Purpose of CR-CO study clear.
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Centric Relation↗
Biomedical subjects
R E Williams
Publications and source records attributed to R E Williams.
The National Prostatectomy Audit: the clinical management of patients during hospital admission.
OBJECTIVE: To determine everyday practice in the hospital management of men undergoing prostatectomy and the extent of its variation. PATIENTS AND METHODS: A total of 5361 patients, who represented 89% of all those undergoing prostatic procedures in four health regions (Mersey, Wessex, Northern and South West Thames) and one test site (within Trent) were recruited by 103 (97%) surgeons. Clinical information was collected on a pre-coded data collection form which was completed during the hospital stay by the principal operator. Patient identification occurred at the time of surgery. RESULTS: Important findings included: (i) both older men and those of higher social class were more likely to undergo prostatectomy with fewer symptoms; (ii) men who waited longer for surgery had worse symptoms by the time of their operation; (iii) there were unexplained differences in routine pre- and post-operative investigation and treatment. Half the men had their flow rate or residual urine measured as part of their pre-operative assessment. About half the men received prophylactic antibiotics; (iv) when large groups were analysed, a consistent proportion of men throughout the study (12%) were undergoing the operation for a second time. The clinical course of men having a repeat operation differed in many ways from those having a first time procedure; (v) the larger proportion of men (62%) had surgery for strong indications as opposed to symptoms alone; (vi) although most operations were performed by consultants, emergency admissions, though symptomatically more severe and sicker, were more likely to be operated on by trainee surgeons; (vii) significant variation in mean pre-operative symptom severity and bother scores were seen between surgeons. CONCLUSION: The clinical management of prostatectomy has been defined in a large and representative UK sample. In some circumstances consistent variations have been identified. It is not yet clear whether these variations influence outcome. These data can be used by surgeons wishing to compare their own patient management with that described here.
Age Factors↗
Human lipopolysaccharide-binding protein potentiates bactericidal activity of human bactericidal/permeability-increasing protein.
Human bactericidal/permeability-increasing protein (BPI) from neutrophils and a recombinant amino-terminal fragment, rBPI23, bind to and are cytotoxic for gram-negative bacteria both in vitro and ex vivo in plasma or whole blood. To function in vivo as an extracellular bactericidal agent, rBPI23 must act in the presence of the lipopolysaccharide-binding protein (LBP), which also binds to but has no reported cytotoxicity for gram-negative bacteria. LBP, which is present at 5 to 10 micrograms/ml in healthy humans and at much higher levels in septic patients, mediates proinflammatory host responses to gram-negative infection. On the basis of these previous observations, we have examined the effect of recombinant LBP (rLBP) on the bactericidal activity of rBPI23 against Escherichia coli J5 in vitro. Physiological concentrations of rLBP (5 to 20 micrograms/ml) had little or no bactericidal activity but reduced by up to approximately 10,000-fold the concentration of BPI required for bactericidal or related activities in assays which measure (i) cell viability as CFUs on solid media or growth in broth culture and (ii) protein synthesis following treatment with BPI. LBP also potentiated BPI-mediated permeabilization of the E. coli outer membrane to actinomycin D by about 100-fold but had no permeabilizing activity of its own. Under optimal conditions for potentiation, fewer than 100 BPI molecules were required to kill a single E. coli J5 bacterium.
Acute-Phase Proteins↗
The feasibility and cost of a large multicentre audit of process and outcome of prostatectomy.
Objective--To determine the feasibility of performing multicentre process and outcome audits of common interventions taking prostatic procedures as an example. Design--Prospective, cohort study. Setting--All National Health Service and independent hospitals in Northern, Wessex, Mersey, and South West Thames health regions. Patients--5361 men undergoing prostatectomy identified by 103 of the 107 urologists and general surgeons performing prostatectomy in the study regions. Main measures-- Rates of participation by surgeons and patients; completeness of clinical data provided by surgeons; patient response rate and completeness of patient derived data; and cost. Results--Most surgeons (103,96%) agreed to participate. Overall, the proportion of eligible patients invited to take part was high (89%), although this was only measured in South West Thames, where dedicated data collectors were employed. Few men (80, 1.5%) declined to participate. Of those surviving for three months after surgery, 82.4% (4226) completed and returned the postal questionnaire. The response rate was higher in South West Thames (86.7%) than in the other regions (80.6%-80.8%). The audit was well received: 91% of patients found the questionnaire easy to complete and only 2.3% of them disapproved. Completeness of data was high with both the hospital and patient questionnaires. Missing data occurred in less than 5% of responses to most questions. The attributable cost was 34.50 pounds per patient identified or 44 pounds for patients in whom either the treatment outcome or vital status was known three months after their prostatectomy. Conclusions--This multicentre audit of process and outcome of prostatectomy proved feasible in terms of surgeon participation, patient identification, and the quantity and quality of data collection. Whether the cost was warranted will depend on how surgeons use the audit data to modify their practice.
Aged↗
Recovery from dynamic exercise.
Minimal information is available on the basic interactions within the metabolic and cardiovascular systems during recovery from exercise. Nine men participated in three experiments: one control and two cost-equivalent (52 liters O2) exercise tests of 30 (EX30) and 45 (EX45) min. Exercise intensities were adjusted accordingly. During recovery, all parameters reestablished baseline levels within 10 min, except for heart rate (30 min). Correlations for each parameter for EX30 and EX45 were obtained by evaluating each subject's exercise cost and recovery "payback." A split, two-factor analysis of variance was run separately on the "fast" (minutes 1-7) and "slow" (minutes 10-60) phases of recovery to determine if the time course of recovery was related to exercise intensity. It was concluded that for a work cost of approximately 300 kcal, 1) the slow phase of recovery was unaffected by the exercise intensity, 2) the fast phase of cardiovascular recovery was unaffected by exercise intensity while minute ventilation and O2 and CO2 uptake were affected, and 3) cardiac output and the ventilatory equivalents for O2 and CO2 correlated well between work cost and recovery payback.
Adult↗
Comments on Dr. Rinchuse's Counterpoint discussion.
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Centric Relation↗
An amino-terminal fragment of human lipopolysaccharide-binding protein retains lipid A binding but not CD14-stimulatory activity.
LPS-binding protein (LBP) mediates the pro-inflammatory effects of bacterial LPS by enhancing LPS-induced cytokine production by monocytic cells. LBP binds specifically to LPS to generate a complex that interacts with the CD14 receptor on the surface of responsive cells. To identify the biologically active regions of the protein responsible for mediating these activities, we cloned and expressed human rLBP (456 amino acids) as well as a truncated form encoding amino acids 1-197 (rLBP25). Both forms of LBP bound to LPS with the same affinity, and similarly inhibited LPS activity in the Limulus amebocyte lysate assay. These results demonstrate that the LPS-binding domain of LBP resides entirely within the N-terminal 197 amino acids of the protein. rLBP and rLBP25 were compared for their ability to mediate CD14-dependent LPS effects on cells. rLBP was effective in mediating uptake of LPS and stimulation of TNF production by human monocytic THP-1 cells, whereas rLBP25 had no significant activity in these assays. Similarly, rLBP was able to mediate LPS-induced TNF production by human PBMC whereas rLBP25 was essentially inactive. These results suggest that the structural features of LBP required for mediating LPS effects via CD14 are probably located in the C-terminal region of the protein. Thus, the LPS-binding activity of LBP can be separated from the CD14-stimulatory activity, suggesting these activities are mediated by structural elements residing in different regions of the protein.
Acute-Phase Proteins↗
Interleukin-6 antisense deoxyoligonucleotides inhibit bone resorption by giant cells from human giant cell tumors of bone.
The effects of antisense constructs to IL-6 on the bone-resorbing capacity of purified giant cells from giant cell tumors of bone were examined to further define the role of IL-6 in human osteoclastic bone resorption. In addition, we wanted to determine the utility of antisense constructs to cytokines produced by osteoclasts as probes to identify the molecular events responsible for the bone-resorptive process. Giant cells were cultured on sperm whale dentin for 24 h in the presence of fluoresceinated antisense or scrambled antisense deoxyoligonucleotides complementary to IL-6 mRNA. The giant cells actively incorporated these oligonucleotides, as evidenced by their intense fluorescence. The number of resorptive lacunae formed and the area of the dentin resorbed were significantly decreased in cultures of giant cells treated with antisense IL-6 constructs compared with control cultures treated with scrambled antisense constructs to IL-6 (60 +/- 13 versus 12 +/- 6 lacunae and 1.2 +/- 0.3 versus 0.26 +/- 0.1 x 10(5) microns2). IL-6 levels in conditioned media from giant cell cultures treated with IL-6 antisense constructs were fourfold lower than those in control media obtained from giant cells treated with scrambled antisense constructs to IL-6. These data confirm the capacity of IL-6 antisense oligomers to block IL-6 production by these cells. These observations show that IL-6 plays an important role in the bone-resorptive process of human osteoclasts and suggest that antisense constructs to cytokines produced by bone cells may be useful for determining the molecular events occurring during bone resorption.
Animals↗
C-terminal fragments of parathyroid hormone-related protein, PTHrP-(107-111) and (107-139), and the N-terminal PTHrP-(1-40) fragment stimulate membrane-associated protein kinase C activity in rat spleen lymphocytes.
Membrane-associated protein kinase C (PKC) activity in lymphocytes freshly isolated from rat spleen was stimulated by the C-terminal parathyroid hormone-related protein fragments, PTHrP-(107-111) and PTHrP-(107-139), at concentrations from 10(-3) to 10(4) pM. By contrast, the same concentrations of PTHrP-(120-139), without the 107-111 TRSAW (-Thr-Arg-Ser-Ala-Trp-) sequence of the other C terminal fragments, did not stimulate spleen lymphocyte PKC. Low concentrations of the N-terminal PTHrP-(1-40) fragment also stimulated membrane-associated PKC activity in the spleen lymphocytes. These results suggest that PTHrP might be an important physiological regulator of the immune response.
Animals↗
Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues.
Humanization of murine monoclonal antibodies for human therapy has commonly been achieved by complementarity-determining region (CDR) grafting, in which murine CDR loops are grafted onto human framework regions. Difficulties with that method have revealed the importance of certain framework residues in determining both the 3-D structure of CDR loops and the overall affinity of the molecule for its specific ligand. In the general model of structure-function relationships presented here, each amino acid position in the variable region is classified according to the benefit of achieving a more human-like antibody versus the risk of decreasing or abolishing specific binding affinity. Substitutions of human residues at low-risk positions (exposed to solvent but not contributing to antigen binding or antibody structure) are likely to decrease immunogenicity with little or no effect on binding affinity. Changes at high-risk positions (directly involved in antigen binding, CDR stabilization or internal packing) are avoided to preserve the biological activity of the antibody. Moderate-risk changes are made with caution. This model has been tested experimentally using H65, an anti-CD5 murine monoclonal antibody, whose binding activity had been greatly reduced by two previous attempts at humanization by conventional CDR grafting. The new 'human-engineered' H65 antibody containing 20 low-risk human consensus substitutions (expressed as either IgG or Fab) retains the full binding avidity of parental murine and chimeric H65 antibodies. A human-engineered antibody with an additional 14 moderate-risk substitutions has unexpectedly enhanced avidity (3- to 7-fold). This method is generally applicable to the design of other human-engineered antibodies with therapeutic potential.
Amino Acid Sequence↗
PUVA and methotrexate therapy of psoriasis: how closely do dermatology departments follow treatment guidelines? Psoriasis Audit Workgroup of the British Association of Dermatologists.
Following publication of treatment guidelines for patients with psoriasis, a six-centre audit was undertaken to assess current therapeutic practice for two second-line treatments, PUVA and methotrexate. The audit consisted of random sampling of casenotes by external auditors from a paired dermatology department, and assessment by questionnaire. One hundred and eight PUVA and 118 methotrexate casenotes were audited. The commonest indications for treatment were: (a) failure of tropical therapy--PUVA (mean 81% of casenotes), methotrexate (84%); (b) repeated hospital admissions--PUVA (16%), methotrexate (25%). For both PUVA and methotrexate, some aspects of treatment were well documented: PUVA--psoralen dosage (91%), response to PUVA (89%), cumulative lifetime UVA dosage (81%); methotrexate--pretreatment assessment of full blood count (91%), urea and electrolytes (85%), liver function tests (84%). For other aspects documentation was less complete: PUVA--no documentation of presence/absence of skin cancer history (66%), note of photoactive drugs (32%); methotrexate--concurrent medication (69%), history of presence/absence of liver disease (36%). Another aspect which was poorly documented in both PUVA and methotrexate notes was whether advice on contraception/fertility had been given. There was no indication in 29 of 32 casenotes of females of child-bearing age receiving PUVA, and 52 of 63 case notes of relevant patients on methotrexate. This project has demonstrated that formal, multicentre audit based on published guidelines is a practical proposition.
Clinical Protocols↗
Endomyocardial gene expression during development of pacing tachycardia-induced heart failure in the dog.
Selective and specific changes in gene expression characterize the end-stage failing heart. However, the pattern and relation of these changes to evolving systolic and diastolic dysfunction during development of heart failure remains undefined. In the present study, we assessed steady-state levels of mRNAs encoding a group of cardiac proteins during the early development of left ventricular dysfunction in dogs with pacing-induced cardiomyopathy. Corresponding hemodynamic assessments were made in the conscious state in the same animals and at the same time points at baseline, after 1 week of ventricular pacing, and at the onset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was undetectable in 7 of 12 hearts at baseline but was expressed in all hearts at 1 week (P < .01 by chi 2 test), and it increased markedly with progression to failure (P = .05). Creatine kinase-B mRNA also rose markedly with heart failure (P < .01). Levels of mRNA encoding beta-myosin heavy chain, mitochondrial creatine kinase, phospholamban, and sarcoplasmic reticulum Ca(2+)-ATPase did not significantly change from baseline, despite development of heart failure. Additional analysis to determine if these mRNA changes were related to the severity of diastolic or systolic dysfunction revealed that phospholamban mRNA decreased in hearts with larger net increases in end-diastolic pressure (+19.2 +/- 1.9 mm Hg) compared with those hearts in which it did not change (+4.0 +/- 4.9, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Effects of high-probability requests on the social interactions of young children with severe disabilities.
High-probability requests were used to increase social interactions in 3 young boys with severe disabilities who had been identified as severely socially withdrawn. A multiple baseline design across participants was used to evaluate the effects of high-probability request intervention on (a) social initiations, (b) social responses, (c) continued interactions, and (d) performance of high- and low-probability requests. The students were observed in a second setting to examine generalization effects across peers who did not participate in the training sequence and settings. The results demonstrated that the high-probability requests increased the students' responsiveness to low-probability requests to initiate social behavior. Increases were also found in (a) unprompted initiations and extended interactions to the training peers, (b) unprompted initiations and extended interactions to peers who were not involved in the training procedure, and (c) generalized unprompted initiations and interactions in a second nontraining setting. The students maintained increased levels of initiations and interactions after all prompts were removed from both the training and nontraining settings.
Autistic Disorder↗
The hydration phenomenon in natural rubber latex gloves and its effect on electronic glove monitors.
A physical model is presented to explain the phenomenon of hydration in natural rubber latex (NRL) gloves and to account for the observed decrease in electrical resistance of these gloves when exposed to normal saline solution. Microporosity in the rubber is attributed to failure of all latex particles making up a typical glove to completely coalesce with each other and form a continuous film free of interstitial voids. Native proteins and chemicals used in the manufacturing process are suspected of inhibiting coalescence and causing allergic reactions to some wearers after repeated uses. The effect of hydration on the performance of electronic glove monitors is discussed. Glove monitors that can distinguish between hydration and holes are considered to be the most reliable.
Electric Impedance↗
The prevalence of epilepsy among a rural Kenyan population. Its association with premature mortality.
During a two year community-based investigation of mortality 3.5% of the deaths to individuals over the age of 5 years were reported by bereaved relatives to have occurred to epileptics and 77% of these deaths were thought to have occurred whilst the patient was in status epilepticus. This prompted us to determine the prevalence of epilepsy in this rural population by interviewing 7,450 residents of a pre-defined study area. The prevalence of 'Kifafa' or 'Vitsala', two local words used to describe epilepsy, but later confirmed through detailed interviews, was 0.4%. This prevalence is clearly an underestimate of the true prevalence of epilepsy in this population but is probably higher than prevalences reported in developed countries. Anti-convulsant prophylaxis is available at the district hospital but this service is only sporadically used by epileptics in this population. Uncontrolled and poorly managed epilepsy may result in an increased risk of premature mortality among epileptics living in this community.
Adolescent↗
Refined genetic mapping of juvenile-onset neuronal ceroid-lipofuscinosis on chromosome 16.
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Chromosome Mapping↗
On the transmissibility of Eperythrozoon suis by Stomoxys calcitrans and Aedes aegypti.
The stable fly, Stomoxys calcitrans (Linnaeus), and the yellow fever mosquito, Aedes aegypti (Linnaeus), were utilized to determine their capability to transmit Eperythrozoon suis Splitter between swine. Three groups of each insect in each trial were allowed to feed on a pig previously infected with E. suis and then transferred to susceptible splenectomized pigs. As a control, one group of each insect was fed on a non-infected pig and then transferred to a susceptible pig. Stable flies were transferred immediately and following a delay of 1, 4, 24 h and 7 days. Aedes aegypti were transferred immediately and following a 7 day delay. Successful transmission was accomplished in three of 15 pigs to which stable flies were transferred immediately and in nine of nine pigs to which A. aegypti were transferred immediately. No pigs became infected when there was a delay before transfer to the susceptible pig. All controls remained non-infected. This indicates that the stable fly and A. aegypti are likely to be mechanical vectors of E. suis under natural conditions. Differences in vector efficiency may be due to differences in mechanisms of blood-feeding which could affect the placement of the inoculum of E. suis.
Aedes↗