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Biomedical subjects

J Bond

Publications and source records attributed to J Bond.

At least 37 records · Page 2Linked to original sources
PubMed2001

Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36.

Kufor-Rakeb syndrome is an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration. The onset is in the teenage years with clinical features of Parkinson's disease plus spasticity, supranuclear upgaze paresis, and dementia. Brain scans show atrophy of the globus pallidus and pyramids and, later, widespread cerebral atrophy. We report linkage in Kufor-Rakeb syndrome to a 9 cM region of chromosome 1p36 delineated by the markers D1S436 and D1S2843, with a maximum multipoint lod score of 3.6.

Chromosome Mapping↗
PubMed2001

Falls and confidence related quality of life outcome measures in an older British cohort.

Falls are common in older subjects and result in loss of confidence and independence. The Falls Efficacy Scale (FES) and the Activities-specific Balance Confidence scale (ABC) were developed in North America to quantify these entities, but contain idiom unfamiliar to an older British population. Neither has been validated in the UK. The FES and the ABC were modified for use within British culture and the internal consistency and test-retest reliability of the modified scales (FES-UK and ABC-UK) assessed. A total of 193 consecutive, ambulant, new, and return patients (n=119; 62%) and their friends and relatives ("visitors", n=74; 38%) were tested on both scales, while the last 60 subjects were retested within one week. Internal reliability was excellent for both scales (Cronbach's alpha 0.97 (FES-UK), and 0.98 (ABC-UK)). Test-retest reliability was good for both scales, though superior for the ABC-UK (intraclass correlation coefficient 0.58 (FES-UK), 0.89 (ABC-UK)). There was evidence to suggest that the ABC-UK was better than the FES-UK at distinguishing between older patients and younger patients ([t(ABC)] = 4.4; [t(FES)] = 2.3); and between fallers and non-fallers ([t(ABC)] = 8.7; [t(FES)] = 5.0) where the t statistics are based on the comparison of two independent samples. The ABC-UK and FES-UK are both reliable and valid measures for the assessment of falls and balance related confidence in older adults. However, better test-retest reliability and more robust differentiation of subgroups in whom falls related quality of life would be expected to be different make the ABC-UK the current instrument of choice in assessing this entity in older British subjects.

Accidental Falls↗
PubMed2001

Costs of dementia in England and Wales in the 21st century.

BACKGROUND: An important factor determining future health care expenditure is the relationship between ageing, health status and development of age-related disorders such as dementia. AIMS: To estimate the formal care costs associated with dementia in England and Wales between 1994 and 2031. METHOD: Epidemiological cost model, applied to individuals aged 65 years or over with dementia, using estimates of life expectancy with dementia and dementia-free life expectancy. RESULTS: Total costs per year were pound 0.95 billion (men) and pound 5.35 billion (women) using 1994 population estimates. For 2031, costs were pound 2.34 billion and pound 11.20 billion, respectively. Reduced dementia prevalence rates and improvements in mental and physical functioning resulted in lower estimates: pound 1.01 billion (men) and pound 5.77 billion (women), and pound 1.65 billion (men) and pound 7.87 billion (women), respectively. CONCLUSIONS: Future increases in the population aged 65 years or over lead to rising formal care costs. However, the magnitude of cost changes depends on assumptions over dementia prevalence and levels of mental and physical functioning.

Aged↗
PubMed2001

Ligand-binding characteristics of recombinant amino- and carboxyl-terminal fragments of human insulin-like growth factor-binding protein-3.

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a member of a family of structurally conserved proteins (IGFBP-1 to -6) which act as carriers and regulators of the mitogenic peptide hormones IGF-I and IGF-II. Members of the IGFBP family share conserved cysteine-rich amino- and carboxyl-terminal regions. The amino-terminal domain of these proteins is recognised to contain an IGF-binding determinant, but evidence to support a binding site in the carboxyl-terminal region of the protein is less rigorous. To further investigate this, we have synthesised both the amino-terminal (residues 1-88; N-88) and carboxyl-terminal (residues 165-264; C-165) domains of human IGFBP-3 in bacteria, as fusion proteins with a carboxyl-terminal FLAG peptide. Although only C-165 showed binding to IGF-I and -II by solution-binding assays, both N-88 and C-165 demonstrated binding to IGF-I and -II by biosensor analysis albeit with reduced affinities compared with full-length IGFBP-3. Only the carboxyl-terminal fragment (C-165) was able to form hetero-trimeric complexes with IGF-I and the acid-labile subunit (ALS). We conclude that the carboxyl-terminal domain of IGFBP-3 contains an IGF-binding determinant and can form ternary complexes with ALS.

Amino Acid Sequence↗
PubMed2000

Structural changes in a hydrophobic domain of the prion protein induced by hydration and by ala-->Val and pro-->Leu substitutions.

X-ray diffraction was used to study the structure of assemblies formed by synthetic peptide fragments of the prion protein (PrP) that include the hydrophobic domain implicated in the Gerstmann-Sträussler-Scheinker (GSS) mutation (P102L). The effects of hydration on polypeptide assembly and of Ala-->Val substitutions in the hydrophobic domain were characterized. Synthetic peptides included: (i) Syrian hamster (SHa) hydrophobic core, SHa106-122 (KTNMKHMAGAAAAGAVV); (ii) SHa104-122(3A-V), with A-->V mutations at 113, 115 and 118 (KPKTNMKHMVGVAAVGAVV); (iii) mouse (Mo) wild-type sequence of the N-terminal hydrophobic domain, Mo89-143WT; and (iv) the same mouse sequence with leucine substitution for proline at residue number 101, Mo89-143(P101L). Samples of SHa106-122 that formed assemblies while drying under ambient conditions showed X-ray patterns indicative of 33 A thick slab-like structures having extensive H-bonding and intersheet stacking. By contrast, lyophilized peptide that was equilibrated against 100 % relative humidity showed assemblies with only a few layers of beta-sheets. The Ala-->Val substitutions in SHa104-122 and Mo89-143(P101L) resulted in the formation of 40 A wide, cross-beta fibrils. Observation of similar size beta-sheet fibrils formed by peptides SHa104-122(3A-V) and the longer Mo89-143(P101L) supports the notion that the hydrophobic sequence forms a template or core that promotes the beta-folding of the longer peptide. The substitution of amino acids in the mutants, e.g. 3A-->V and P101L, enhances the folding of the peptide into compact structural units, significantly enhancing the formation of the extensive beta-sheet fibrils.

Amino Acid Sequence↗
PubMed2000

Betabellins 15D and 16D, de Novo designed beta-sandwich proteins that have amyloidogenic properties.

The betabellin structure is a de novo designed beta-sandwich protein consisting of two 32-residue beta-sheets packed against one another by hydrophobic interactions. d-Amino acid residues are used to energetically favor formation of type-I' beta turns. Air oxidation of betabellin 15S (B15S) (HSLTAKIpkLTFSIAphTYTCAVpkYTAKVSH, where p denotes d-Pro, h denotes d-His, and k denotes d-Lys) yields betabellin 15D (B15D), a 64-residue disulfide-bridged protein. The amino acid sequence of B15D contains a conformationally constrained d-Pro residue at the i + 1 position of each type-I' beta turn. To test whether d-Pro residues are necessary for folding at these positions, the six d-Pro residues of B15D are replaced by d-Ala residues in betabellin 16D (B16D). Previously, transmission electron microscopy showed that B15D forms unbranched, 35-A wide fibrils that associate into bundles in 5.0 mM 3-(N-morpholino)propanesulfonate and 250 mM NaCl at pH 7; under these conditions, B16D forms ribbon-like assemblies. The B15D fibrils resemble the protofilaments that constitute amyloid fibrils. The present studies show that both B15D and B16D have characteristics of amyloidogenic proteins: the unbranched fibrils and ribbons stained with Congo red and displayed a green birefringence, exhibited a cross-beta structure, and bound 1-anilino-8-naphthalenesulfonate. Thus, these de novo designed beta-sandwich proteins should provide useful models for studying the mechanism of amyloid protofilament formation and assembly into amyloid fibrils and for designing potential inhibitors of amyloidogenesis.

Amino Acid Sequence↗
PubMed2000

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model.

RATIONALE: Previous pre-clinical studies with an anti-cocaine monoclonal antibody left open several issues critical to assessing the effectiveness of a vaccine for altering cocaine self-administration behavior. OBJECTIVES: The objectives of this study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine. METHODS: Two experiments were conducted using a second-order schedule of drug delivery in rats. The first was a passive-administration study using the anti-cocaine monoclonal antibody MO240 to examine the relationship between antibody level and cocaine self-administration behavior, and the second was an active-immunization study to examine the efficacy of the cocaine vaccine IPC-1010 for blocking various doses of self-administered cocaine. RESULTS: The passive-administration experiment with control and 4-mg or 12-mg MO240 treatments showed that antagonism of the 1 mg/kg cocaine training dose was dependent on antibody level. In animals whose serum antibody levels were sustained above 0.05 mg/ml, there was a sufficient amount of antibody to reduce drug-seeking behavior and drug intake. In the active-immunization experiment, the cocaine vaccine IPC-1010 induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of behavior by 1 mg/kg cocaine. Antagonism of cocaine self-administration after immunization was evident across a range of doses of cocaine and was only apparent in animals whose serum antibody levels exceeded 0.05 mg/ml. Furthermore, there was no evidence that the antagonism was surmountable within the dose range examined (up to 5.6 mg/kg). CONCLUSIONS: Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

Animals↗
PubMed2000

Complications of carotid sinus massage--a prospective series of older patients.

BACKGROUND: there is a causal association between carotid sinus hypersensitivity, falls and syncope in elderly subjects. Neurological complications during carotid sinus massage have been reported in case studies and two retrospective series. Our aim was prospectively to ascertain the incidence of complications occurring after carotid sinus massage performed for diagnostic purposes in a consecutive series of patients. METHODS: 1000 consecutive subjects aged 50 years or over who attended the accident and emergency department with syncope or 'unexplained' falls had carotid sinus massage. Carotid sinus massage was performed for 5 s on the right and then left sides both supine and upright (70 degrees head-up tilt) with continuous heart rate and phasic blood pressure recording. Contraindications to carotid sinus massage were the presence of a carotid bruit, recent history of stroke or myocardial infarction or previous ventricular tachyarrhythmia. RESULTS: complications occurred in nine patients immediately after cessation of carotid sinus massage. Eight had transient neurological complications possibly attributable to carotid sinus massage: visual disturbance, 'pins and needles' and sensation of finger numbness in two cases each, leg weakness in one and sensation of 'being drunk' in one. All transient complications resolved within 24 h. In one patient mild weakness of the right hand persisted. CONCLUSIONS: no subjects had cardiac complications and 1% had possible neurological symptoms, which resolved in most cases. Persistent neurological complications are uncommon, occurring in 1:1000 patients (0.1%) or 1: 3805 episodes of carotid sinus massage (0.03%).

Accidental Falls↗
PubMed2000

Polymorphism and divergence in the beta-globin replication origin initiation region.

DNA sequence polymorphism and divergence was examined in the vicinity of the human beta-globin gene cluster origin of replication initiation region (IR), a 1.3-kb genomic region located immediately 5' of the adult-expressed beta-globin gene. DNA sequence variation in the replication origin IR and 5 kb of flanking DNA was surveyed in samples drawn from two populations, one African (from the Gambia, West Africa) and the other European (from Oxford, England). In these samples, levels of nucleotide and length polymorphism in the IR were found to be more than two times as high as adjacent non-IR-associated regions (estimates of per-nucleotide heterozygosity were 0.30% and 0.12%, respectively). Most polymorphic positions identified in the origin IR fall within or just adjacent to a 52-bp alternating purine-pyrimidine ((RY)n) sequence repeat. Within- and between-populations divergence is highest in this portion of the IR, and interspecific divergence in the same region, determined by comparison with an orthologous sequence from the chimpanzee, is also pronounced. Higher levels of diversity in this subregion are not, however, primarily attributable to slippage-mediated repeat unit changes, as nucleotide substitution contributes disproportionately to allelic heterogeneity. An estimate of helical stability in the sequenced region suggests that the hypervariable (RY)n constitutes the major DNA unwinding element (DUE) of the replication origin IR, the location at which the DNA duplex first unwinds and new strand synthesis begins. These findings suggest that the beta-globin IR experiences a higher underlying rate of neutral mutation than do adjacent genomic regions and that enzyme fidelity associated with the initiation of DNA replication at this origin may be compromised. The significance of these findings for our understanding of eukaryotic replication origin biology is discussed.

Animals↗
PubMed2000

Socioeconomic status and the expectation of disability in old age: estimates for England.

OBJECTIVES: The longer life expectancy in old age of more privileged socioeconomic groups is well established, but less clear is whether the net effect of additional years of life is a lengthened, stable or reduced duration of disability. Estimates of healthy and disabled life expectancy (using definitions including dependency in activities of daily living and cognitive impairment) were made, contrasting occupational classes I and II (professional and managerial) with the rest. DESIGN: Disability prevalence was estimated from the Medical Research Council Cognitive Function and Ageing study. Sullivan's method was used to calculate health expectancy. SUBJECTS: 10,377 people aged 65 years or over in Cambridgeshire, Newcastle, Nottingham and Oxford. Subjects were classified as disabled if they had evidence of dementia (using the Automated Geriatric Examination Computer Assisted Taxonomy) or scored 11 or more on the modified Townsend Disability scale, at baseline screen. RESULTS: The prevalence of disability overall and need for "constant care" was lower in both men and women in social classes I and II compared with the rest. Men aged 65 to 69 in classes I and II can expect nearly 14 years of life free of disability compared with 11.5 years for those in classes III to V: for women the equivalent expectations are 15.5 and 13.8 years. Men aged 65 to 69 in classes I and II can also expect a shorter duration of disability: 1 year compared with 1.6 years for classes III to V. In women expectation of disability is higher overall, but shows little difference by occupational class. CONCLUSIONS: Relatively privileged socioeconomic groups in England, especially men, can expect fewer years of disability despite longer overall life expectancy. These findings lend weight to optimistic scenarios for the future numbers of older people with disability.

Aged↗
PubMed2000

Predicting place of discharge from hospital for patients with a stroke or hip fracture on admission.

OBJECTIVES: To determine the predictive power of patient and service characteristics on place of discharge following hospital admission for an acute stroke and for hip fracture. METHODS: Prospective cohort of 440 acute stroke and 572 hip fracture patients aged 65 years or over admitted from home to six district general hospitals and associated community hospitals, three in the North and three in the South of England. RESULTS: Age, marital status, living arrangements, mental health status at admission, pre-admission self-rated disability, pre-admission use of home-care services, post-admission staff assessments of functional dependency as measured by Barthel Index and of confusion as measured by the modified Crichton Royal Behavioural Rating Scale and nursing staffs' expectation of place of discharge are all significantly related to place of discharge for stroke and hip fracture participants. Logistic regression correctly predicted discharge destination for 87% of stroke patients from data available at time of admission and 83% of hip fracture patients. Of the 30% of stroke patients discharged to an institution, the model correctly predicted 73%. However, of the 19% of hip fracture patients discharged to an institution, only 28% were correctly predicted. CONCLUSIONS: Data about older patients admitted to hospital with an acute condition should be routinely collected by hospital staff to inform clinical management and to permit risk-adjusted audit.

Aftercare↗
PubMed1999

An aminoacyl-tRNA synthetase paralog with a catalytic role in histidine biosynthesis.

In addition to their essential catalytic role in protein biosynthesis, aminoacyl-tRNA synthetases participate in numerous other functions, including regulation of gene expression and amino acid biosynthesis via transamidation pathways. Herein, we describe a class of aminoacyl-tRNA synthetase-like (HisZ) proteins based on the catalytic core of the contemporary class II histidyl-tRNA synthetase whose members lack aminoacylation activity but are instead essential components of the first enzyme in histidine biosynthesis ATP phosphoribosyltransferase (HisG). Prediction of the function of HisZ in Lactococcus lactis was assisted by comparative genomics, a technique that revealed a link between the presence or the absence of HisZ and a systematic variation in the length of the HisG polypeptide. HisZ is required for histidine prototrophy, and three other lines of evidence support the direct involvement of HisZ in the transferase function. (i) Genetic experiments demonstrate that complementation of an in-frame deletion of HisG from Escherichia coli (which does not possess HisZ) requires both HisG and HisZ from L. lactis. (ii) Coelution of HisG and HisZ during affinity chromatography provides evidence of direct physical interaction. (iii) Both HisG and HisZ are required for catalysis of the ATP phosphoribosyltransferase reaction. This observation of a common protein domain linking amino acid biosynthesis and protein synthesis implies an early connection between the biosynthesis of amino acids and proteins.

ATP Phosphoribosyltransferase↗
PubMed1999

Profile of disability in elderly people: estimates from a longitudinal population study.

OBJECTIVES: To provide estimates of the numbers of cognitively impaired and physically disabled elderly people in England and Wales, subdivided by a range of sociodemographic, dependency, care receipt, and survival variables, to support debates on the form and funding of health and welfare programmes. DESIGN: Interviews at baseline and 2 year follow up plus data on resource use extracted from records for those with disability. SUBJECTS: 10 377 people aged 65 years and over in Cambridgeshire, Newcastle, Nottingham, and Oxford. All estimates weighted to population of England and Wales in 1996. RESULTS: 11% of men and 19% of women aged 65 and over were disabled, totalling 1.3 million people; 38% of these were aged 85 or over and a similar percentage were cognitively impaired. Overall, more than 80% of elderly disabled people needed help on at least a daily basis. Over a third of people with limitations to daily activity living in private households were wholly or partly dependent on formal services for help. 63% of disabled elderly people used acute hospitals during the 2 year follow up, 43% as inpatients. 53% of those with cognitive impairment and limitations to daily activity were living in institutions. CONCLUSIONS: Very elderly people and those with cognitive impairment make up a large proportion of those in need of long term care. A large proportion of even the most disabled elderly people currently live outside institutions and depend on formal services as well as informal care givers. Disabled elderly people use acute hospitals extensively, underlining the interrelations between acute and long term care.

Activities of Daily Living↗
PubMed1999

Telomerase repressor sequences on chromosome 3 and induction of permanent growth arrest in human breast cancer cells.

BACKGROUND: Activation of the enzyme telomerase, which has been associated with cellular immortality, may constitute a key step in the development of human cancer. Telomerase is repressed in most normal human somatic cells. This study was conducted, using a genetic complementation approach, with the aim of identifying and mapping the genes responsible for repressing telomerase and, simultaneously, to establish the effect of experimentally induced telomerase repression on human tumor cell growth. METHODS: Individual human chromosomes isolated from normal diploid cells and tagged with bacterial antibiotic resistance genes (for later selection) were introduced into cells of the human breast carcinoma cell line 21NT by means of microcell transfer. Selected hybrid clones were screened for telomerase activity by use of the polymerase chain reaction-based telomere repeat amplification protocol (TRAP) assay, and the proliferative fate of the hybrid clones was determined. Regions of the introduced chromosomes associated with telomerase repression were mapped using segregant hybrids and a deletion analysis that employed microsatellite DNA markers. RESULTS: Strong repression of telomerase was observed following transfer of human chromosome 3 into 21NT cells but not after transfer of chromosomes 8, 12, or 20. The vast majority of hybrid clones with repressed telomerase entered permanent growth arrest after 10-18 population doublings. Deletion analysis of nonrepressed segregant monochromosome 3 hybrids indicated two regions on the short arm of chromosome 3 (3p21.3-p22 and 3p12-21.1) where telomerase regulator genes may be located. CONCLUSIONS: Telomerase in human breast cancer cells is efficiently repressed by a gene or genes on normal human chromosome 3p, and this repression is associated with permanent growth arrest of the tumor cells.

Adult↗
PubMed1999

Connexins in the lens: are they to blame in diabetic cataractogenesis?

The pathohistology of the diabetic lens is an enigma. Under normal conditions the lens behaves as a functional syncitium, whereas the diabetic lens exhibits a localized zone of fibre cell swelling and rupture that is confined to the lens outer cortex. Because the lens fibre cells are extensively coupled by gap junction channels, it is believed that the abnormal closure of these channels is responsible for this phenomenon. New evidence concerning regional differences in gap junction gating supports this contention, and it is used to propose a new hypothesis that may explain the cellular changes observed in the diabetic lens.

Animals↗
PubMed1999

Minisatellite mutational processes reduce F(st) estimates.

We have used a new method for binning minisatellite alleles (semi-automated allele aggregation) and report the extent of population diversity detectable by eleven minisatellite loci in 2,689 individuals from 19 human populations distributed widely throughout the world. Whereas population relationships are consistent with those found in other studies, our estimate of genetic differentiation (F(st)) between populations is less than 8%, which is lower than comparative estimates of between 10%-15% obtained by using other sources of polymorphism data. We infer that mutational processes are involved in reducing F(st) estimates from minisatellite data because, first, the lowest F(st) estimates are found at loci showing autocorrelated frequencies among alleles of similar size and, second, F(st) declines with heterozygosity but by more than predicted assuming simple models of mutation. These conclusions are consistent with the view that minisatellites are subject to selective or mutational constraints in addition to those expected under simple step-wise mutation models.

Alleles↗
PubMed1999

Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy.

BACKGROUND: Current diagnostics and therapeutics for cat allergy are based on cat epithelial extracts originating from highly variable source materials. This gives rise to several problems: variability of allergen composition, contamination with house dust mite allergens, and potential transfer of pathogenic agents. OBJECTIVE: The aim of this study was to investigate the feasibility of replacing cat epithelial extracts with purified natural or recombinant allergens. METHODS: Sera (n = 509) were selected on the basis of a positive cat RAST result and tested in a RAST for IgE reactivity to purified Fel d 1, cat albumin (CA), or both. The analysis was performed with both natural and recombinant allergens. In addition, some sera were further analyzed by means of immunoblotting. A serum pool was used for cat RAST inhibition with purified natural and recombinant allergens as inhibitors. RESULTS: Natural and recombinant Fel d 1 caused very similar results: 94.1% and 96.1% positive test results, respectively. In general, the negative sera were low responders to cat extract. The addition of CA (16.7% positive sera) resulted in a decrease in the number of discrepencies between purified allergens and whole extract to 2.8%. Only for 2% of all sera, sensitization to cat was largely explained by IgE reactivity to CA. IgE reactivity to Fel d 1 accounts for 88% of the total IgE response to cat allergens, as was demonstrated by RAST, with Fel d 1 concentrations nearing saturation. Recombinant Fel d 1 performed equally well in the RAST analysis. Recombinant CA was succesfully expressed in the yeast Pichia pastoris, and its immune reactivity closely resembled that of its natural counterpart. CONCLUSION: Natural and recombinant Fel d 1 and CA are good candidates for replacing ill-defined cat dander extracts in diagnostics for cat allergy. Although CA is not essential for the vast majority of cat-sensitized patients, some subjects are selectively sensitized to this serum protein.

Allergens↗