Biomedical subjects
D Evans
Publications and source records attributed to D Evans.
In that case: two-year-old Sarah is admitted to the paediatric ward with acute myeloblastic leukaemia. Commentary.
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Core beliefs and abortion attitudes: a look at Latinos.
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The complete DNA sequence of myxoma virus.
Myxomatosis in European rabbits is a severely debilitating disease characterized by profound systemic cellular immunosuppression and a high rate of mortality. The causative agent, myxoma virus, is a member of the poxvirus family and prototype of the Leporipoxvirus genus. As a major step toward defining the genetic strategies by which the virus circumvents host antiviral responses, the genomic DNA sequence of myxoma virus, strain Lausanne, was determined. A total of 171 open reading frames were assigned to cover the 161.8-kb genome, including two copies each of the 12 genes that map within the 11.5-kb terminal inverted repeats. Database searches revealed a central core of approximately 120 kb that encodes more than 100 genes that exhibit close relationships to the conserved genes of members of other poxvirus genera. Open reading frames with predicted signal sequences, localization motifs, or homology to known proteins with immunomodulatory or host-range functions were examined more extensively for predicted features such as hydrophobic regions, nucleic acid binding domains, ankyrin repeats, serpin signatures, lectin domains. and structural cysteine spacings. As a result, several novel, potentially immunomodulatory proteins have been identified, including a family with multiple ankyrin-repeat domains, an OX-2 like member of the neural cell adhesion molecule family, a third myxoma serpin, a putative chemokine receptor fragment, two natural killer receptor-like species, and a variety of species with domains closely related to diverse host immune regulatory proteins. Coupled with the genomic sequencing of the related leporipoxvirus Shope fibroma virus, this work affirms the existence of a conserved complement of poxvirus-specific core genes and expands the growing repertoire of virus genes that confer the unique capacity of each poxvirus family member to counter the immune responses of the infected host.
TeV Observations of Markarian 501 with the Milagrito Water Cerenkov Detector.
The Milagrito water Cerenkov detector near Los Alamos, New Mexico, was operated as a sky monitor at energies of a few TeV between 1997 February and 1998 May, including the period of the strong, long-lasting 1997 flare of Markarian 501. Milagrito served as a test run for the full Milagro detector. An event excess with a significance of 3.7 sigma from Markarian 501 was observed, in agreement with expectations.
Half of Saccharomyces cerevisiae carbamoyl phosphate synthetase produces and channels carbamoyl phosphate to the fused aspartate transcarbamoylase domain.
The first two steps of the de novo pyrimidine biosynthetic pathway in Saccharomyces cerevisiae are catalyzed by a 240-kDa bifunctional protein encoded by the ura2 locus. Although the constituent enzymes, carbamoyl phosphate synthetase (CPSase) and aspartate transcarbamoylase (ATCase) function independently, there are interdomain interactions uniquely associated with the multifunctional protein. Both CPSase and ATCase are feedback inhibited by UTP. Moreover, the intermediate carbamoyl phosphate is channeled from the CPSase domain where it is synthesized to the ATCase domain where it is used in the synthesis of carbamoyl aspartate. To better understand these processes, a recombinant plasmid was constructed that encoded a protein lacking the amidotransferase domain and the amino half of the CPSase domain, a 100-kDa chain segment. The truncated complex consisted of the carboxyl half of the CPSase domain fused to the ATCase domain via the pDHO domain, an inactive dihydroorotase homologue that bridges the two functional domains in the native molecule. Not only was the "half CPSase" catalytically active, but it was regulated by UTP to the same extent as the parent molecule. In contrast, the ATCase domain was no longer sensitive to the nucleotide, suggesting that the two catalytic activities are controlled by distinct mechanisms. Most remarkably, isotope dilution and transient time measurements showed that the truncated complex channels carbamoyl phosphate. The overall CPSase-ATCase reaction is much less sensitive than the parent molecule to the ATCase bisubstrate analogue, N-phosphonacetyl-L-aspartate (PALA), providing evidence that the endogenously produced carbamoyl phosphate is sequestered and channeled to the ATCase active site.
Ethical viewpoint.
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The privatised water industry and public health: back to square one.
No real progress has taken place in implementing new water fluoridation schemes within the UK since the ownership of most water companies passed into the private sector. A recent High Court judgement has confirmed that English water companies have absolute and unfettered discretion in deciding not to proceed with any new fluoridation schemes. Current legislation must be changed if this important public health measure is to be extended to benefit a greater number of people.
Sedation is not the only answer.
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The Bone Tie. A new device for interfragmentary fixation.
A new method of bone fixation is described, using a small stainless steel device to provide compression between fragments with a single drill hole. The Bone Tie uses an old architectural principle to hold bone fragments together with minimal surgical dissection for access. The technique has been used in 14 cases, and the results are presented. In ten cases the outcome was good. Complications were encountered in four, mostly through technical error, although the final outcomes were acceptable.
The impact of a quasi-market on sexually transmitted disease services in the UK.
This article reports the results of a study of the impact of quasi-market reforms on sexually transmitted disease (STD) services in one UK health region. An internal or quasi-market was introduced into UK health care in the 1991 reforms of the National Health Service (NHS). Health authorities (HAs) and general practitioner fundholders were given major new responsibilities for purchasing (later called commissioning) health services. The NHS quasi-market was designed to address recurrent difficulties in acute health services by promoting efficiency and consumer choice. The arrangements for commissioning STD services are important because these diseases are major threats to public health and HAs face a number of constraints in bringing about service changes through market mechanisms. In the UK, STD services are provided on a self-referral and confidential basis; patients experience STDs as stigmatizing and often have low expectations of service and little desire for involvement in commissioning decisions. HAs have only limited routine intelligence about STD services and little or no choice of local providers. This study adopted a qualitative case-study approach to examine HA commissioning of STD services. The study found that the introduction of the NHS quasi-market did not equip HAs with mechanisms for bringing about change in STD service provision or STD-related health outcomes. The findings are consistent with other recent studies of HA commissioning and provide further cumulative evidence of the limits to HA leverage in the NHS quasi-market. The study concludes that the commissioning of STD services is likely to remain a low priority in the new NHS structures based on primary care groups.
Analysis of the neurotrophic effects of GPI-1046 on neuron survival and regeneration in culture and in vivo.
The putative neurotrophic effects of the immunophilin ligand GPI-1046 were evaluated in established experimental systems of neuron survival and axon growth in vitro and in vivo. GPI-1046 marginally increased neurite outgrowth of chick dorsal root ganglia in culture under conditions where a very robust effect of nerve growth factor was seen. GPI-1046 failed to protect dopaminergic neurons from 1-methyl-4-phenylpyridinium in culture or to protect cultured cortical neurons from experimentally induced apoptosis in vitro. In adult rats in vivo, daily administration of GPI-1046 (10 mg/kg, s.c.) for three days enhanced the maximal regeneration distance of both motor and large myelinated sensory axons measured using an electrophysiological assay. However, detailed morphometric analysis of these animals failed to provide evidence for an increase in axon numbers in GPI-1046-treated animals. The ability of GPI-1046 to promote the recovery of dopaminergic function following unilateral 6-hydroxydopamine lesions of the substantia nigra was also tested in rats. In the first study, the duration of amphetamine (3 mg/kg, s.c.)-induced circling, but not the maximal number of rotations, was significantly reduced in animals treated with GPI-1046 for five days (10 mg/kg/day). In a second study, testing the effects of delayed GPI-1046 administration, chronic treatment with GPI-1046 (10 mg/kg/day) for two weeks, beginning one month after surgery, did not alter circling responses. Morphometric analysis failed to reveal any changes in either the density of tyrosine hyroxylase-positive fibres in dopaminergic target areas or in cell numbers in the substantia nigra in both experiments. Thus, while GPI-1046 produced marginal effects on neurite outgrowth in dorsal root ganglia cultures and on functional paramaters of nerve regeneration in vivo, we failed to obtain evidence in support of the notion of a general neuroprotective effect of the compound or for an effect on morphologic nerve regeneration in vivo.
Effect of material deprivation on Epstein-Barr virus infection in Hodgkin's disease in the West Midlands.
We have used Townsend scores from postcode data to compare levels of material deprivation and Epstein-Barr virus (EBV)-positivity for 223 patients diagnosed with Hodgkin's disease (HD) in the period 1981-1997. The presence of EBV in HD tumours was determined using in situ hybridization to target the abundantly expressed EBV early RNAs. EBV was detected in the malignant Hodgkin and Reed-Sternberg cells in 47/223 HD cases (21%). There was found to be a tendency for higher Townsend scores (indicative of higher levels of material deprivation) in EBV-positive HD patients, but this association was not statistically significant. When various subgroups of patients from the study were examined separately the indication of higher Townsend scores in EBV-positive patients was found to be more marked for patients with mixed cellularity disease (P = 0.09) and for females (P = 0.03). The results of this study suggest that differences in the level of material deprivation are important in determining the likelihood of EBV-positive HD in the UK, particularly for certain subgroups of patients. It is not known what specific socioeconomic factors are responsible for these differences, although alterations in the timing or rate of primary EBV infection, or decline in the level of EBV-specific immunity, may be important.
Lack of association between a human beta-2 adrenoceptor gene polymorphism (gln27glu) and morbid obesity.
OBJECTIVE: To determine the frequency of the gln27glu polymorphism in the beta-2 adrenoceptor gene in patients with morbid obesity. SUBJECTS: 243 patients with morbid obesity (mean body mass index 51. 6) and 199 healthy blood donors. RESULTS: The same frequency, 0.42, of the glu allele was observed in both groups. Neither the incidence in obese women (0.41, n=197) compared to control women (0.43, n=61), nor that in obese men (0.44, n=46) compared to control men (0.41, n=138) was significantly different. The difference in frequency between obese men and women, 0.44 vs 0.41 was not significant (P=0. 68). Genotype information from the families of 18 of the obese patients showed no association between the glu27 allele and BMI. CONCLUSIONS: We find no evidence for a role of the glu27 variant in the beta-2 adrenoceptor gene in the development of morbid obesity.
Neutrophil hypersegmentation in iron deficiency anaemia: a case-control study.
Neutrophil hypersegmentation (NH) is an important haematological feature of cobalamin or folate deficiency. As iron deficiency and folate deficiency often occur in the same target groups it is important to establish whether iron deficiency alone is a cause of NH. We report a case-control study which addresses this issue. Two groups of hospital patients were studied. Group 1 comprised 50 patients with iron deficiency anaemia (IDA). Group II comprised 50 control age- and sex-matched patients who were haematologically normal without evidence of iron deficiency from the iron studies. Patients with other factors which could affect the degree of neutrophil segmentation (cobalamin/folate deficiency, renal failure, infection and drug exposures) were excluded from the study. A total of 10 000 neutrophils were examined, 100 from each patient. NH was defined as the presence of five or more five-lobed neutrophils per 100, or any neutrophils with six or more lobes. The results were as follows: IDA, mean neutrophil lobe count 3.36; number of patients with NH 31/50 (62%): controls, mean neutrophil lobe count 2.96, number of patients with NH 2/50 (4%). These differences were statistically significant. We conclude that NH is common in IDA. The mechanism whereby iron deficiency results in NH is not clear.
Vascular surgical society of great britain and ireland: transcranial doppler-directed dextran therapy in the prevention of postoperative carotid thrombosis
BACKGROUND: Evidence suggests that embolization precedes carotid thrombosis, a previously unpredictable event complicating 2-3 per cent of all carotid endarterectomies. It was hypothesized that dextran 40 therapy might prevent progression to complete thrombosis in high-risk patients. METHODS: Between October 1995 and July 1998, 400 consecutive patients were monitored following carotid endarterectomy using transcranial Doppler ultrasonography. Those with sustained embolization (more than 25 in 10 min) or those with emboli that distorted the middle cerebral artery waveform were commenced on an incremental dextran 40 infusion. RESULTS: Two hundred and sixteen patients (54 per cent) had one or more emboli detected (96 per cent within 2 h of flow restoration) but only 15 (4 per cent) required dextran therapy. Embolization ceased in each case although the dextran dose had to be adjusted in four. In one of the latter patients, embolization recurred on day 5 but was again controlled with high-dose dextran. Overall, the death and any stroke rate was 2 per cent and no patient suffered a stroke due to carotid thrombosis. CONCLUSION: A few patients develop sustained embolization following carotid endarterectomy which, in previous studies, has been shown to be highly predictive of carotid thrombosis. The authors' experience to date suggests that dextran can stop this phase of embolization and prevent progression to complete carotid thrombosis. However, the dose of dextran has to be adjusted in 25 per cent of patients (i.e. blind administration of dextran may not be effective) and, very rarely, embolization may recur later.
Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N-domain of CD66 molecules.
The human pathogens Neisseria meningitidis and Neisseria gonorrhoeae express a family of variable outer membrane opacity-associated (Opa) proteins that recognize multiple human cell surface receptors. Most Opa proteins target the highly conserved N-terminal domain of the CD66 family of adhesion molecules, although a few also interact with heparan sulphate proteoglycans. In this study, we observed that at least two Opa proteins of a N. meningitidis strain C751 have the dual capacity to interact with both receptors. In addition, all three Opa proteins of C751 bind equally well to HeLa cells transfected with cDNA encoding the carcinoembryonic antigen [CEA (CD66e)] subgroup of the CD66 family, but show distinct tropism for CGM1- (CD66d) and NCA (CD66c)-expressing cells. Because the C751 Opa proteins make up distinct structures via the surface-exposed hypervariable domains (HV-1 and HV-2), these combinations appear to be involved in tropism for the distinct CD66 subgroups. To define the determinants of receptor recognition, we used mutant proteins of biliary glycoprotein [BGP (CD66a)] carrying substitutions at several predicted exposed sites in the N-domain and compared their interactions with several Opa proteins of both N. meningitidis and N. gonorrhoeae. The observations applied to the molecular model of the BGP N-domain that we constructed show that the binding of all Opa proteins tested occurs at the non-glycosylated (CFG) face of the molecule and, in general, appears to require Tyr-34 and Ile-91. Further, efficient interaction of distinct Opa proteins depends on different non-adjacent amino acids. In the three-dimensional model, these residues lie in close proximity to Tyr-34 and Ile-91 at the CFG face, making continuous binding domains (adhesiotopes). The epitope of the monoclonal antibody YTH71.3 that inhibits Opa/CD66 interactions was also identified within the Opa adhesiotopes on the N-domain. These studies define the molecular basis that directs the Opa specificity for the CD66 family and the rationale for tropism of the Opa proteins for the CD66 subgroups.