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A Lees

Publications and source records attributed to A Lees.

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

No pathogenic mutations in the synphilin-1 gene in Parkinson's disease.

alpha-Synuclein is mutated in rare autosomal dominant forms of Parkinson's disease and is a major component of Lewy bodies and neurites. Synphilin-1, a novel protein interacts in vivo and co-localises with alpha-synuclein in Lewy bodies. We analysed the synphilin-1 gene in familial Parkinson's disease by single-strand conformation polymorphism (SSCP) and automated sequencing but found no coding mutations. However, we identified two novel intronic polymorphisms; an A/T polymorphism in intron 2, resulting in the introduction of an Alu1 site and a second G/T polymorphism in intron 4. We analysed the intron 2 polymorphism for allelic association as it was conducive to rapid screening but observed no changes in frequency between Parkinson's disease cases and controls.

Aged↗
PubMed2001

Exploiting molecular mimicry to broaden the immune response to carbohydrate antigens for vaccine development.

Peptide mimetics of carbohydrates represent an alternative approach to induce anti-carbohydrate responses. Depending on their formulation, peptide mimetics can mediate T-independent or T-dependent responses. Multivalent peptide mimeotopes can induce high IgM/IgG ratios, as non-conjugated carbohydrates do. Here we observe that immunization with multivalent peptide mimeotope conjugated to BSA enhances carbohydrate reactive antibodies in Balb/c mice and xid mice, with IgG1 greater than IgG2a, in xid mice. These results suggest that mimeotope-conjugate formulations might augment carbohydrate-specific immune responses in immuno-compromised hosts.

Amino Acid Sequence↗
PubMed2001

A cryptococcal capsular polysaccharide mimotope prolongs the survival of mice with Cryptococcus neoformans infection.

Defined Abs to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM) have been shown to be protective against experimental cryptococcosis. This suggests that if a vaccine could induce similar Abs it might protect against infection. However, the potential use of a GXM-based vaccine has been limited by evidence that GXM is a poor immunogen that can induce nonprotective and deleterious, as well as protective, Abs, and that the nature of GXM oligosaccharide epitopes that can elicit a protective response is unknown. In this study, we investigated whether a peptide surrogate for a GXM epitope could induce an Ab response to GXM in mice. The immunogenicity of peptide-protein conjugates produced by linking a peptide mimetic of GXM, P13, to either BSA, P13-BSA, or tetanus toxoid, P13-tetanus toxoid, was examined in BALB/c and CBA/n mice that received four s.c. injections of the conjugates at 14- to 30-day intervals. All mice immunized with conjugate produced IgM and IgG to P13 and GXM. Challenge of conjugate-immunized mice with C. neoformans revealed longer survival and lower serum GXM levels than control mice. These results indicate that 1) P13 is a GXM mimotope and 2) that it induced a protective response against C. neoformans in mice. P13 is the first reported mimotope of a C. neoformans Ag. Therefore, the P13 conjugates are vaccine candidates for C. neoformans and their efficacy in this study suggests that peptide mimotopes selected by protective Abs deserve further consideration as vaccine candidates for encapsulated pathogens.

Animals↗
PubMed2001

Rapid and complete adsorption of unconjugated protein from protein-polysaccharide conjugate vaccines.

We have developed a rapid and inexpensive approach to remove unconjugated protein from protein-polysaccharide conjugate vaccines, without using gel filtration or ultrafiltration. We employ porous particles that adsorb the protein, whether bound or free, but with a pore size that allows only the unconjugated protein to enter the particle. Using limited amounts of media there is preferential binding of the unconjugated protein over the high molecular weight protein-polysaccharide conjugate. Adsorption of the unconjugated protein is rapid, with greater than 90% recovery of the conjugate. The approach is applicable to both neutral and charged polysaccharides and is not dependent on the chemistry used to make the conjugate vaccine. We have used this method to prepare tetanus toxoid-polysaccharide conjugates and found their immunogenicity in mice comparable to conjugates prepared using gel filtration. The method described can be used to reduce the cost and increase the yields of protein-polysaccharide conjugate vaccines.

Adsorption↗
PubMed2001

Jumpers.

Explore the source record for details and available documents.

Genetic Predisposition to Disease↗
PubMed2001

Randomized trial of tolcapone versus pergolide as add-on to levodopa therapy in Parkinson's disease patients with motor fluctuations.

In this 12-week, randomized, open-label, blinded-rater, parallel-group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included "off" time (reduced by 2-3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinson's disease questionnaire (PDQ)-39 scores, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ-39 score at week 12 were -8.7 and -14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigator's global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone-treated patients and in 78% of pergolide-treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3-month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse-event profile than pergolide.

Antiparkinson Agents↗
PubMed2001

Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation.

The motor and neuropsychological abnormalities in eight Greek patients with Parkinson's disease (PD) carrying the alpha-synuclein gene mutation (G209A) were studied. These patients (five men, three women) belonged to six different families. Their symptoms started between 32-50 years of age (mean +/- SD, 39.7 +/- 7.6 years) and they had a mean disease duration of 5.4 +/- 2.1 years (range, 2-9 years) at the time of examination. Rigidity and bradykinesia predominated both at disease onset as well as in the later stages and rest tremor was relatively uncommon. Neuropsychological assessment showed that one patient was mildly demented while another had impairment in memory, visuoconstructive abilities, and executive function. Depression was present in only one patient. Our findings indicate that genetic forms of parkinsonism share common motor and cognitive characteristics with sporadic PD but raise the possibility that greater cognitive impairment and the relative rarity of tremor may be distinctive features worthy of further investigation.

Adult↗
PubMed2001

Developing a prioritisation framework: experiences from a Scottish Health Authority.

OBJECTIVES: To describe the development of the Prioritisation Scoring Index (PSI) and its use in a prioritisation framework, providing examples where it has been used to prioritise between bids from different specialities and to assist in decision-making regarding funding of service developments. To outline lessons learned for other health authorities when developing their own prioritisation methodologies. BACKGROUND: The PSI was designed for prioritising: investments and dis-investments; non-recurring and recurring monies as well as differing specialities, care groups and types of intervention. METHODS: The PSI consists of a 'basket' of utility criteria and takes account of the numbers of people that would receive the proposed intervention and the marginal cost for each additional person receiving the intervention. A multidisciplinary panel scored and ranked the bids. Two rankings were produced for each intervention according to (1) the average panel score for the utility criteria and (2) the cost per additional person receiving the intervention. An average of these two rankings produced the overall PSI rankings. RESULTS: Almost 200 bids, with a total value of pound 50 million, were ranked, using the PSI, to prioritise developments worth approximately pound 17.5 million that could be funded in a phased implementation through the Health Improvement Programme. CONCLUSIONS: Use of the PSI has allowed explicit prioritisation of development bids in substantial exercises for both non-recurring and recurring funding. We describe steps to be considered when other health authorities are developing their own prioritisation frameworks.

Cost-Benefit Analysis↗
PubMed2001

Drooling in Parkinson's disease: a novel speech and language therapy intervention.

Drooling and difficulty swallowing saliva are commonly reported in people with Parkinson's disease (PD). Drooling in PD is the result of swallowing difficulties rather than excessive saliva production. Currently, there is little research into the effectiveness of treatments to reduce drooling. The aims of the study were to develop objective measures of saliva volume and drooling for PD and to assess the efficacy of two therapeutic strategies to control drooling, i.e. specific speech and language therapy (SLT) including a portable metronome brooch to cue swallowing and injections of botulinum toxin into both parotid glands to reduce the amount of saliva produced. This paper will describe the assessments used, including the measurement of saliva, swallowing and drooling. The main focus will be the strategies used in the SLT intervention. The preliminary results are presented.

Aged↗
PubMed2001

Parkinson's disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype.

A recent study showed significant association of sporadic Parkinson's disease with a polymorphism within the alpha-synuclein gene and closely linked DNA markers on chromosome 4q and the APOE epsilon4 allele. A combined alpha-synuclein/APOE-epsilon4 genotype increased the relative risk of developing Parkinson's disease 12-fold. We failed to confirm this association in a much larger sample of histopathologically proven cases of Parkinson's disease and controls.

Alleles↗
PubMed2000

B7 requirements for primary and secondary protein- and polysaccharide-specific Ig isotype responses to Streptococcus pneumoniae.

The requirements for B7 costimulation during an in vivo humoral response to an intact extracellular bacteria have not been reported. In this study we immunized mice with Streptococcus pneumoniae (R36A) to determine the B7 requirements for induction of Ig, specific for two determinants on R36A, the phosphorylcholine (PC) determinant of C-polysaccharide and pneumococcal surface protein A (PspA). We show that the primary anti-PspA response, the development of PspA-specific memory, and the induction of the secondary anti-PspA response in primed mice were completely dependent upon B7 costimulation. Of note, costimulation was required only briefly after the secondary immunization compared with after the primary immunization for optimal induction of Ig. Blockade of B7 costimulation at the time of secondary immunization also completely abrogated the established state of memory, but did not induce tolerance. In contrast to the anti-PspA response, the primary anti-PC response involved only a very short period of B7 costimulation. Whereas B7-2 alone was required for induction of the primary anti-PspA and anti-PC responses, a redundant role for B7-1 and B7-2 was noted for the PspA-specific secondary response. CTLA4Ig blocked both the anti-PC and anti-PspA responses equally well over a wide range of bacterial doses. These studies demonstrate a critical, but variable, role for B7-dependent costimulation during an Ig response to an extracellular bacteria.

Abatacept↗
PubMed2000

Activation of soluble polysaccharides with 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) for use in protein-polysaccharide conjugate vaccines and immunological reagents. II. Selective crosslinking of proteins to CDAP-activated polysaccharides.

Covalently linking protein to polysaccharides converts the anti-polysaccharide immune response from a T-cell independent response to one which is T-cell dependent. The organic cyanylating reagent 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) (Vaccine 14:190, 1996) has been used to activate polysaccharides, which can then be reacted with spacer reagents or directly with protein. We wished to explore ways in which proteins could be linked to CDAP-activated polysaccharides to conjugate in a more controlled and selective fashion. To this end, we examined the reaction of nucleophilic amino acids with CDAP-activated polysaccharides under basic and acidic conditions. We found that lysine, cysteine and histidine but not methionine, serine or tyrosine conjugated to CDAP-activated dextran. We also examined the reaction of various spacer reagents with CDAP-activated dextran as a function of pH. The addition of hexanediamine was highly pH dependent and maximal at pH 9.3. In contrast, the addition of adipic dihydrazide, which has a pKa of ca 2.5 was essentially independent of pH. By performing the conjugation reaction at pH 5, we were able to selectively couple hydrazides even in the presence of high concentrations of amines. Proteins derivatized with limited numbers of hydrazides could be conjugated to CDAP-activated polysaccharides at pH5, where the native protein was not reactive. Proteins could be derivatized with hydrazides on carboxyls using adipic dihydrazide and a water soluble carbodiimide or on amines using a mild two-step reaction. Tetanus toxoid-pneumococcal type 14 conjugates produced by coupling hydrazide-derivatized tetanus toxoid under acidic conditions induced anti-polysaccharide antibodies at titers comparable to that stimulated by conjugates produced using a basic coupling pH. Our data suggest that crosslinking was occurring only with the limited number of hydrazides on the protein and that we achieved limited and selective crosslinking between the protein and CDAP-activated polysaccharide. This work also demonstrates that CDAP-mediated conjugation to polysaccharides can be applied even to very pH sensitive proteins and polysaccharides.

Amines↗
PubMed2000

Enhanced and sustained activation of human B cells by anti-immunoglobulin conjugated to the EBV glycoprotein gp350.

We coupled a monoclonal anti-human IgD to the gp350 gylcoprotein of Epstein-Barr virus, which has been shown to bind to the complement receptor 2 (CR2), and compared its B cell stimulatory ability to that of anti-Ig and to a multivalent anti-Ig-dextran conjugate. The anti-Ig-gp350 conjugate stimulated higher levels of human B cell proliferation in vitro than did anti-Ig or anti-Ig conjugated to control viral protein, comparable to the proliferation stimulated by the multivalent anti-Ig-dextran. This enhanced proliferation was dependent on binding of the conjugate to CR2, inasmuch as an anti-CD2 antibody blocked the enhanced proliferative response. This enhanced proliferative response was associated with prolonged elevations of intracellular ionized calcium, which was comparable to the response stimulated by anti-Ig-dextran. These findings suggest the use of gp350 as a carrier molecule for weakly immunogenic peptides or antigens which, when bound to gp350, would enhance B cell clonal expansion and activation of antigen-specific B cells.

Antibodies, Anti-Idiotypic↗
PubMed2000

B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms.

Antigens that are expressed on the surface of pathogens in an organized, highly repetitive form can activate specific B cells by cross-linking of antigen receptors in a multivalent fashion. B cells respond to these multivalent antigens in the absence of MHC class II-restricted T-cell help by a mechanism that depends on the expression of a functional Bruton's tyrosine kinase (Btk). Accordingly, this class of immunogens has been designated T-cell-independent type 2 (TI-2) antigens. The unique properties of the B-cell response to TI-2 antigens are critically dependent on the formation of a small number of antigen receptor clusters, each of which contains approximately 10 to 20 antigen-bound membrane Ig (mIg) molecules. These clusters induce local membrane association of multiple activated Btk molecules, which results in long-term mobilization of intracellular ionized calcium. Such persistent calcium fluxes efficiently recruit transcription factors and thereby induce T-cell-independent B-cell activation and proliferation. While this first signal of multivalent mIg cross-linking can induce B-cell proliferation, we propose that a second signal is required for a TI-2 Ig secretory response. We have found that engagement of members of the Toll-like receptor (TLR) family could provide second signals that selectively induce Ig secretion in B cells that were activated by multivalent, but not by bivalent, antigen receptor engagement. This finding demonstrates a general mechanism by which TLRs recognize molecular motifs on the surface of pathogens and provide the TI-2-activated B cell with a second signal. In addition, TLR-dependent recognition of these non-self motifs by cells of the innate immune system can induce these cells to provide alternative and/or additional second signals in the TI-2 response. The complement system provides another link between the B cell and the innate immune system, and facilitates the mIg signal transduction by recruitment of CD21 in the immune response. Thus, the TI-2 response provides the host with a combination of "the best of both worlds": the recruitment of the fine specificity of the adaptive immune response and the utilization of both the speed of the innate immune system and the wealth of cytokines produced by its member cells upon stimulation by pathogenic organisms or their products. By combining these two pathways, the TI-2 response enables the host to rapidly produce antigen-specific Ig effector molecules that can be secreted at a sufficient rate to keep up with the rapid multiplication of invading infectious microorganisms, and will also prevent the intracellular spreading of a significant part of this population.

Animals↗
PubMed2000

Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality.

We retrospectively evaluated 75 allogeneic stem cell transplant recipients to ascertain the incidence, risk factors and outcome of infection with Clostridium difficile. Ten patients (13%) had Clostridium difficile infection at a median of 38 days (range day -6 to day +72) following the transplant. There was no difference in the duration or severity of diarrhoea in patients with Clostridium difficile infection compared to the uninfected patients and no relationship to the prior antibiotic or chemotherapy usage, age, gender, underlying disease, donor type, CMV serostatus, total body irradiation or time to engraftment. The incidence of viral infections was increased in patients infected with Clostridium difficile (7/10 vs 15/65, P = 0.005, odds ratio 7.7), but the strongest association was with GVHD >grade 2 (5/10 vs 6/65 uninfected patients, P = 0.004, odds ratio 9.8). Patients infected with Clostridium difficile also suffered a higher non-relapse mortality with 7/10 patients succumbing to either GVHD or infections, compared to 19/65 patients in the uninfected group (P = 0.02, odds ratio 5.6). Thus Clostridium difficile infections in our study had a strong association with GVHD and increased non-relapse mortality. It is possible that Clostridium difficile toxin might predispose to increased severity of GVHD leading to an adverse outcome.

Adolescent↗
PubMed2000

How the free limbs are used by elite high jumpers in generating vertical velocity.

The aim of this study was to quantify how elite high jumpers used their free limbs in a competitive high jump and to estimate the contribution that these made to vertical take-off velocity. This was achieved by analysing the competitive performances of six elite male high jumpers using 3D motion analysis and assessing limb function using the relative momentum method. The mean peak relative momentum of the arm nearest to the bar at take-off was 9.4 kg m s(-1), while that of the arm furthest away from the bar was 11.3 kg m s(-1) and these did not differ significantly. The free (lead) leg reached a mean peak relative momentum of 20.9 kg m s(-1). At touch-down the free leg had a large positive relative momentum that was offset by the negative relative momentum of the arms, although their combined value still remained positive. The mean combined free limbs' relative momentum at touch-down was 13.8 kg m s(-1) and reached a peak of 37.6 kg m s(-1). The difference between these two values amounted to 7.1 % of whole-body momentum, which was judged to be the amount by which the free limbs contributed to performance. The arms had a greater influence on performance than had the lead leg. This was because the lead leg increased its relative momentum little during the contact period while the arms had an initial negative value that increased markedly after touch-down. The compressive force exerted by the motion of the free limbs, estimated by the change in the combined free limbs' relative momentum, reached a mean peak of 366 N and was greatest at 37% of the contact period. It was concluded that to maximize the contribution the free limbs can make to performance, given the restraints imposed on technique by other performance requirements, the arms should have a vigorous downward motion at touch-down to make the most use of the high (but little changing) relative momentum of the lead leg.

Ankle Joint↗
PubMed2000

Touch-down and take-off characteristics of the long jump performance of world level above- and below-knee amputee athletes.

The aims of this study were to establish the take-off characteristics of long jump performance of disabled amputee athletes, and to establish to what extent amputee athletes conform to a model of performance defined for elite able-bodied athletes. The jumps of 8 male below-knee (trans-tibial) and 8 male above-knee (trans-femoral) amputee athletes who competed in the finals of the long jump at the 1998 World Disabled Championships were recorded in the sagittal plane on video (50 Hz). Approach speed was measured using a laser Doppler system. The best jump for each athlete was digitized, and kinematic data from the key instants of touch-down (TD), maximum knee flexion (MKF) and take-off (TO) were obtained. Amputees demonstrated a lower approach speed and jumped less far than able-bodied athletes although below-knee amputees performed better than above-knee amputees. For each amputee group there was a significant (p < 0.05) linear relationship between approach speed and distance jumped. With the exception of their slower horizontal speed and greater negative vertical speed at touch-down, below-knee amputees demonstrated characteristics of technique that were similar to elite able-bodied long jumpers. Above-knee amputees at touchdown had a more upright trunk, smaller hip and knee angles and consequently a smaller leg angle. This was attributed to the difficulty of taking off on the last stride on the prosthetic limb. Consequently, above-knee amputees were less able to gain vertical velocity during the compression (TD-MKF) phase, but were able to compensate for this by using a greater hip range of motion during the extension (MKF-TO) phase. It was concluded that below-knee amputees displayed the same basic jumping technique as elite able-bodied long jumpers, but above-knee amputees did not. These findings have implications for the training and technical preparation of amputee long jumpers.

Amputees↗