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Biomedical subjects

A L Mitchell

Publications and source records attributed to A L Mitchell.

At least 19 recordsLinked to original sources
PubMed2005

METIS: multiple extraction techniques for informative sentences.

SUMMARY: METIS is a web-based integrated annotation tool. From single query sequences, the PRECIS component allows users to generate structured protein family reports from sets of related Swiss-Prot entries. These reports may then be augmented with pertinent sentences extracted from online biomedical literature via support vector machine and rule-based sentence classification systems. AVAILABILITY: http://umber.sbs.man.ac.uk/dbbrowser/metis/

Algorithms↗
PubMed2005

Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene.

BACKGROUND: Cutis laxa is an acquired or inherited condition characterized by redundant, pendulous and inelastic skin. Autosomal dominant cutis laxa has been described as a benign disease with minor systemic involvement. OBJECTIVE: To report a family with autosomal dominant cutis laxa and a young girl with sporadic cutis laxa, both with variable expression of an aortic aneurysmal phenotype ranging from mild dilatation to severe aneurysm or aortic rupture. METHODS AND RESULTS: Histological evaluation of aortic aneurysmal specimens indicated classical hallmarks of medial degeneration, paucity of elastic fibres, and an absence of inflammatory or atherosclerotic lesions. Electron microscopy showed extracellular elastin deposits lacking microfibrillar elements. Direct sequencing of genomic amplimers detected defects in exon 30 of the elastin gene in affected individuals, but did not in 121 normal controls. The expression of mutant elastin mRNA forms was demonstrated by reverse transcriptase polymerase chain reaction analysis of cutis laxa fibroblasts. These mRNAs coded for multiple mutant tropoelastins, including C-terminally truncated and extended forms as well as for molecules lacking the constitutive exon 30. CONCLUSIONS: ELN mutations may cause severe aortic disease in patients with cutis laxa. Thus regular cardiac monitoring is necessary in this disease to avert fatal aortic rupture.

Adult↗
PubMed2005

Sequence variation in mitochondrial complex I genes: mutation or polymorphism?

BACKGROUND: Defects of the mitochondrial genome are recognised as common causes of genetic disease. Sequencing of large portions or even the entire mitochondrial genome is routine in many laboratories for the investigation of mitochondrial disease. However, establishing whether a detected sequence change is polymorphic or pathogenic is still a major difficulty because of its highly polymorphic nature. This has major implications for the patient and the family. OBJECTIVE: To describe a scoring system for determining the likelihood that a given sequence variant in one of the seven mitochondrially encoded complex I (MTND) genes is truly pathogenic. RESULTS: The scoring system was applied to 50 reported MTND mutations. Using this system, 21 of the mutations analysed fell into the group of neutral sequence variants, 10 were classified as possibly pathogenic, three as probably pathogenic, and 16 as almost certainly pathogenic. CONCLUSIONS: The proposed scoring system should advance the interpretation of sequence variants and ensure that candidate pathogenic mutations are rigorously investigated.

DNA, Mitochondrial↗
PubMed2003

PRECIS: protein reports engineered from concise information in SWISS-PROT.

MOTIVATION: There have been several endeavours to address the problem of annotating sequence data computationally, but the task is non-trivial and few tools have emerged that gather useful information on a given sequence, or set of sequences, in a simple and convenient manner. As more genome projects bear fruit, the mass of uncharacterized sequence data accumulating in public repositories grows ever larger. There is thus a pressing need for tools to support the process of automatic analysis and annotation of newly determined sequences. With this in mind, we have developed PRECIS, which automatically creates protein reports from sets of SWISS-PROT entries, collating results into structured reports, detailing known biological and medical information, literature and database cross-references, and relevant keywords.

Abstracting and Indexing↗
PubMed2003

PRINTS and its automatic supplement, prePRINTS.

The PRINTS database houses a collection of protein fingerprints. These may be used to assign uncharacterised sequences to known families and hence to infer tentative functions. The September 2002 release (version 36.0) includes 1800 fingerprints, encoding approximately 11 000 motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. In addition to its continued steady growth, we report here the development of an automatic supplement, prePRINTS, designed to increase the coverage of the resource and reduce some of the manual burdens inherent in its maintenance. The databases are accessible for interrogation and searching at http://www.bioinf.man.ac.uk/dbbrowser/PRINTS/.

Amino Acid Motifs↗
PubMed2003

Intratympanic gentamicin for unilateral Meniere's disease: results of therapy.

Patients with Meniere's disease that remains refractory to conservative treatment have traditionally been subjected to ablative surgery. The purpose of this prospective study was to evaluate the use of intratympanic gentamicin in eliminating incapacitating vertigo, while preserving hearing. Over the past 8 years, 83 patients have received between 1 and 6 intratympanic injections of gentamicin in an out-patient setting, with duration of therapy titrated to individual symptom response and effect on hearing. Using established AAO-HNS guidelines, we present data on 50 patients who have a minimum of 2 years follow-up. Control or significant improvement of definitive Meniere's attacks was achieved in 92% of patients and hearing preserved or improved in 76%. Only one patient experienced profound sensorineural hearing loss. We feel this treatment option should be considered and offered to patients in whom medical treatment has failed.

Adult↗
PubMed2002

PRINTS and PRINTS-S shed light on protein ancestry.

The PRINTS database houses a collection of protein fingerprints. These may be used to make family and tentative functional assignments for uncharacterised sequences. The September 2001 release (version 32.0) includes 1600 fingerprints, encoding approximately 10 000 motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. In addition to its continued steady growth, we report here its use as a source of annotation in the InterPro resource, and the use of its relational cousin, PRINTS-S, to model relationships between families, including those beyond the reach of conventional sequence analysis approaches. The database is accessible for BLAST, fingerprint and text searches at http://www.bioinf.man.ac.uk/dbbrowser/PRINTS/.

Amino Acid Motifs↗
PubMed1999

Circadian regulation of prion protein messenger RNA in the rat forebrain: a widespread and synchronous rhythm.

Although the expression of the normal prion protein in the host is critical to the development of transmissible spongiform encephalopathies, the physiological role of this protein and the processes regulating its expression remain obscure. We now report that the messenger RNA for the prion protein is regulated in the rat brain in a marked circadian manner not only in the suprachiasmatic nuclei, the principal site for the generation of mammalian circadian rhythms, but also in other forebrain regions. The data show a remarkable consistency in the concurrence of a single peak of prion protein messenger RNA at each of the sites early in the animal's phase of increased locomotor activity; behavioural arousal does not, however, appear to affect this expression. We believe this to be the first study demonstrating that the expression of prion protein messenger RNA can change over a relatively short period in vivo. The results are discussed with reference to the range of recently discovered "clock-related" transcripts which also have widespread tissue expression; these include the messenger RNAs for D-box binding protein and thyroid embryonic factor, transcription factors which bind to the prion protein promoter.

Animals↗
PubMed1999

Hippocampal T(2) abnormalities correlate with antecedent events and help predict seizure intractability.

INTRODUCTION: We performed hippocampal T(2) relaxometry as part of a routine magnetic resonance imaging (MRI) examination in 50 normal controls and 127 consecutive patients referred because of suspected seizures. METHODS: On the basis of T(2) values in controls (100.2 +/- 4.2 ms) we defined normal as <110 ms ( 113 ms (>mean + 3 SD). RESULTS: After detailed investigation, 103 of these 127 patients had epilepsy and 24 did not. In the nonepilepsy group, none had abnormal hippocampal T(2) values. Twenty-seven of the 103 patients in the epilepsy group had abnormal values, 7 were borderline and 69 were normal. Only 5 patients with abnormal T(2) values did not have temporal lobe epilepsy: 1 had extratemporal lobe epilepsy, 1 had generalized epilepsy and 3 had unclassified epilepsy. Twenty-two of 27 (81%) patients with abnormal hippocampal T(2) values had intractable epilepsy [compared with 32 of 69 (46%) patients with normal values; p < 0.05, chi(2) test]. Two thirds of patients with abnormal values had a history of a major antecedent event (compared to only 7% of those with normal values, p < 0.05, chi(2) test). CONCLUSION: Abnormal T(2) relaxometry is significantly associated with intractable epilepsy as well as with major antecedent events.

Adult↗
PubMed1997

The effects of gonadal steroids on brain stimulation reward in female rats.

The present study examined possible estrogen and/or progesterone effects on the mesolimbic dopamine (DA) system using brain stimulation reward (BSR). It is well known that BSR with electrical stimulation of the medial forebrain bundle (MFB) depends on the functioning of the mesolimbic DA system. If estrogen affects this system in a manner similar to its effects on the nigrostriatal DA system, reward measures would be expected to vary across the estrous cycle. Cycling female rats were trained to bar press for electrical stimulation to the MFB. Animals were tested at each stage of the estrous cycle, after ovariectomy and 4, 24, 48, 72 and 96 h after hormone replacement with estradiol (10 micrograms, s.c.), estradiol and progesterone (0.5 mg, s.c.), or oil (s.c.). The rewarding value of the stimulation and the maximum rate of bar pressing increased during estrus, but not during proestrus or metestrus, as compared with diestrus. Hormone replacement had differing effects on reward and motor performance. Motor performance increased 4 and 24 h after estrogen alone and 24 h after estrogen with the addition of progesterone 4 h before testing. The rewarding value of the stimulation increased only 24 h after estrogen together with an injection of progesterone 4 h before testing. These results indicate that gonadal steroids affect the functioning of the mesolimbic DA system.

Animals↗
PubMed1997

Effects of Plasmodium berghei infection on arteether metabolism and disposition.

Arteether (AE) is primarily deethylated to dihydroqinghaosu (DQHS) in rats and humans. Conversion of AE to DQHS was impaired in microsomes from rats infected with Plasmodium berghei. The Km for AE was 175.1 +/- 49.1 and 124.4 +/- 115.1 mumol/l, and Vmax was 2.24 +/- 0.45 and 1.22 +/- 0.67 nmol AE formed/mg protein/min in control and infected microsomes (p < 0.05), respectively. Calculated intrinsic clearance (CLint = initial Vmax/Km) for AE was only 4% lower in infected microsomes. Apparent pharmacokinetic parameter estimates for AE using the isolated perfused rat liver demonstrated no differences (p > 0.05) in volume of distribution, clearance, and half-life between normal and infected animals. Malaria infection resulted in decreased biliary excretion of free AE and DQHS. The majority of AE is eliminated via biliary excretion of conjugated DQHS, which is approximately 500-fold higher than free DQHS and 75-fold higher than free AE on a molar basis.

Animals↗
PubMed1996

N-terminal sequences contained in the Src homology 2 and 3 domains of p120 GTPase-activating protein are required for full catalytic activity toward Ras.

The p120 GTPase-activating protein (GAP) is a negative regulator of Ras, which has a central role in signal transduction pathways that control cell proliferation. p120 GAP accelerates the conversion of activated Ras-GTP to its inactive form, Ras-GDP, thereby inhibiting mitogenic signaling. To examine potential contributions of p120 N-terminal sequences to regulation of its C-terminal catalytic domain, we constructed deletion mutants lacking defined regions, including the variable hydrophobic region as well as the Src homology 2 (SH2) and 3 (SH3) domains. These mutant proteins were expressed in infected Sf9 insect cells from recombinant baculoviruses and assayed in vitro for their ability to stimulate the intrinsic GTPase activity of purified Ras. While deletion of the variable hydrophobic region had no effect on p120 GAP activity, deletion of the entire SH2/SH3/SH2 region severely impaired catalytic activity toward Ras. Deletion of individual SH2 and SH3 domains within this region partially inhibited p120 GAP activity. Moreover, p120 N-terminal sequences enhanced the Ras GTPase-stimulating activity of the neurofibromin GAP-related domain. These results demonstrate that sequences in the SH2/SH3/SH2 region of p120 GAP are required for full catalytic activity toward Ras. Together with earlier findings that the p120 GAP SH2 domains mediate interactions with several GAP-associated proteins, our results suggest multiple roles for the N-terminal sequences in regulating p120 GAP catalytic activity and mitogenic signaling pathways. In addition, our results raise the possibility that SH2 domain point mutations in p120 GAP detected in some basal cell carcinomas reduce catalytic activity toward Ras and thereby contribute to oncogenesis.

Animals↗
PubMed1992

The Caretaker Obstreperous-Behavior Rating Assessment (COBRA) Scale.

OBJECTIVE: To evaluate the usefulness and reliability of the Caretaker Obstreperous-Behavior Rating Assessment (COBRA), a new test instrument for caretaker assessment of types and severity of "obstreperous behaviors" (OBs) in demented patients. DESIGN: COBRA was completed by caretakers of 31 outpatients and 36 nursing home inpatients with dementia. Test-retest reliability was determined when 25 of the outpatient caretakers re-evaluated their demented relative 1 week later; inter-rater reliability was determined on nursing home inpatients by comparing the reports of two nurse's aids with equivalent knowledge of seven of the patients. SETTING: (1) University medical center Alzheimer's Disease and Related Disorders Clinic; (2) community nursing home. PATIENTS: Thirty-one sequentially-seen outpatients with dementia; 36 nursing home patients with dementia. INTERVENTION: Following instruction in the use of the COBRA Scale, caretakers provided scores for their demented patient. The instrument has three unique features: (1) it divides OBs into four categories for ease of comprehension: Aggressive/Assaultive; Mechanical/Motor; Ideational/Personality; and Vegetative; (2) a companion videotape shown to caretakers in advance illustrates each behavior to improve reliability of reporting; (3) the significance of each OB is estimated with severity and frequency measures. MAIN OUTCOME MEASUREMENTS: Frequency and severity of OBs are epitomized in 12 summary scores. Test-retest correlations (for outpatients) and inter-rater correlations (for inpatients) were analyzed with Pearson Product Moment and Spearman Rank Order correlations. RESULTS: Prevalence of OBs and severity was reported for the experimental groups. Summary scores revealed test-retest correlations of .95 to .73 for 11 of 12 scores (outpatients), and inter-rater correlations of .99 to .73 for 8 of 12 scores (inpatients). Age, gender, and disease etiology were not significantly related to OBs; clinical severity correlated with type and severity of OBs. CONCLUSIONS: The COBRA scale provides a convenient, comprehensive, and reliable means for caretakers to identify the types and measure the severity of OBs in demented outpatients and nursing home inpatients. If additional studies confirm these observations, COBRA will be a useful instrument for assessing the effects of interventions on OBs in patients with dementia.

Aged↗
PubMed1991

cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product.

Von Recklinghausen neurofibromatosis, or type 1 neurofibromatosis (NF1), is a common autosomal dominant disorder characterized by abnormalities in multiple tissues derived from the embryonic neural crest. Portions of the gene have been recently identified by positional cloning, and sequence analysis has shown homology to the GTPase activating protein (GAP) family. In this report we present the results of an extensive cDNA walk resulting in the cloning of the complete coding region of the NF1 transcript. Analysis of the sequences reveals an open reading frame of 2818 amino acids, although alternatively spliced products may code for different protein isoforms. The gene extends for approximately 300 kb on chromosome 17, with its promoter in a CpG-rich island.

Adult↗
PubMed1991

Localization of CYP2F1 by multipoint linkage analysis and pulsed-field gel electrophoresis.

CYP2F1, which encodes a P450 enzyme capable of metabolizing several mono-oxygenase substrates with the highest activity toward ethoxycoumarin, has been mapped to human chromosome 19 by somatic cell hybrid studies. The CYP2A and CYP2B subfamilies are known to lie within 350 kb of each other on chromosome 19. To determine the locations of CYP2F1 with respect to CYP2A and CYP2B, multipoint linkage analysis and pulsed-field gel electrophoresis were performed. No recombinants were found between CYP2F1 and CYP2B in more than 50 meioses, and one recombinant was found between CYP2F1 and CYP2A (50 meioses). Pulsed-field gel electrophoresis showed the three loci to lie within a 240-kb region. Multipoint analysis of the haplotyped CYP cluster with four other chromosome 19 loci yielded the order D19S7-D19S9-APOC2-D19S8-CYP, although four other orders could not be excluded. The odds were 4.4 x 10(3) against the order proposed by the HGM10 consortium, D19S7-D19S9-CYP-D19S8-APOC2.

Chromosome Mapping↗