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Biomedical subjects

N Walker

Publications and source records attributed to N Walker.

At least 19 recordsLinked to original sources
PubMed2001

Epidemiological analysis of the quality of HIV sero-surveillance in the world: how well do we track the epidemic?

OBJECTIVE: The objective of this paper was to analyse the quality of HIV/AIDS sentinel surveillance systems in countries and the resulting quality of the data used to make estimates of HIV/AIDS prevalence and mortality. METHODS: Available data on sero-surveillance of HIV/AIDS in countries were compiled in the process of making the end of 1999 estimates of HIV/AIDS. These data came primarily from the HIV/AIDS Surveillance Database developed by the United States Census Bureau, from a database maintained by the European Centre for the Epidemiological Monitoring of AIDS and all country reports on sentinel surveillance that had been provided to World Health Organization or UNAIDS. Procedures were developed to score quality of surveillance systems based on four dimensions of quality: timeliness and frequency; appropriateness of groups; consistency of sites over time; and coverage provided by the system. In total, the surveillance systems from 167 countries were analysed. RESULTS: Forty-seven of the 167 countries whose surveillance systems were rated were judged to have fully implemented sentinel surveillance systems; 51 were judged to have systems that had some or most aspects of a good HIV surveillance system in place and 69 were rated as having poorly functioning or non-existent surveillance systems. CONCLUSION: This analysis suggests that the quality of HIV surveillance varies considerably. The majority of countries most affected by HIV/AIDS have systems that are providing sufficient sero-prevalence data for tracking the epidemic and making reasonable estimates of HIV prevalence. However, many countries have poor systems and strengthening these is an urgent priority.

Adolescent↗
PubMed2001

The global impact of HIV/AIDS.

The scale of the human immunodeficiency virus (HIV)/AIDS epidemic has exceeded all expectations since its identification 20 years ago. Globally, an estimated 36 million people are currently living with HIV, and some 20 million people have already died, with the worst of the epidemic centred on sub-Saharan Africa. But just as the spread of HIV has been greater than predicted, so too has been its impact on social capital, population structure and economic growth. Responding to AIDS on a scale commensurate with the epidemic is a global imperative, and the tools for an effective response are known. Nothing less than a sustained social mobilization is necessary to combat one of the most serious crises facing human development.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Treatment of Felty's syndrome with leflunomide.

Felty's syndrome (FS) is a rare manifestation of severe rheumatoid arthritis (RA). It is an immune mediated inflammatory process, usually treated with standard disease modifying antirheumatic drugs. We describe a case of severe FS that developed in a patient receiving methotrexate therapy for RA. Treatment with etanercept resulted in severe allergic cutaneous reactions. The patient subsequently responded to treatment with leflunomide. The response included dramatic improvement of leukopenia and neutropenia as well as excellent control of his arthritis. Leflunomide has recently been used effectively for the treatment of RA and may be useful for the management of patients with FS.

Antirheumatic Agents↗
PubMed2000

Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials.

OBJECTIVES: To obtain reliable estimates of the effects of neuraxial blockade with epidural or spinal anaesthesia on postoperative morbidity and mortality. DESIGN: Systematic review of all trials with randomisation to intraoperative neuraxial blockade or not. STUDIES: 141 trials including 9559 patients for which data were available before 1 January 1997. Trials were eligible irrespective of their primary aims, concomitant use of general anaesthesia, publication status, or language. Trials were identified by extensive search methods, and substantial amounts of data were obtained or confirmed by correspondence with trialists. MAIN OUTCOME MEASURES: All cause mortality, deep vein thrombosis, pulmonary embolism, myocardial infarction, transfusion requirements, pneumonia, other infections, respiratory depression, and renal failure. RESULTS: Overall mortality was reduced by about a third in patients allocated to neuraxial blockade (103 deaths/4871 patients versus 144/4688 patients, odds ratio=0.70, 95% confidence interval 0.54 to 0.90, P=0. 006). Neuraxial blockade reduced the odds of deep vein thrombosis by 44%, pulmonary embolism by 55%, transfusion requirements by 50%, pneumonia by 39%, and respiratory depression by 59% (all P<0.001). There were also reductions in myocardial infarction and renal failure. Although there was limited power to assess subgroup effects, the proportional reductions in mortality did not clearly differ by surgical group, type of blockade (epidural or spinal), or in those trials in which neuraxial blockade was combined with general anaesthesia compared with trials in which neuraxial blockade was used alone. CONCLUSIONS: Neuraxial blockade reduces postoperative mortality and other serious complications. The size of some of these benefits remains uncertain, and further research is required to determine whether these effects are due solely to benefits of neuraxial blockade or partly to avoidance of general anaesthesia. Nevertheless, these findings support more widespread use of neuraxial blockade.

Anesthesia, Epidural↗
PubMed2000

Identification of residues in the carboxy-terminal domain of Clostridium perfringens alpha-toxin (phospholipase C) which are required for its biological activities.

A panel of random mutants within the DNA encoding the carboxy-terminal domain of Clostridium perfringens alpha-toxin was constructed. Three mutants were identified which encoded alpha-toxin variants (Lys330Glu, Asp305Gly, and Asp293Ser) with reduced hemolytic activity. These variants also had diminished phospholipase C activity toward aggregated egg yolk phospholipid and reduced cytotoxic and myotoxic activities. Asp305Gly showed a significantly increased enzymatic activity toward the monodisperse substrate rhoNPPC, whereas Asp293Ser displayed a reduced activity toward this phospholipid analogue. In addition, Asp293Ser showed an increased dependence on calcium for enzymatic activity toward aggregated phospholipid and appeared calcium-depleted in PAGE band-shift assays. In contrast, neither Lys330Glu nor Asp305Gly showed altered dependence on calcium for enzymatic activity toward aggregated phospholipid. Asp305 is located in the interface between the amino- and carboxy-terminal domains, whereas Asp293 and Lys330 are surface exposed residues which may play a role in the recognition of membrane phospholipids.

Amino Acid Substitution↗
PubMed2000

AIDS in a new millennium.

As we enter the new millennium the world is still facing the challenge of responding to the AIDS pandemic. A new report from the Joint United Nations Programme on HIV/AIDS presents the latest statistics on prevalence, spread, and impact of the disease. In their Perspective, Schwartländer and his colleagues discuss the newly released statistics and the strategies needed to combat the further spread of HIV/AIDS and to reduce prevalence in the most severely affected countries.

Acquired Immunodeficiency Syndrome↗
PubMed2000

p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.

p73 (ref. 1) has high homology with the tumour suppressor p53 (refs 2-4), as well as with p63, a gene implicated in the maintenance of epithelial stem cells. Despite the localization of the p73 gene to chromosome 1p36.3, a region of frequent aberration in a wide range of human cancers, and the ability of p73 to transactivate p53 target genes, it is unclear whether p73 functions as a tumour suppressor. Here we show that mice functionally deficient for all p73 isoforms exhibit profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways. In contrast to p53-deficient mice, however, those lacking p73 show no increased susceptibility to spontaneous tumorigenesis. We report the mechanistic basis of the hippocampal dysgenesis and the loss of pheromone responses, and show that new, potentially dominant-negative, p73 variants are the predominant expression products of this gene in developing and adult tissues. Our data suggest that there is a marked divergence in the physiological functions of the p53 family members, and reveal unique roles for p73 in neurogenesis, sensory pathways and homeostatic control.

Abnormalities, Multiple↗
PubMed2000

Characterization of ricin heterogeneity by electrospray mass spectrometry, capillary electrophoresis, and resonant mirror.

Electrospray mass spectrometry (ES/MS), capillary-zone electrophoresis (CZE), capillary isoelectric focusing (CIEF), and multianalyte resonant mirror are used to evaluate the heterogeneity of samples of ricin toxins extracted from five horticultural varieties of Ricinus communis seeds: R. communis zanzibariensis, carmencita, impala, sanguineus, and gibsonii. The investigation is also extended to the geographical provenance of the beans. Combining mass spectrometry, CE techniques, and resonant mirror results in a powerful analytical tool capable to characterize and differentiate between different varieties of ricin toxins. Each technique complements the others, adding another level of information. This study reveals a large extent of heterogeneity for each cultivar, demonstrating that ricin toxins consist of a series of glycosylated proteins most likely originating from a multigene family. By combining these techniques, it is possible to differentiate between zanzibariensis and the other four varieties, and that variations in the functional characteristics may be observed between the different cultivars. This study demonstrates that knowledge of the variety of R. communis beans used and their geographical provenance is essential before any type of investigation of ricin toxins is carried out. Consequently, any unusual behavior observed can only be attributed to that particular cultivar studied and not automatically extended to include all R. communis varieties.

Biosensing Techniques↗
PubMed2000

The development of competency standards for specialist critical care nurses.

In defining the contemporary role of the specialist nurse it is necessary to challenge the concept of nursing as merely a combination of skills and knowledge. Nursing must be demonstrated and defined in the context of client care and include the broader notions of professional development and competence. This qualitative study sought to identify the competency standards for nurse specialists in critical care and to articulate the differences between entry-to-practice standards and the advanced practice of specialist nurses. Over 800 hours of specialist critical care nursing practice were observed and grouped into 'domains' or major themes of specialist practice using a constant comparison qualitative technique. These domains were further refined to describe attributes of the registered nurses which resulted in effective and/or superior performance (competency standards) and to provide examples of performance (performance criteria) which met the defined standard. Constant comparison of the emerging domains, competency standards and performance criteria to observations of specialist critical care practice, ensured the results provided a true reflection of the specialist nursing role. Data analysis resulted in 20 competency standards grouped into six domains: professional practice, reflective practice, enabling, clinical problem solving, teamwork, and leadership. Each of these domains is comprised of between two and seven competency standards. Each standard is further divided into component parts or 'elements' and the elements are illustrated with performance criteria. The competency standards are currently being used in several Australian critical care educational programmes and are the foundation for an emerging critical care credentialling process. They have been viewed with interest by a variety of non-critical care specialty groups and may form a common precursor from which further specialist nursing practice assessment will evolve.

Australia↗
PubMed2000

Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria.

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost in the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these "costs of resistance" in Escherichia coli, HIV, and Salmonella typhimurium found that evolution in the absence of these drugs commonly results in the ascent of mutations that ameliorate these costs, rather than higher-fitness, drug-sensitive revertants. To ascertain the conditions under which this compensatory evolution, rather than reversion, will occur, we did computer simulations, in vitro experiments, and DNA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutants of E. coli with and without mutations that compensate for the fitness costs of these ribosomal protein mutations. The results of our investigation support the hypothesis that in these experiments, the ascent of intermediate-fitness compensatory mutants, rather than high-fitness revertants, can be attributed to higher rates of compensatory mutations relative to that of reversion and to the numerical bottlenecks associated with serial passage. We argue that these bottlenecks are intrinsic to the population dynamics of parasitic and commensal microbes and discuss the implications of these results to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.

Adaptation, Biological↗
PubMed2000

Discriminant validity of temporomandibular joint range of motion measurements obtained with a ruler.

STUDY DESIGN: Prospective, descriptive study. OBJECTIVE: To determine the discriminant validity and intrarater and interrater reliability of measurements of temporomandibular joint (TMJ) range of motion (ROM). BACKGROUND: Although ROM measurements are a routine part of the examination of patients with TMJ disorders, few studies have examined the validity of these measures for identifying pathology of the TMJ. METHODS AND MEASURES: Two groups of subjects were tested: 15 subjects (2 men, 13 women; mean age = 35.2 years) with a TMJ disorder and 15 subjects (3 men, 12 women; mean age = 42.9 years) without a TMJ disorder. Six motions were measured (opening, left excursion, right excursion, protrusion, overbite, and overjet) by 2 therapists. RESULTS: Mouth opening was the only TMJ ROM measurement to discriminate between subjects with and without TMJ disorders (mean 36.2 +/- 6.4 versus 43.5 +/- 6.1 mm). The technical error of measurement of the measures varied from .2 to 2.5 mm. Intrarater reliability coefficients (ICC 3,1) varied from .70 to .99. Interrater reliability coefficients (ICC 2,k) varied from .90 to 1.0. CONCLUSIONS: Although all TMJ ROM measurements tended to be reliable, only mouth opening was found to be valid in discriminating between patients with and without a TMJ disorder.

Adult↗
PubMed1999

Country-specific estimates and models of HIV and AIDS: methods and limitations.

OBJECTIVE: This paper presents the methods used to calculate the end of 1997 country-specific estimates of HIV and AIDS produced by the UNAIDS/WHO Working Group on Global HIV/AIDS and STD Surveillance. The objective of this exercise was to improve estimates on HIV/AIDS by using country-specific models of HIV/AIDS epidemics. The paper describes and discusses the processes and obstacles that were encountered in this multi-partner collaboration including national and international experts. METHODS: The 1997 estimates required two basic steps. First, point prevalence estimates for 1994 and 1997 were carried out and the starting year of the epidemic was determined for each country. The procedures used to calculate the estimates of prevalence differed according to the assumed type of the epidemic and the available data. The second step involved using these estimates of prevalence over time and the starting date of the epidemic to determine the epidemic curve that best described the spread of HIV in each particular country. A simple epidemiological program (EPIMODEL) was used for the calculation of estimates on incidence and mortality from this epidemic curve. RESULTS: Regional models that were used in previous estimation exercises were not able to capture the diversity of HIV epidemics between countries and regions. The result of this first country-specific estimation process yielded higher estimates of HIV infection than previously thought likely, with over 30 million people estimated to be living with HIV/AIDS. The application of survival times that are specific to countries and regions also resulted in higher estimates of mortality, which more accurately describe the impact of the epidemics. At the end of 1997, it was estimated that 11.7 million people worldwide had died as a result of HIV/AIDS since the beginning of the epidemic. CONCLUSION: This exercise is an important step in improving understanding of the spread of HIV in different parts of the world. There are, however, shortcomings in the current systems of monitoring the epidemic. Improvements in HIV surveillance systems are needed in many parts of the world. In addition, further research is needed to understand fully the effects of the fertility reduction as a result of HIV, differing sex ratios in HIV infection and other factors influencing the course and measurement of the epidemic.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Mortality after hip fracture: regional variations in New Zealand.

AIM: To determine the 35-day and one-year mortality rates following a hospital admission for hip fracture, among individuals aged 60 years or older in New Zealand. METHODS: New Zealand Health Information Service mortality data for the years 1988 to 1992 were examined to determine the case fatality rate among individuals aged 60 years or older admitted to hospital for fractures of the neck of femur (ICD-9 N-code 820). Case fatality rates assessed at 35 days and one year after admission to hospital were examined by age, gender, year of admission, place of residence, area health board region and cause of death. RESULTS: Between 1988 and 1992, the case fatality rate was 8% within 35 days of admission to hospital and 24% within one year of admission. Case fatality rates were found to be twice as high in men compared to women and four to five times higher in individuals aged 85 years and older, compared to people aged between 60 and 64 years. The only regional difference in hip fracture mortality was found in the Canterbury area health board region, which had a 30% higher rate of hip fracture mortality compared to all regions combined. The two main cited underlying causes of death after hip fracture were accidental falls (ICD E880-E888) and ischaemic heart disease (ICD 410-414). CONCLUSION: Over three-quarters of individuals aged 60 years or older who are hospitalised with a hip fracture in New Zealand survive for at least one year after admission. However, significant variations in mortality exist with age and gender. These data highlight the importance of preventive strategies for hip fracture in older people and the need to identify ways of improving post-admission care.

Age Distribution↗
PubMed1999

p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.

The p63 gene, a homologue of the tumour-suppressor p53, is highly expressed in the basal or progenitor layers of many epithelial tissues. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63-/- mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.

Animals↗
PubMed1999

Are lipid phase transitions responsible for chilling damage in human platelets?

In previous studies we have proposed that the well-known chilling-induced activation of human blood platelets can be ascribed at least in part to a thermotropic phase transition in membrane lipids. The evidence that this is the case is reviewed and amplified in this review, followed by an examination of the available physical data concerning phase transitions in lipid mixtures that mimic the mixture found in platelet membranes. Assuming complete mixing at all temperatures and equal contributions of the members of the mixture to the phase transition, the lipid mixture found in platelets should give values for Tm ranging from about 1 degrees C to about 16 degrees C, depending on the isomers present in the mixture. (The former value is not in agreement with the observed Tm, but the latter is in excellent agreement.) However, examination of the phase diagram for a binary pair of lipids found in platelet membranes shows that ideal mixing almost certainly does not occur; instead of a linear phase diagram, a convex one was obtained. This shape for the phase diagram, which would displace Tm to an unexpectedly elevated temperature, is in agreement with previously published phase diagrams for mixtures of this type. The prediction, based on thermodynamic properties of lipids found in the platelets, is that Tm will be displaced upward in more complex mixtures of the composition found in platelets, a prediction that requires experimental testing.

Blood Platelets↗
PubMed1999

A catalytic mechanism for caspase-1 and for bimodal inhibition of caspase-1 by activated aspartic ketones.

We have evaluated 619 aspartic ketones with 9 different types of prime-side groups (acyloxymethyl, aryloxymethyl, arylthiomethyl, alkylthiomethyl, acylamino-oxymethyl, sulfonylaminomethyl, alpha-ketoamide, alpha-(1-phenyl-3-trifluoromethyl-pyrazol-5-yl)oxymethyl (PTP), and aliphatic ketones) as inhibitors of caspase-1. The inhibitory behaviors could be classified as reversible, inactivating, or bimodal (i.e. reversible inhibition followed by slow inactivation) based on the kinetically observed formation of reversible thiohemiketal complexes and conversion to an irreversible thioether adduct, and the mechanism of any given ketone was only poorly predictable on the basis of leaving group structure and chemistry. Among 201 bimodal inhibitors, the rate of conversion of the reversible thiohemiketal complex to the inactive thioether (k(i)) was strictly first-order, consistent with direct conversion of the thiohemiketal to the thioether with no intermediate collapse to free ketone and thiolate. We have examined 22 crystallographic structures of caspase-1 complexed as a thiohemiketal with the inhibitors from 8 different ketone classes, and found the Cys285S-C-C(alpha)-leaving group dihedral angle to be near either to 60 degrees or to 180 degrees. Only the 180 degrees conformation was permissive for SN2 displacement of the leaving group and, furthermore, positioned His237Ndelta to stabilize developing charge on the leaving group. Among these structures and 19 additional complexes, all showed a strong interaction between His237Ndelta and the ketone or thiohemiketal oxygen. We therefore propose a proteolytic mechanism for caspase-1 involving polarization of the scissile carbonyl by the His237 imidazolium group. During thiohemiketal/thioether conversion (but probably not during peptide hydrolysis), the leaving group is stabilized by the His237 imidazolium.

Caspase 1↗