a site that confers the responsiveness to IFN-gamma and that binds the transcription factor STAT-91. Other keratin gene promoters tested were not induced by IFN-gamma. These results characterize at the molecular level a signaling pathway produced by the infiltration of lymphocytes in skin and resulting in the specific alteration of gene expression in keratinocytes.

Base Sequence↗
PubMed1994

Molecular effects of T lymphocytes on the regulation of keratin gene expression.

The interactions between lymphocytes and the epidermis are very important in autoimmune skin diseases. Mutual interaction between keratinocytes and T cells is effected both by soluble peptides and by direct cell-to-cell contact. We investigated the possibility that direct cell-to-cell contact with T cells may also play a role in the regulation of keratin gene expression. We have transfected human epidermal keratinocytes with the constructs containing promoters of keratin genes and then cocultured them with the HUT78 strain of human T cells. We found that T cells induce transcription of K5, K6, K14 and K16 genes, as well as the RSV viral promoter, but not K17, K10 or the SV40 viral promoter controls.

Cell Communication↗
PubMed1993

Heat stress regulates the human 70-kDa heat-shock gene through the 3'-untranslated region.

Cells respond to a variety of stresses by synthesizing a family of proteins termed heat-shock proteins (HSP). Recently, the 3'-untranslated regions (UTRs) of some mRNAs have been shown to be important in the posttranscriptional regulation of protein production. Therefore, we hypothesized that heat could regulate HSP70 production through the HSP70 3'-UTR, in addition to its known effects on transcription. To test this hypothesis, cells were transfected with either a plasmid containing sequences encoding the human HSP70 or beta-globin 3'-untranslated region placed downstream of a chloramphenicol acetyltransferase (CAT) reporter gene. In both plasmids, the CAT gene was driven by an SV40 promoter. Following heat stress, cells transfected with the CAT construct containing the HSP70 3'-UTR showed increased CAT activity relative to the beta-globin 3'-UTR construct. This effect paralleled increases in HSP70 mRNA and levels of the inducible HSP70 protein by Western blot. These studies identify a heat-induced mechanism of posttranscriptional control of HSP70 synthesis utilizing the HSP70 3'-UTR, which may be important in the cells ability to regulate the heat-shock response.

Base Sequence↗
PubMed1993

A cluster of five nuclear proteins regulates keratin gene transcription.

A common feature of all epithelial cells is the presence of keratin proteins that assemble into an intermediate filament cytoskeletal network. Whereas other cell types often use a specific master transcription factor to coordinate cell type-specific transcription, analysis of transcriptional regulation of keratin genes suggests that specific groupings of widely expressed transcription factors, acting on clusters of recognition elements in the promoter regions, confer epithelia-specific transcription. We define such a cluster of three sites that binds five transcription factors in the human K5 keratin gene. Within this cluster, an unusual Sp1 site binds the Sp1 transcription factor and two additional proteins. Flanking the Sp1 site are an AP2 site and another sequence, Site A; each binds a transcription factor. Similar clusters of recognition sites for the same five transcription factors have been also identified in other keratin genes. Such clusters may play a role in epithelia-specific expression of keratins.

Base Sequence↗
PubMed1989

Mutated and hypermutated genes of persistent measles viruses which caused lethal human brain diseases.

Persistent measles viruses (MVs) causing lethal human brain diseases are defective, and the structure of several mutated matrix genes has been elucidated previously. The present study of four persistent MVs revealed a high number of differences from a consensus sequence also in other genes. Amino acid changes accumulated in the carboxyl terminus of the nucleocapsid protein and in the amino terminus of the phosphoprotein, but did not significantly alter these products, which are implicated in viral replication and transcription. The contrary is true for the envelope glycoproteins: In three of four cases, mutations caused partial deletion of the short intracellular domain of the fusion protein, most likely compromising efficient viral budding. Moreover, in the hemagglutinin gene of a strain showing strongly reduced hemadsorption, 20 clustered A to G mutations, resulting in 16 amino acid changes, were detected. This hypermutation might be due to unwinding modification of a part of the MV RNA genome accidentally present in a double-stranded form. Finally, we classified four lytic and seven persistent MV strains on the basis of their sequences. Surprisingly, the four lytic viruses considered belong to the same class. The persistent viruses form more loosely defined groups, which all differ from the vaccine strain Edmonston.

Amino Acid Sequence↗
PubMed1982

Muscarinic cholinergic receptor binding: in vivo depiction using single photon emission computed tomography and radioiodinated quinuclidinyl benzilate.

An attempt was made to characterize, in vivo, specific binding to the muscarinic cholinergic receptor in the calf using the radioiodinated ligand quinuclidinyl benzilate (123I-OH-QNB) and single photon detection emission computed tomography (SPECT). The supratentorial brain activity was significantly increased after the intravenous infusion of 123I-OH-QNB as compared to free 123I. Scopolamine, a muscarinic cholinergic receptor antagonist, decreased the measured brain activity when infused prior to 123I-OH-QNB consistent with pharmacologic blockade of specific receptor binding. Quantitative in vitro tissue distribution studies obtained following SPECT imaging were consistent with regionally distinct specific receptor binding in the striatum and cortical gray matter, nonspecific binding in the cerebellum, and pharmacologic blockade of specific binding sites with scopolamine. Although 123I-OH-QNB is not the ideal radioligand, our limited success will hopefully encourage the development of improved binding probes for SPECT imaging and quantitation.

Animals↗