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C Freeman

Publications and source records attributed to C Freeman.

At least 19 recordsLinked to original sources
PubMed2006

The distribution and causes of meiotic recombination in the human genome.

Using the statistical analysis of genetic variation, we have developed a high-resolution genetic map of recombination hotspots and recombination rate variation across the human genome. This map, which has a resolution several orders of magnitude greater than previous studies, identifies over 25,000 recombination hotspots and gives new insights into the distribution and determination of recombination. Wavelet-based analysis demonstrates scale-specific influences of base composition, coding context and DNA repeats on recombination rates, though, in contrast with other species, no association with DNase I hypersensitivity. We have also identified specific DNA motifs that are strongly associated with recombination hotspots and whose activity is influenced by local context. Comparative analysis of recombination rates in humans and chimpanzees demonstrates very high rates of evolution of the fine-scale structure of the recombination landscape. In the light of these observations, we suggest possible resolutions of the hotspot paradox.

Animals↗
PubMed2006

Evaluation of the ventricular assist device programme in the UK.

OBJECTIVES: To summarise the relevant clinical effectiveness and cost-effectiveness literature, to collect data on survival, transplantation rates, health-related quality of life (HRQoL) and resource use for ventricular assist device (VAD) and non-VAD transplant candidates in the UK, and to construct cost-effectiveness and cost-utility models of VADs in a UK context. Also to investigate the factors that drive costs and survival. DESIGN: A comprehensive systematic review was carried out. Data were collected from April 2002 to December 2004, with follow-up to March 2005. Cost-effectiveness and cost-utility models of VAD devices were developed based on UK activity and outcomes collected from April 2002 to March 2005. SETTING: National Specialist Commissioning Advisory Group funded VAD implantation was carried out at the Freeman, Harefield and Papworth transplant centres in the UK. PARTICIPANTS: Seventy patients were implanted with a VAD as a bridge to transplantation between April 2002 and December 2004. Non-VAD-supported transplant candidates (n = 250), listed at the three centres between April 2002 and December 2004, were divided into an inotrope-dependent group (n = 71) and a non-inotrope-dependent group (n = 179). Although patients in the inotrope-dependent group were closest to the VAD group they were less sick. The last group comprised a hypothetical worst case scenario, which assumed that all VAD patients would die in the intensive care unit (ICU) within 1 month without VAD technology. INTERVENTIONS: Patients were included who were implanted with a VAD designed for circulatory support for more than 30 days, with intention to bridge to transplantation. A multistate model of VAD and transplant activity was constructed; this was populated by data from the UK. MAIN OUTCOME MEASURES: Survival from VAD implant or from transplant listing for non-VAD patients to 31 March 2005. Serious adverse events and quality of life measures were used. Cognitive functioning was also assessed. Utility weights were derived from EuroQoL responses to estimate quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were defined as the additional cost of VADs divided by additional QALYs. Time-horizons were 3 years, 10 years and the lifetime of the patients. RESULTS: Of 70 VAD patients, 30 (43%) died pretransplant, 31 (44%) underwent transplantation, and four (6%) recovered and had the VAD removed. Five patients (7%) were still supported for median of 279 days at the end of March 2005. Successful bridge-to-transplantation/recovery rates were consistent with published rates. Survival from VAD implantation was 74% at 30 days and 52% at 12 months. There were 320 non-fatal adverse events in 62 patients during 300 months of VAD support, mostly in the first month after implantation. Commonly observed events were bleeding, infection and respiratory dysfunction. Twenty-nine (41%) patients were discharged from hospital with a VAD. The 1-year survival post-transplantation was 84%. For the inotrope-dependent and non-inotrope-dependent transplant candidates, death rates while listed were 10% and 8% and the median waiting times were 16 and 87 days, respectively. For transplant recipients, 1-year survival was 85% and 84%, respectively. Both VAD and non-VAD patients demonstrated similar significant improvements in their New York Heart Association class after transplantation. All patients had poor EQ-5D pretransplantation; after transplantation the groups had similar EQ-5D of 0.76 irrespective of time after surgery. HRQoL was poor in the first month for VAD patients but better for those who waited longer in all groups. VAD patients reported more problems with sleep and rest and with ambulation in the first month. Symptom scores were similar in all groups pretransplant. After transplantation all groups showed a marked and similar improvement in physical and psychosocial function. Mean VAD implant cost, including device, was pound 63,830, with costs of VAD support for survivors of pound 21,696 in month 1 and pound 11,312 in month 2. Main cost drivers were device itself, staffing, ICU stay, hospital stay and events such as bleeding, stroke and infection. For the base case, extrapolating over the lifetime of the patients the mean cost for a VAD patient was pound 173,841, with mean survival of 5.63 years and mean QALYs of 3.27. Corresponding costs for inotrope-dependent patients were pound 130,905, with mean survival 8.62 years and mean QALYs 4.99. Since inotrope-dependent patients had lower costs and higher QALYs than VAD patients, this group is said to be dominant. Non-inotrope-dependent transplant candidates had similar survival rates to those on inotropes but lower costs, also dominant. Compared with the worst case scenario the mean lifetime ICER for VADs was pound 49,384 per QALY. In a range of sensitivity analyses this ranged from pound 35,121 if the device cost was zero to pound 49,384. Since neither inotrope-dependent transplant candidates nor the worst case scenario were considered fair controls the assumption was investigated that, without VAD technology, there would be a mixture of these situations. For mixtures considered the ICER for VADs ranged from pound 79,212 per QALY to the non-VAD group being both cheaper and more effective. CONCLUSIONS: There are insufficient data from either published studies or the current study to construct a fair comparison group for VADs. Overall survival of 52% is an excellent clinical achievement for those young patients with rapidly failing hearts. However, if the worst case scenario were plausible, and one could reliably extrapolate results to the lifetime of the patients, VADs would not be cost-effective at traditional thresholds. Further randomised controlled trials are required, using current second generation devices or subsequent devices and conducted in the UK.

Cost-Benefit Analysis↗
PubMed2005

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers.

RATIONALE: Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be "switched off" by the alpha2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects. OBJECTIVE: The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers. METHODS: Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary "fatigue waves" (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons. RESULTS: Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions. CONCLUSIONS: Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.

Adrenergic alpha-Agonists↗
PubMed2005

Exogenous enzyme supplements to promote treatment efficiency in constructed wetlands.

Extracellular enzymes play a central role in the breakdown of organic pollutants. In wetlands constructed to treat wastewaters, supplementing the naturally occurring soil enzymes may result in faster pollutant removal, or breakdown of novel pollutants, but only if the added enzymes could retain their catalytic activity. In this study, the persistence of exogenous enzyme supplements was investigated. Adding cellobiohydrolase and beta-glucosidase to sterilised soil increased enzyme activity (range 375-4210%); although the increased activity began to decline after just 10-15 days. Thus, without an active microbial population, enhanced enzyme activity is unlikely to be long lived. However, with the naturally occurring soil microbes present to maintain the improved biodegradative capacity, cellobiohydrolase and beta-glucosidase additions created significant increases (range 173-530%) in activity and these persisted for more than 6 weeks. These findings therefore support the proposal that enzyme additions can enhance enzymic biodegradation processes, and suggest that this may be achieved primarily through a 'pump-priming' mechanism.

Biodegradation, Environmental↗
PubMed2004

Export of dissolved organic carbon from peatlands under elevated carbon dioxide levels.

Peatlands represent a vast store of global carbon. Observations of rapidly rising dissolved organic carbon concentrations in rivers draining peatlands have created concerns that those stores are beginning to destabilize. Three main factors have been put forward as potential causal mechanisms, but it appears that two alternatives--warming and increased river discharge--cannot offer satisfactory explanations. Here we show that the third proposed mechanism, namely shifting trends in the proportion of annual rainfall arriving in summer, is similarly unable to account for the trend. Instead we infer that a previously unrecognized mechanism--carbon dioxide mediated stimulation of primary productivity--is responsible. Under elevated carbon dioxide levels, the proportion of dissolved organic carbon derived from recently assimilated carbon dioxide was ten times higher than that of the control cases. Concentrations of dissolved organic carbon appear far more sensitive to environmental drivers that affect net primary productivity than those affecting decomposition alone.

Atmosphere↗
PubMed2003

Randomized controlled trial of brief cognitive behaviour therapy versus treatment as usual in recurrent deliberate self-harm: the POPMACT study.

BACKGROUND: We carried out a large randomized trial of a brief form of cognitive therapy, manual-assisted cognitive behaviour therapy (MACT) versus treatment as usual (TAU) for deliberate self-harm. METHOD: Patients presenting with recurrent deliberate self-harm in five centres were randomized to either MACT or (TAU) and followed up over 1 year. MACT patients received a booklet based on cognitive behaviour therapy (CBT) principles and were offered up to five plus two booster sessions of CBT from a therapist in the first 3 months of the study. Ratings of parasuicide risk, anxiety, depression, social functioning and global function, positive and negative thinking, and quality of life were measured at baseline and after 6 and 12 months. RESULTS: Four hundred and eighty patients were randomized. Sixty per cent of the MACT group had both the booklet and CBT sessions. There were seven suicides, five in the TAU group. The main outcome measure, the proportion of those repeating deliberate self-harm in the 12 months of the study, showed no significant difference between those treated with MACT (39%) and treatment as usual (46%) (OR 0.78, 95% CI 0.53 to 1.14, P=0.20). CONCLUSION: Brief cognitive behaviour therapy is of limited efficacy in reducing self-harm repetition, but the findings taken in conjunctin with the economic evaluation (Byford et al. 2003) indicate superiority of MACT over TAU in terms of cost and effectiveness combined.

Adult↗
PubMed2002

Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma.

PURPOSE: Morbidity associated with wound complications may translate into disability and quality-of-life disadvantages for patients treated with radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional outcome and health status of extremity STS patients randomized in a phase III trial comparing preoperative versus postoperative RT is described. PATIENTS AND METHODS: One hundred ninety patients with extremity STS were randomized after stratification by tumor size dichotomized at 10 cm. Function and quality of life were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery. RESULTS: One hundred eighty-five patients had function data. Patients treated with postoperative RT had better function with higher MSTS (25.8 v 21.3, P <.01), TESS (69.8 v 60.6, P =.01), and SF-36 bodily pain (67.7 v 58.5, P =.03) scores at 6 weeks after surgery. There were no differences at later time points. Scores on the physical function, role-physical, and general health subscales of the SF-36 were significantly lower than Canadian normative data at all time points. After treatment arm was controlled for, MSTS change scores were predicted by a lower-extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS change scores were predicted by lower-extremity tumor and prior incomplete excision. When wound complication was included in the model, patients with complications had lower MSTS and TESS scores in the first 2 years after treatment. CONCLUSION: The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.

Adult↗
PubMed2002

Implant treatment.

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Alveolar Bone Loss↗
PubMed2002

Genetic substructure in South African Bantu-speakers: evidence from autosomal DNA and Y-chromosome studies.

The extent of genetic differentiation between seven South African Bantu-speaking groups (Zulu, Xhosa, Tsonga/Shangaan, Southern Sotho, Pedi, Tswana, and Venda) was assessed from coancestry coefficients (F(ST)) estimated from autosomal serogenetic, DNA, and Y-chromosome DNA haplotypes. The overall F(ST) obtained from the autosomal data was 0.002, and that from the Y chromosome data was 0.014. The genetic relationships between groups examined were inferred from their cluster affinities in phylogenetic trees constructed from the genetic distances between them. Both autosomal and Y-chromosome DNA studies reveal that 6 of the 7 South African Bantu-speaking groups cluster according to their linguistic groupings, the exception being the Tsonga, who do not cluster with other Nguni language speakers, but rather with the Venda who live close to them. This suggests that the invading Shangaan-speakers, whose Nguni language was adopted by the Tsonga, did not have a major effect on the Tsonga gene pool, and that gene flow from the Venda into the Tsonga may have been considerable. Genetic distances were found to correlate with geographic distances between the regions where each group's apparent population density is the highest. Linguistic distances were also found to correlate with genetic distances, but linguistic and geographic distances showed no correlation. Together, these results suggest that linguistic and some genetic differentiation took place before the groups (or their forerunners) reached their present-day locations, and that further genetic change occurred after their arrival.

Adult↗
PubMed2002

Quality improvement for patients with hip fracture: experience from a multi-site audit.

PROBLEM: The first East Anglian audit of hip fracture was conducted in eight hospitals during 1992. There were significant differences between hospitals in 90-day mortality, development of pressure sores, median lengths of hospital stay, and in most other process measures. Only about half the survivors recovered their pre-fracture physical function. A marked decrease in physical function (for 31%) was associated with postoperative complications. DESIGN: A re-audit was conducted in 1997 as part of a process of continuing quality improvement. This was an interview and record based prospective audit of process and outcome of care with 3 month follow up. Seven hospitals with trauma orthopaedic departments took part in both audits. Results from the 1992 audit and indicator standards for re-audit were circulated to all orthopaedic consultants, care of the elderly consultants, and lead audit facilitators at each hospital. KEY MEASURES FOR IMPROVEMENT: Processes likely to reduce postoperative complications and improve patient outcomes at 90 days. STRATEGY FOR CHANGE: As this was a multi-site audit, the project group had no direct power to bring about changes within individual NHS hospital trusts. RESULTS: Significant increases were seen in pharmaceutical thromboembolic prophylaxis (from 45% to 81%) and early mobilisation (from 56% to 70%) between 1992 and 1997. There were reduced levels of pneumonia, wound infection, pressure sores, and fatal pulmonary embolism, but no change was recorded in 3 month functional outcomes or mortality. LESSONS LEARNT: While some hospitals had made improvements in care by 1997, others were failing to maintain their level of good practice. This highlights the need for continuous quality improvement by repeating the audit cycle in order to reach and then improve standards. Rehabilitation and long term support to improve functional outcomes are key areas for future audit and research.

Aged↗
PubMed2001

Effects of elevated CO2 on fen peat biogeochemistry.

Effects of elevated atmospheric CO2 concentration on northern peatland biogeochemistry was studied in a short-term experiment. Eight intact soil cores (11-cm diameter x 40-cm depth) with Juncus and Festuca spp. were collected from a calcareous fen in north Wales. Half of the cores were incubated under 350 ppm CO2 concentration, whilst the other four cores were maintained at 700 ppm CO2. After a 4-month incubation, significantly higher biomass (root + shoot + algal mat) was determined under elevated CO2 conditions. Higher emissions of N2O and CO2, and higher concentration of pore-water DOC (dissolved organic carbon) were also observed under elevated CO2. However, no significant differences were found in CH4 emission or soil enzyme activities (beta-glucosidase, phosphatase, and N-acetylglucosaminidase) in the bulk soil. Overall, the results suggest that elevated CO2 would increase the primary productivity of the fen vegetation, and stimulate N2O and CO2 emissions as a consequence of an enhanced DOC supply from the vegetation to the soil microbes.

Carbon↗
PubMed2001

Mild tagging procedures for the structural analysis of glycans.

The reductive oxyamination of model glycan structures has been investigated as a mild, alternative tagging procedure to reductive amination using O-(4-nitrobenzyl)-hydroxylamine. Oxime formation was quantitative, but the reduction step did not always go to completion. Novel O- and N-substituted 7-hydroxycoumaryl- and 3-methoxybenzylhydroxylamines were synthesized and shown to couple quantitatively with model saccharides by oxime formation and reductive hydroxyamination, respectively, under very mild, aqueous conditions. The fluorescent derivatives produced show good chromatographic and mass spectrometric properties. Both procedures are suitable for the labeling of carbohydrates and oligosaccharide fragments from glycosaminoglycan structures, such as heparin and heparan sulfate.

Chromatography, High Pressure Liquid↗
PubMed2001

Outer membrane protein-specific monoclonal antibodies protect SCID mice from fatal infection by the obligate intracellular bacterial pathogen Ehrlichia chaffeensis.

Previous studies of Ehrlichia chaffeensis infection in the mouse have demonstrated that passive transfer of polyclonal Abs from resistant immunocompetent mice to susceptible SCID mice ameliorated infection and disease, even when Abs were administered during established infection. To identify particular Abs that could mediate bacterial clearance in vivo, E. chaffeensis-specific mAbs were generated and administered to infected SCID mice. Bacterial infection in the livers was significantly lowered after administration of either of two Abs of different isotypes (IgG2a and IgG3). Moreover, repeated administration of one Ab (Ec56.5; IgG2a) rescued mice from an otherwise lethal infection for at least 5 wk. Both protective Abs recognized the E. chaffeensis major outer membrane protein (OMP)-1g. Further studies revealed that both Abs recognized closely related epitopes within the amino terminus of the first hypervariable region of OMP-1g. Analyses of human sera showed that E. chaffeensis-infected patients also generated serological responses to OMP-1g hypervariable region 1, indicating that humans and mice recognize identical or closely related epitopes. These studies demonstrate that OMP-specific mAbs can mediate bacterial elimination in SCID mice, and indicate that Abs, in the absence of cell-mediated immunity, can play a significant role in host defense during infection by this obligate intracellular bacterium.

Amino Acid Sequence↗