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Biomedical subjects

P A Robinson

Publications and source records attributed to P A Robinson.

At least 19 recordsLinked to original sources
PubMed2000

Mechanisms of cortical electrical activity and emergence of gamma rhythm.

A continuum model of the electrical activity of the cerebral cortex is described which predicts the occurrence of a resonance in the gamma range near 40 Hz. The emergence of this resonance is due to two refinements to a previous model, namely the inclusion of a modulation of synaptic strength due to finite reversal potentials, and use of parameters that better match physiological measurements. Analytical expressions for the fixed points of the system and for its linear dynamics are found in terms of average neuronal properties, and together explain the occurrence and modulation of the gamma-like resonance. The analytical results are confirmed by a numerical simulation.

Cerebral Cortex↗
PubMed2000

Promoter analysis of the human ubiquitin-conjugating enzyme gene family UBE2L1-4, including UBE2L3 which encodes UbcH7.

UbcH7 is a ubiquitin-conjugating enzyme mediating c-fos degradation, transcription factor NF-kappaB maturation, human papilloma virus-mediated p53 and Myc protein degradation, in vitro. Previously, we characterised a highly dispersed gene family, UBE2L1-UBE2L4, whose members could potentially encode different isoforms of the UbcH7 protein. UBE2L3, located at chromosome 22q11.2, is the only identified family member with introns and encodes a polypeptide sequence identical to that of UbcH7. Promoter characterisation of UBE2L1, UBE2L3 and UBE2L4 5'-upstream regions was performed to establish which are transcribed under normal physiological conditions and after heat shock. Promoter activity was observed only with the UBE2L3 construct, the minimal promoter lying within a region 100 bp upstream of the transcriptional start site. No evidence for the presence of UBE2L1 or UBE2L4 transcripts was observed in human or murine tissues and cell lines. These data strongly suggest that UBE2L1 and UBE2L4 are likely to encode pseudogenes. Sequencing revealed that the UBE2L3 promoter contained no TATA or CCAAT boxes. Protein:DNA interaction studies confirmed the presence of binding sites for the transcription factors AP2 and Sp1 in the UBE2L3 minimal promoter. Deletion of these binding sites indicated that these factors are crucial for transcription of this gene.

Animals↗
PubMed2000

Vertebrate pseudogenes.

Pseudogenes are commonly encountered during investigation of the genomes of a wide range of life forms. This review concentrates on vertebrate, and in particular mammalian, pseudogenes and describes their origin and subsequent evolution. Consideration is also given to pseudogenes that are transcribed and to the unusual group of genes that exist at the interface between functional genes and non-functional pseudogenes. As the sequences of different genomes are characterised, the recognition and interpretation of pseudogene sequences will become more important and have a greater impact in the field of molecular genetics.

Animals↗
PubMed2000

Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family.

An intrinsic component of colorectal carcinogenesis may be the capacity to activate regenerative responses simultaneously with inhibition of apoptosis. Since apoptosis is known to be inhibited in colorectal cancer, this study sought evidence for the activation of the REG family of genes which are considered to be activated during regeneration of intestinal mucosa. Transcripts for the REG gene were found in 53% of colorectal cancers and for the PAP gene in 60% of colorectal cancers, by RT-PCR. Using in situ hybridization, the REG transcripts were found to be present in the tumour cells themselves rather than inflammatory or stromal cells. There were no significant correlations between the expression of these two genes and tumour stage, age or sex of the patient population or tumour site. However, in patients with non-metastatic disease who underwent ostensibly curative surgery, the expression of REG alone and co-expression of REG with PAP had a highly significantly adverse effect on survival. These data provide support for the concept that, in some tumours, carcinogenesis involves a regenerative process which co-exists with apoptotic inhibition and may provide a valuable selective indicator of the need for adjuvant therapy in those patients with early-stage colorectal cancer whose disease is destined to recur after curative surgery.

ADP-Ribosylation Factors↗
PubMed2000

Carotid-subclavian bypass grafting with polytetrafluoroethylene grafts for symptomatic subclavian artery stenosis or occlusion: a 20-year experience.

BACKGROUND AND PURPOSE: Since the advent of subclavian artery percutaneous transluminal angioplasty/stenting, several authorities advocate it as the treatment of choice for patients with subclavian artery disease, claiming results equal to or better than those of reconstructive vascular surgery. However, most of their quoted surgical series included patients who may have other brachiocephalic disease who were treated nonuniformly by means of various bypass grafts with different grafts in the same series (eg, Dacron, polytetrafluoroethylene [PTFE], or vein). In this study, we analyze the long-term results of a large series of carotid-subclavian bypass grafts for subclavian artery disease in which PTFE was uniformly used; the study can be used as a future reference to compare the results of subclavian artery percutaneous transluminal angioplasty/stenting. PATIENT POPULATION AND METHODS: Fifty-one patients with symptomatic subclavian artery disease (40 occlusions and 11 stenoses) who were treated with carotid-subclavian bypass grafts (PTFE [Goretex]) during a 20-year period were analyzed. Graft patency was determined clinically and confirmed with Doppler scanning pressures and duplex ultrasound scanning. The cumulative patency, overall survival, and symptom-free survival rates were calculated with the life table method. RESULTS: Indications for surgery were arm ischemia in 34 patients (67%), vertebrobasilar insufficiency (VBI) in 27 (53%), and symptomatic subclavian steal in 7 (14%). A combination of arm ischemia and VBI occurred in 17 (33%) of these patients. The mean follow-up was 7.7 years with a median of 7.0 years (range, 1-19 years). The 30-day morbidity rate was 6%, with no perioperative stroke or mortality. Immediate relief of symptoms was achieved in 100% of patients; however, four patients (8%) had late recurrent symptoms (three with VBI). The primary patency and secondary patency rates at 1, 3, 5, and 10 years were 100%, 98%, 96%, and 92% and 100%, 98%, 98%, and 95%, respectively. The symptom-free survival rates at 1, 3, 5, and 10 years were 100%, 96%, 82%, and 47%, respectively. The overall survival rates at 1, 3, 5, and 10 years were 100%, 98%, 86%, and 57%. The mean hospital stay was 3.5 days in the late 70s and 80s and 2.1 days in the 90s (P <. 001). CONCLUSIONS: Carotid-subclavian bypass grafts with PTFE grafts for subclavian artery disease are safe, effective, and durable and should remain the procedure of choice, particularly in good-risk patients.

Aged↗
PubMed2000

No polymorphism in the tissue transglutaminase gene detected in coeliac disease patients.

BACKGROUND: The autoantigen for the anti-endomysial antibody (AEA) found in coeliac disease has recently been reported to be the enzyme tissue transglutaminase (tTG). Polymorphisms in the gene for tTG would result in different enzymic isoforms being expressed. Certain isoforms may interact with gliadin to create antigenic neoepitopes, which could then generate an immune response in genetically predisposed individuals possessing major histocompatibility complex (MHC) class II DQ2. METHODS: We have sequenced the coding region of tTG in coeliac patients and normal controls. Total RNA was extracted from mucosal biopsies from eight AEA-positive histologically proven coeliac disease patients and four control patients with a histologically normal duodenum and a negative AEA. The 2-kb coding region of tTG was amplified in overlapping fragments by reverse transcription polymerase chain reaction (PCR), using five sets of PCR primers. Each overlapping PCR fragment was sequenced using the fmol DNA sequencing system. RESULTS: tTG transcripts were detected in all samples. There was no difference in the coding sequence of tTG between the four control and eight coeliac patients, even though we observed differences in sequence between our study and the original published sequence. These differences have also been reported in sequences published subsequent to the original description. CONCLUSIONS: Polymorphisms in the tTG gene have not been observed in coeliac disease patients and therefore cannot explain the creation of neoepitopes.

Amino Acid Sequence↗
PubMed2000

A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: a randomized, double-blind, crossover study.

To investigate single and combined effects of daily dietary supplementation with 50 mg of vitamin B6 and 200 mg magnesium (as MgO) for one cycle for the relief of mild premenstrual symptoms, a randomized, double-blind, placebo-controlled, crossover design was used. Forty-four women with an average age of 32 years took part in the study. Each woman was randomly assigned, according to a Latin square design, to take consecutively all four of the following treatments daily for one menstrual cycle: (1) 200 mg Mg, (2) 50 mg vitamin B6, (3) 200 mg Mg + 50 mg vitamin B6 and (4) placebo. Throughout the study, each volunteer kept a daily record of symptoms using a 5-point ordinal scale in a menstrual diary of 30 symptoms. Symptoms were grouped into six categories: anxiety, craving, depression, hydration, other, and total. Urinary magnesium output for 24 hours was estimated using the Mg/creatinine concentration ratio. ANOVA showed no overall difference between individual treatments, but predefined treatment comparisons using factorial contrasts in ANOVA showed a significant effect of 200 mg/day Mg + 50 mg/day vitamin B6 on reducing anxiety-related premenstrual symptoms (nervous tension, mood swings, irritability, or anxiety) (p = 0.040). Urinary Mg output was not affected by treatment. A small synergistic effect of a daily dietary supplementation with a combination of Mg + vitamin B6 in the reduction of mild premenstrual anxiety-related symptoms was demonstrated during treatment of 44 women for one menstrual cycle. In view of the modest effect found, further studies are needed before making general recommendations for the treatment of premenstrual symptoms. The study indicated that absorption from MgO was poor and daily supplementation for longer than 1 month is necessary for tissue repletion.

Adult↗
PubMed2000

Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12.

The human UBE2L6 gene encodes UbcH8(Kumar), a ubiquitin-conjugating enzyme (E2) highly simliar in primary structure to UbcH7 which is encoded by UBE2L3. Like UBC4 and UBC5 in yeast, these proteins demonstrate functional redundancy. Herein we report the intron/exon structure of UBE2L6. Comparison of the genomic organization of UBE2L6 with UBE2L3 demonstrates that these genes remain highly conserved at the genomic as well as at the protein level. We also describe the chromosomal localization of UBE2L6, which maps to chromosome 11q12.

Amino Acid Sequence↗
PubMed2000

Effort subclavian vein thrombosis: evolution of management.

PURPOSE: To analyze changes in the management of effort subclavian vein thrombosis at our institution. METHODS: Records of 23 patients with effort subclavian vein thrombosis treated over a 10-year period were analyzed to compare the results of conventional therapy (heparin/warfarin) used in the first half of this period to a multimodality treatment strategy (thrombolysis and other adjunctive treatment as indicated, e.g., first rib resection, angioplasty/stenting, and vein reconstruction). Diagnostic testing included duplex ultrasound and venography. All patients had at least 1-year follow-up. RESULTS: Eight patients (7 men; mean age 34 years, range 15-54) had conventional treatment (group A) and 15 patients (14 men; mean age 36 years, range 17-55) had multimodality therapy (group B). Demographics and clinical characteristics were comparable for both groups. Initial thrombolysis was achieved in 14 (93%) group B patients; 10 received adjunctive treatment to relieve external compression or vein stenosis. Four patients had successful first or cervical rib resection and scalenectomy, and first rib resection followed by angioplasty/stenting was successful in 2. However, angioplasty and stenting alone failed in 2 patients, while venous reconstruction was successful in only 1 of 2 cases. Mean follow-up was 72 months in group A patients and 59 months in group B. One (13%) group A patient and 12 (80%) group B patients demonstrated total venous recanalization and symptom resolution (p = 0.003). Overall, clinical resolution (total and partial symptom relief) was achieved in 3 (38%) group A patients and 13 (87%) group B patients (p = 0.026). CONCLUSIONS: Initial lytic therapy followed by adjunctive treatment to relieve external venous compression or venous stenosis is effective in treating patients with effort subclavian vein thrombosis.

Adolescent↗
PubMed1999

The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact with RING finger/IBR motif-containing domains of HHARI and H7-AP1.

Ubiquitinylation of proteins appears to be mediated by the specific interplay between ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s). However, cognate E3s and/or substrate proteins have been identified for only a few E2s. To identify proteins that can interact with the human E2 UbcH7, a yeast two-hybrid screen was performed. Two proteins were identified and termed human homologue of Drosophila ariadne (HHARI) and UbcH7-associated protein (H7-AP1). Both proteins, which are widely expressed, are characterized by the presence of RING finger and in between RING fingers (IBR) domains. No other overt structural similarity was observed between the two proteins. In vitro binding studies revealed that an N-terminal RING finger motif (HHARI) and the IBR domain (HHARI and H7-AP1) are involved in the interaction of these proteins with UbcH7. Furthermore, binding of these two proteins to UbcH7 is specific insofar that both HHARI and H7-AP1 can bind to the closely related E2, UbcH8, but not to the unrelated E2s UbcH5 and UbcH1. Although it is not clear at present whether HHARI and H7-AP1 serve, for instance, as substrates for UbcH7 or represent proteins with E3 activity, our data suggests that a subset of RING finger/IBR proteins are functionally linked to the ubiquitin/proteasome pathway.

Amino Acid Sequence↗
PubMed1999

Characterization of the mouse ubiquitin-conjugating enzyme gene UbcM4.

The ubiquitination pathway targets not only normal (short-lived) intracellular eukaryotic proteins for degradation when appropriate, but also serves to eliminate mutant/misfolded proteins from the cell. An understanding of the molecular basis of the interaction between the ubiquitin-conjugating enzymes (E2s), ubiquitin protein ligases (E3s), and target proteins is essential to explain the process in normal cellular function and in disease. UbcM4 is the mouse ortholog of the human E2, UbcH7, which can participate in the in vitro degradation of many proteins including p53. We describe the characterization of the mouse UbcM4 gene and the identification of a UbcM4 pseudogene. Four UbcM4 transcripts of approximately 0.7, 1.5, 2.1, and 2.6 kb, observed on Northern blots, are differentiated by their utilization of alternative UbcM4 polyadenylation sites. A single alternative splice variant cDNA, termed UbcM4Deltaex2, was also identified. The polypeptide encoded by UbcM4Deltaex2 is incapable of forming an ubiquitin-thioester in contrast to UbcM4, despite retaining the key cysteine residue essential for ubiquitin thioester formation and the active site consensus sequence that defines the ubiquitin-conjugating enzyme class. These observations are of particular relevance for analysis of UbcM4 function in vivo as our studies indicate that the targeted deletion of the coding exon absent in UbcM4Deltaex2 would produce an inactive UbcM4 protein and presents an alternative to disruption of its transcriptional initiation site/promoter region. Furthermore, it suggests that a similar strategy may be applicable to disrupt the function of other ubiquitin-conjugating enzymes in vivo.

Alternative Splicing↗
PubMed1999

A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue.

Mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes account for the majority of cases of early-onset familial Alzheimer's disease (AD). Alternative splicing forms of the PS-1 and PS-2 gene products have previously been reported in fibroblast and brain tissue from both familial and sporadic AD patients, as well as from normal tissues and cell lines. We demonstrate here unusual alternative splicing of the PS-2 gene that leads to the generation of mRNA lacking exon 5 in human brain tissue. This product was more frequently detected in brain tissue from sporadic AD patients (70.0%; 21 of 30) than from normal age-matched controls (17.6%; three of 17). In cultured neuroblastoma cells, this splice variant was generated in hypoxia but not under other forms of cellular stress. Hypoxia-mediated induction of this splice variant was blocked by pretreatment of neuroblastoma cells with the protein synthesis inhibitor cycloheximide or antioxidants such as N-acetylcysteine and diphenyl iodonium, suggesting that hypoxia-mediated oxidant stress might, at least in part, underlie the alternative splicing of PS-2 mRNA through de novo protein synthesis. Furthermore, the stable transfectants of this splice variant produced the N-terminal part of PS-2 protein (15 kDa) and were more susceptible to cellular stresses than control transfectants. These results suggest the possibility that altered presenilin gene products in stress conditions may also participate in the pathogenesis of AD.

Aged↗
PubMed1999

Early mycological treatment failure in AIDS-associated cryptococcal meningitis.

Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.

AIDS-Related Opportunistic Infections↗
PubMed1999

Analysis of regression of postoperative carotid stenosis from prospective randomized trial of carotid endarterectomy comparing primary closure versus patching.

BACKGROUND AND PURPOSE: Recurrent stenosis after carotid endarterectomy (CEA) has been reported to vary between a few percent and 30%. Regression of recurrent stenosis has been reported sporadically in the literature, but studies analyzing the factors affecting regression are lacking. This study analyzed factors affecting the regression of postoperative stenosis from a prospective randomized trial of CEA comparing primary closure (PC) versus patching. PATIENT POPULATION AND METHODS: Three hundred ninety-nine CEAs were randomized into three groups: 135 PCs, 135 polytetrafluoroethylene patch closures (PTFE), and 130 vein patch closures (VPC). Postoperative duplex ultrasounds were done at 1, 6, and 12 months, and then yearly. The subgroup of these CEAs that exhibited postoperative stenosis was followed for possible regression of the stenosis. Analyses of various risk factors were examined for possible association with regression of recurrent stenosis. Mean follow-up was 46 months. RESULTS: Of 105 postoperative stenoses, regression was noted in 6/64 (9%) in PC, 6/13 (46%) in PTFE, and 10/28 (36%) in VPC. Overall, 22 recurrent stenoses regressed; 19 regressed to normal and 3 regressed from 50% to 80% stenosis to 20% to <50% stenosis. The mean time to regression was 383 days. Regression was more common in patching than PC. Both VPC and PTFE had significantly more regression than PC. When stenoses of 50% to 80% were analyzed, patching had more regression than PC. None of the recurrent stenoses > or = 80% regressed. There was no association between regression and other factors, including gender, hypertension, diabetes mellitus, coronary artery disease, smoking, internal carotid artery diameter, hyperlipidemia, hypercholesterolemia, or aspirin intake. CONCLUSIONS: Regression of recurrent stenosis was associated more strongly with patching than with PC. There was no association between regression and other factors.

Carotid Stenosis↗
PubMed1999

Signal recognition particle receptor (SRPR) is downregulated in a rat model of cyclosporin A-induced gingival overgrowth.

Differential display is a powerful technique which can be used to identify those genes whose expression is altered between two or more tissues under investigation. We have applied differential display to a rat model of cyclosporin A-induced gingival overgrowth (CIGO) to identify genes which are differentially expressed as a result of drug treatment. Ten weanling Wistar rats were fed with a pelleted diet containing cyclosporin A (CsA) at 120 mg/kg for 10 d and then 200 mg/kg for a further 30 d prior to culling. Experimental rats were compared with 10 age/sex-matched rats on a control diet. Significant evidence of overgrowth was observed in the interdental papilla between the mandibular first and second molar teeth in the CsA group. Differential display was performed on total cellular RNA extracted from the mandibular buccal gingiva. A cDNA product was isolated which was underexpressed in the overgrowth tissue and demonstrated a 95% sequence homology to the human signal recognition particle receptor (Human Docking Protein). Preliminary studies indicate that this gene is also underexpressed in human CIGO tissue. The method of approach and the potential implications of our findings are discussed.

Animals↗
PubMed1999

Prospective randomized trial of bilateral carotid endarterectomies: primary closure versus patching.

BACKGROUND AND PURPOSE: Although several studies have compared the results of carotid endarterectomy (CEA) with primary closure (PC) versus patch closure, none have compared the outcome of bilateral CEAs with patch versus PC performed on the same patient. This prospective randomized study compares the clinical outcome and incidence of recurrent stenosis (>/=80%) for CEA with PC versus patch closure in patients with bilateral CEAs. METHODS: This study includes 74 patients with bilateral CEAs with PC on one side and patching on the other. Patients were randomized to sequential operative treatment of either patching/PC or PC/patching. Postoperative duplex ultrasounds and clinical follow-up were done at 1, 6, and 12 months and every year thereafter. A Kaplan-Meier analysis was used to estimate the risk of significant restenosis (>/=80%). RESULTS: Demographic characteristics and the mean operative diameter of the internal carotid artery were similar for both PC and patching. The mean follow-up was 29 months (range, 6 to 65 months). The incidence of ipsilateral stroke was 4% for PC versus 0% for patching. PC had a significantly higher incidence of neurological complications (transient ischemic attacks and stroke combined) than patching (12% versus 1%; P=0.02). Operative mortality was 0%. PC had a higher incidence of recurrent stenosis (22% versus 1%; P<0.003) and total internal carotid artery occlusion (8% versus 0%; P=0.04) than patching. Restenoses necessitating a repeated CEA were also higher for PC (14%) than for patching (1%; P=0.01). The Kaplan-Meier analysis showed that patching had a significantly better cumulative patency rate than PC (P<0.01). This analysis also showed that freedom from recurrent stenosis at 24 months was 75% for PC and 98% for patching. CONCLUSIONS: Patch closure is less likely than PC to cause ipsilateral stroke, transient ischemic attacks, and recurrent carotid stenosis. The higher rate of unilateral recurrent stenosis may suggest that local factors play a more significant role than systemic factors in the etiology of recurrent carotid stenosis.

Carotid Arteries↗
PubMed1999

The role of carotid duplex ultrasound in evaluating plaque morphology: potential use in selecting patients for carotid stenting.

PURPOSE: To study the role of duplex ultrasonography in evaluating plaque morphology and its correlation to neurological symptoms and cerebral infarctions on computed tomographic scans. METHODS: The hospital records of 181 patients (107 males; average age 66 years, range 41 to 89) with > 50% carotid stenosis (29 bilateral lesions) who had undergone duplex ultrasonography, carotid arteriography, and cerebral computed tomography were studied retrospectively. Of 210 duplex examinations, 139 were appropriate for morphological analysis of surface characteristics and echogenicity. RESULTS: Over half of the plaques examined had irregular surfaces (81, 58%) and displayed mixed (i.e., heterogeneous) echogenic patterns (74, 53%). Irregular (68 of 81, 84%) and heterogeneous (65 of 74, 88%) plaques were associated with ipsilateral neurological symptoms (p < 0.0001). Similarly, 44 (54%) of 81 irregular plaques and 42 (57%) of 74 heterogeneous plaques were found in patients with cerebral infarctions in the carotid territory (p < 0.0001). CONCLUSIONS: Heterogeneous and/or irregular plaques were more often associated with both neurological symptoms and infarctions than smooth or homogeneous plaques. These findings may have implications in patient selection for endoluminal therapy.

Adult↗