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Biomedical subjects

D Baker

Publications and source records attributed to D Baker.

At least 91 records · Page 5Linked to original sources
PubMed2000

Bypass surgery for chronic lower limb ischaemia.

BACKGROUND: Surgical bypass of an occluded arterial segment is the mainstay of treatment for patients with critical limb ischaemia. As with many surgical interventions, however, it was introduced without formal evaluation. OBJECTIVES: The objective of this review was to determine the effects of bypass surgery in patients with chronic lower limb ischaemia. SEARCH STRATEGY: The reviewers searched the Cochrane Peripheral Vascular Diseases Group trials register, MEDLINE, EMBASE, reference lists of relevant articles, and contacted principal trial investigators. SELECTION CRITERIA: All randomised controlled trials of bypass surgery versus control, or versus any other form of treatment. DATA COLLECTION AND ANALYSIS: At least two reviewers extracted data and assessed trial quality independently. The reviewers contacted investigators to obtain information or data needed for the review that could not be found in published reports. Dichotomous data were analysed using the Peto odds ratio (OR), and continuous data with the weighted mean difference (fixed effect and random effects models). MAIN RESULTS: Eight trials were identified which appeared to meet the inclusion criteria, but two were subsequently excluded. The remaining six trials involved a total of just over 700 patients, two trials comparing bypass surgery with angioplasty (PTA), and one with each of thromboendarterectomy, thrombolysis, exercise, and spinal cord stimulation. Four trials included patients with a range of disease severity (intermittent claudication and critical limb ischaemia), one was restricted to claudicants only and another to only critical limb ischaemia. The type of bypass procedure performed in each trial was similar: vein grafts for distal reconstructions; synthetic prostheses for aorto-iliac or ilio-femoral bypasses. The outcome measures varied, but four of the six trials included mortality and operative failure. In general the quality of the trials was good, but none was blinded because of the nature of the intervention. There were no clear differences between bypass surgery and PTA. Mortality and amputation rates did not differ significantly, although primary patency was significantly higher in the bypass group after 12 months (Peto OR 1. 6, 95% CI 1.0, 2.6) but not after four years (p=0.14). Compared with thrombolysis, amputation rates were significantly lower in the bypass group (Peto OR 0.2, 95% CI 0.1, 0.6), but mortality rates did not differ. Compared with thromboendarterectomy, restoration of blood flow was significantly greater in the bypass patients (Peto OR 9.2, 95% CI 1.7, 50.6), but mortality and amputation rates did not differ. Bypass did not differ significantly from exercise or spinal cord stimulation. REVIEWER'S CONCLUSIONS: There is limited evidence for the effectiveness of bypass surgery and further large trials are required.

Angioplasty, Balloon↗
PubMed2000

ENVIRONMENTAL AUDITING: An Integrated Approach to Reservoir Management: The Williston Reservoir Case Study.

/ The management of industrial reservoirs for hydroelectric energy can cause severe impacts to surrounding communities. This study examines the generation of dust along the northern foreshore zones of Williston Reservoir in northern British Columbia. The dust is generated in the spring when the reservoir levels are low and impacts a relocated First Nations' village (Tsay Keh) at the north end of the reservoir. Data were gathered to provide an overview of the physical conditions that contribute to the dust problem, including a social survey, soil analysis, and vegetation inventory. The study provides a scoping method to assess a large-scale and complex problem with respect to dust management along a large reservoir. Methods for dust control include short- and long-term solutions that integrate the use of native vegetation along the foreshore zones of the reservoir.

Journal Article↗
PubMed2000

Unrelated donors selected prospectively by block-matching have superior bone marrow transplant outcome.

Previous retrospective studies have demonstrated improved outcome in patients whose donors were matched for non-HLA markers in the MHC as well as for HLA genes. Forty patients receiving transplants from unrelated donors were typed prospectively for HLA and non-HLA markers. Non-HLA markers near HLA-B (beta-block markers) and in the DRB1 introns (delta-block markers) were used to assess MHC match between donors and recipient. Patients whose donors were matched at the beta- and delta-blocks had improved event free survival (63%) compared to patients whose donors were mismatched at one or both blocks (25%) (p < 0.05). Patients whose donors were matched at the beta-block had significantly less severe acute graft versus host disease (p < 0.05). In order to investigate the basis for improved outcome block matching was correlated with HLA matching as determined by DNA sequencing. Beta-block matching was highly correlated with matching for exons 2 and 3 of HLA-B but less so for HLA-C. Delta-block matching was highly correlated with matching for exon 2 of HLA DRB1. It is concluded that matching for non-HLA markers in the MHC improves matching for HLA genes. Further studies are required to determine whether matching for non-HLA markers improves outcome to a greater extent than matching for the HLA genes alone.

Adolescent↗
PubMed2000

De novo protein structure determination using sparse NMR data.

We describe a method for generating moderate to high-resolution protein structures using limited NMR data combined with the ab initio protein structure prediction method Rosetta. Peptide fragments are selected from proteins of known structure based on sequence similarity and consistency with chemical shift and NOE data. Models are built from these fragments by minimizing an energy function that favors hydrophobic burial, strand pairing, and satisfaction of NOE constraints. Models generated using this procedure with approximately 1 NOE constraint per residue are in some cases closer to the corresponding X-ray structures than the published NMR solution structures. The method requires only the sparse constraints available during initial stages of NMR structure determination, and thus holds promise for increasing the speed with which protein solution structures can be determined.

Humans↗
PubMed2000

Critical role of beta-hairpin formation in protein G folding.

Comparison of the folding mechanisms of proteins with similar structures but very different sequences can provide fundamental insights into the determinants of protein folding mechanisms. Despite very little sequence similarity, the approximately 60 residue IgG binding domains of protein G and protein L both consist of a single helix packed against a four-stranded sheet formed by two symmetrically disposed beta-hairpins. We demonstrate that, as in the case of protein L, one of the two beta-turns of protein G is formed and the other disrupted in the folding transition state. Unlike protein L, however, in protein G it is the second beta-turn that is formed in the folding transition state ensemble. Substitution of an Asp residue by Ala in protein G that eliminates an i,i+2 side chain-main chain hydrogen bond in the second beta-turn slows the folding rate approximately 20-fold but has virtually no effect on the unfolding rate. Taken together with previous results, these findings suggest that the presence of an intact beta-turn in the folding transition state is a consequence of the overall topology of protein L and protein G, but the particular hairpin that is formed is determined by the detailed interatomic interactions that determine the free energies of formation of the isolated beta-hairpins.

Amino Acid Substitution↗
PubMed2000

High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors.

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.

Adolescent↗
PubMed2000

Immuno- and genetic therapy in autoimmune diseases.

Animal models of autoimmune disease have been developed that mimic some aspects of the pathophysiology of human disease. These models have increased our understanding of possible mechanisms of pathogenesis at the molecular and cellular level and have been important in the testing, development and validation of new immunotherapies. The susceptibility to develop disease in the majority of these models is polygenic as is the case in humans. The exceptions to this rule are gene knock outs and transgenic models of particular genes which, in particular genetic backgrounds, have also contributed to the understanding of single gene function and their possible contribution to pathogenesis. Gene therapy approaches that target immune functions are being developed with encouraging results, despite the polygenic nature of these diseases. Basically this novel immuno-genetic therapy harnesses the knowledge of immunology with the myriad of biotechnological breakthroughs in vector design and delivery. Autoimmune disease is the result of genetic dysregulation which could be controlled by gene therapy. Here we summarize the genetic basis of these human diseases as well as some of the best characterized murine models. We discuss the strategies for their treatment using immuno- and gene therapy.

Animals↗
PubMed2000

Rhytidectomy with lateral SMASectomy.

Since 1992 an alternative to formal elevation of the superficial fascia is to perform a lateral SMASectomy, removing a portion of the SMAS in the region directly overlying the anterior edge of the parotid gland. Excision of the superficial fascia in this region secures mobile anterior SMAS to the fixed portion of the superficial fascia overlying the parotid. The direction in which the SMASectomy is performed is oriented so that the vectors of elevation following SMAS closure lie perpendicular to the nasolabial fold, thereby producing improvement not only of the nasolabial fold but also of the jowl and jawline. This method represents a rapid, safe, and reproducible operation, allowing the surgeon the versatility obtained with formal SMAS flap undermining while producing both the safety and rapidity of SMAS plication.

Cheek↗
PubMed2000

Crystallization and preliminary X-ray diffraction studies of mutants of B1 IgG-binding domain of protein L from Peptostreptococcus magnus.

The small 62-residue IgG-binding domain B1 of protein L from Peptostreptococcus magnus (Ppl-B1) has proven to be a simple system for the study of the thermodynamics and kinetics of protein folding. X-ray diffraction studies have been initiated in order to determine how the thermostability, folding and unfolding rates of a series of point mutations spanning Ppl-B1 correlate with the high-resolution structures. To this end, a tryptophan-containing variant of Ppl-B1 (herein known as wild type) and two mutants, Lys61Ala and Val49Ala, have been crystallized. Full data sets have been collected for the wild type and the Lys61Ala and Val49Ala mutants to resolutions of 1. 7, 2.3 and 1.8 A, respectively. Interestingly, all three crystallize using different precipitants and in different space groups. This may be a consequence of the relatively large effects of single-site mutations on surface-charge distribution or structural conformation, which might affect crystal contact sites.

Alanine↗
PubMed2000

Pharmacological characterization of phospholipid growth-factor receptors.

The phospholipid growth-factor (PLGE) terminology is proposed to describe a group of endogenous glycerol- and sphingolipid mediators that regulate cell proliferation through plasma membrane receptors. In addition to LPA and SPP, multiple PLGFs are present in blood plasma and serum. PLGF activity is regulated by its stimulus-coupled production and by endogenous inhibitors. In addition to LPA and SPP, alkenyl-glycerophosphate, cyclic-phosphatidic acid, and sphingosylphosphorylcholine were detected in biological fluids using mass spectrometry. Heterologous desensitization studies indicate the expression of multiple LPA-activated receptors in a variety of cell types, which are differentially activated by the different PLGFs. Northern blot and RT-PCR results reinforce the coexpression of PSP24 alpha and different members of the EDG1-7 receptors in the same cell. Stable heterologous expression of the PSP24 alpha, EDG2, and EDG4 receptors in HEK293 cells show distinct PLGF specificities and dose-response properties for each receptor subtype. Thus, both the controlled availability of the different agonists/inhibitors and the regulated expression of their receptors regulate the biological effects of PLGFs.

Animals↗
PubMed2000

Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy.

Efavirenz is a potent and selective nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Nucleotide sequence analyses of the protease and RT genes (coding region for amino acids 1 to 229) of multiple cloned HIV-1 genomes from virus found in the plasma of patients in phase II clinical studies of efavirenz combination therapy were undertaken in order to identify the spectrum of mutations in plasma-borne HIV-1 associated with virological treatment failure. A K103N substitution was the HIV-1 RT gene mutation most frequently observed among plasma samples from patients for whom combination therapy including efavirenz failed, occurring in at least 90% of cases of efavirenz-indinavir or efavirenz-zidovudine (ZDV)-lamivudine (3TC) treatment failure. V108I and P225H mutations were observed frequently, predominantly in viral genomes that also contained other nonnucleoside RT inhibitor (NNRTI) resistance mutations. L100I, K101E, K101Q, Y188H, Y188L, G190S, G190A, and G190E mutations were also observed. V106A, Y181C, and Y188C mutations, which have been associated with high levels of resistance to other NNRTIs, were rare in the patient samples in this study, both before and after exposure to efavirenz. The spectrum of mutations observed in cases of virological treatment failure was similar for patients initially dosed with efavirenz at 200, 400, or 600 mg once a day and for patients treated with efavirenz in combination with indinavir, stavudine, or ZDV-3TC. The proportion of patients carrying NNRTI resistance mutations, usually K103N, increased dramatically at the time of initial viral load rebound in cases of treatment failure after exposure to efavirenz. Viruses with multiple, linked NNRTI mutations, especially K103N-V108I and K103N-P225H double mutants, accumulated more slowly following the emergence of K103N mutant viruses.

Alkynes↗
PubMed2000

Domiciliary visits to the old and the mentally ill: how valuable?

In the early days of the British National Health Service, domiciliary visits were a continuation of the tradition whereby general practitioners (GPs) met consultants in the patient's home. The nature of domiciliary visits, which still attract a special fee, has since changed. We analysed the effectiveness of all domiciliary visits undertaken in a NHS trust providing primary care, mental health and elderly care services to a population of 470,000. Data were obtained from domiciliary visit claim forms and from questionnaires completed by the consultant, the referring GP and consultant peer reviewers. The largest number of visits (total 234) was in geriatric medicine 48.9%, followed by old-age psychiatry 44.9%. Geriatric medicine was more likely than psychiatry to admit patients to hospital (19%) after a visit. All domiciliary visits in old-age psychiatry were done during the day (9 am to 5 pm). Only 2% of GPs stated that they attended any of the domiciliary visits; almost all thought that the outcome of domiciliary visits was of value. Old-age-psychiatry peer reviewers believed that all visits in that specialty were appropriate; in geriatric medicine this figure was 77% and in other psychiatric specialties 65%. The findings indicate that domiciliary visits were not being used routinely as a pathway to hospital admission, though they were often used to expedite admission or gain a quick consultant opinion; the visits were valued by GPs. The practice of domiciliary visits differs greatly from the definition in NHS terms and conditions of service. One or other should be altered.

Aged↗
PubMed2000

HIV/AIDS consultations.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed2000

The use of time step simulations and difference equations (TSSADEQ) in modeling heparin pharmacokinetics.

A model in which the clearance of heparin requires the binding of heparin to a finite and regenerated pool of binding was constructed using time step simulations and difference equations (TSSADEQ). A simulation of a heparin i.v. bolus demonstrated a dose-dependent, triphasic pharmacokinetic curve with (1) an initial log-linear phase representing first-order association of heparin with binding sites, (2) an intermediate plateau phase representing constant regeneration of heparin binding sites, and (3) a terminal log-linear phase occurring when the quantity of regenerated sites exceeded the remaining heparin. Sensitivity analysis based on the literature produced estimates of the k at 1.39 to 2.77 h-1, the pool of binding sites of 50 units/kg, and the regeneration rate of 15 to 20 unit/kg/h--virtually identical to the empirically derived guidelines for the bolus size and infusion rate for unfractionated heparin. A pilot study of bolus dosing of unfractionated heparin in normal volunteers confirmed the model.

Adult↗
PubMed1999

Structural transitions in the protein L denatured state ensemble.

We use a broad array of biophysical methods to probe the extent of structure and time scale of structural transitions in the protein L denatured state ensemble. Measurement of amide proton exchange protection during the first several milliseconds following initiation of refolding in 0.4 M sodium sulfate revealed weak protection in the first beta-hairpin and helix. A tryptophan residue was introduced into the first beta-hairpin to probe the extent of structure formation in this part of the protein; the intrinsic fluorescence of this tryptophan was found to deviate from that expected given its local sequence context in 2-3 M guanidine, suggesting some partial ordering of this region in the unfolded state ensemble. To further probe this partial ordering, dansyl groups were introduced via cysteine residues at three sites in the protein. It was found that fluorescence energy transfer from the introduced tryptophan to the dansyl groups decreased dramatically upon unfolding. Stopped-flow fluorescence studies showed that the recovery of dansyl fluorescence upon refolding occurred on a submillisecond time scale. To probe the interactions responsible for the residual structure observed in the denatured state ensemble, the conformation of a peptide corresponding to the first beta-hairpin and helix of protein L was studied using circular dichroism spectroscopy and compared to that of full-length protein L and previously characterized peptides corresponding to the isolated helix and second beta-hairpin.

Amino Acid Sequence↗
PubMed1999

Prediction of protein-folding mechanisms from free-energy landscapes derived from native structures.

Guided by recent experimental results suggesting that protein-folding rates and mechanisms are determined largely by native-state topology, we develop a simple model for protein folding free-energy landscapes based on native-state structures. The configurations considered by the model contain one or two contiguous stretches of residues ordered as in the native structure with all other residues completely disordered; the free energy of each configuration is the difference between the entropic cost of ordering the residues, which depends on the total number of residues ordered and the length of the loop between the two ordered segments, and the favorable attractive interactions, which are taken to be proportional to the total surface area buried by the ordered residues in the native structure. Folding kinetics are modeled by allowing only one residue to become ordered/disordered at a time, and a rigorous and exact method is used to identify free-energy maxima on the lowest free-energy paths connecting the fully disordered and fully ordered configurations. The distribution of structure in these free-energy maxima, which comprise the transition-state ensemble in the model, are reasonably consistent with experimental data on the folding transition state for five of seven proteins studied. Thus, the model appears to capture, at least in part, the basic physics underlying protein folding and the aspects of native-state topology that determine protein-folding mechanisms.

Models, Theoretical↗
PubMed1999

Hierarchy of structure loss in MD simulations of src SH3 domain unfolding.

To complement experimental studies of the src SH3 domain folding, we studied 30 independent, high-temperature, molecular dynamics simulations of src SH3 domain unfolding. These trajectories were observed to differ widely from each other. Thus, rather than analyzing individual trajectories, we sought to identify the recurrent features of the high-temperature unfolding process. The conformations from all simulations were combined and then divided into groups based on the number of native contacts. Average occupancies of each side-chain hydrophobic contact and hydrogen bond in the protein were then determined. In the symmetric funnel limit, the occupancies of all contacts should decrease in concert with the loss in total number of native contacts. If there is a lack of symmetry or hierarchy to the unfolding process, the occupancies of some contacts should decrease more slowly, and others more rapidly. Despite the heterogeneity of the individual trajectories, the ensemble averaging revealed an order to the unfolding process: contacts between the N and C-terminal strands are the first to disappear, whereas contacts within the distal beta-hairpin and a hydrogen-bonding network involving the distal loop beta-turn and the diverging turn persist well after the majority of the native contacts are lost. This hierarchy of events resembles but is somewhat less pronounced than that observed in our experimental studies of the folding of src SH3 domain.

Computer Simulation↗