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Biomedical subjects

R A Scott

Publications and source records attributed to R A Scott.

At least 19 recordsLinked to original sources
PubMed2007

The impact of ACE genotype on serum ACE activity in a black South African male population.

The strong association between the angiotensin I-converting enzyme (ACE) gene I/D polymorphism with serum ACE activity appears lacking in Nigerians and Kenyans, but has not previously been well assessed in others of African origin. This study addressed this issue in an ethnically well defined black South African population. A putative association for the A22982G ACE gene variant, a QTL likely to impact on serum ACE activity, was also sought. Subjects were 200 healthy male black South African volunteers from the Xhosa ethnic group. Venous blood was obtained from all subjects for DNA extraction. ACE I/D and A22982G genotypes were determined and serum ACE activity measured. Age and blood pressure were recorded. For the group as a whole (mean +/- SD age 38.5 +/- 9.8 years, SBP 119.6 +/- 14.1 mmHg, DBP 78.2 +/- 10.1 mmHg) serum ACE activity was 38.2 +/- 11.2 nmol ml(-1)min(-1). ACE I/D genotype was not significantly associated with serum ACE activity. In contrast, the A22982G variant was significantly associated with serum ACE activity, being 35.9 +/- 9.6, 38.1 +/- 10.6 and 42.4 +/- 15.3 nmol ml(-1)min(-1) for AA, AG and GG genotypes respectively; p = 0.03 by ANOVA and p = 0.01 by linear trend. In keeping with the findings in some other African populations, the ACE I/D polymorphism is not strongly associated with serum ACE activity in Xhosa South Africans. As such, it cannot be used as a marker of ACE activity in these subjects. In this regard the use of the A22982G gene variant may be more appropriate.

Black People↗
PubMed2003

The treatment of epilepsy in developing countries: where do we go from here?

Epilepsy is the most common serious neurological disorder and is one of the world's most prevalent noncommunicable diseases. As the understanding of its physical and social burden has increased it has moved higher up the world health agenda. Over four-fifths of the 50 million people with epilepsy are thought to be in developing countries; much of this condition results from preventable causes. Around 90% of people with epilepsy in developing countries are not receiving appropriate treatment. Consequently, people with epilepsy continue to be stigmatized and have a lower quality of life than people with other chronic illnesses. However, bridging the treatment gap and reducing the burden of epilepsy is not straightforward and faces many constraints. Cultural attitudes, a lack of prioritization, poor health system infrastructure, and inadequate supplies of antiepileptic drugs all conspire to hinder appropriate treatment. Nevertheless, there have been successful attempts to provide treatment, which have shown the importance of community-based approaches and also indicate that provision for sustained intervention over the long term is necessary in any treatment programme. Approaches being adopted in the demonstration projects of the Global Campaign Against Epilepsy--implemented by the International League Against Epilepsy, the International Bureau for Epilepsy, and the World Health Organization--may provide further advances. Much remains to be done but it is hoped that current efforts will lead to better treatment of people with epilepsy in developing countries.

Anticonvulsants↗
PubMed2003

The prevalence and treatment gap in epilepsy in China: an ILAE/IBE/WHO study.

The authors carried out a door-to-door survey to determine the prevalence of epilepsy among 55,000 people in China. The lifetime prevalence was 7.0/1000, and 41% of all persons had never received appropriate treatment. The prevalence of active epilepsy was 4.6/1000, and 63% of people with active epilepsy had not received antiepileptic treatment in the week before the survey. Figures for the prevalence and the treatment gap were significantly higher than previous estimates.

Anticonvulsants↗
PubMed2003

Vitreous surgery in the management of chronic endogenous posterior uveitis.

OBJECTIVES: There is evidence that pars plana vitrectomy (PPV) has a beneficial effect on the clinical course of chronic endogenous posterior uveitis (EPU) possibly by physically removing any resident inflammatory cells with the vitreous. We assessed the anatomical and therapeutic effects of PPV performed on patients with chronic EPU for any indication. PATIENTS AND METHODS: Retrospective review of 41 eyes of 38 consecutive patients with EPU who underwent a PPV for any reason, over a 5-year period. The mean age of the patients was 36.2 years, 46% of the eyes had intermediate uveitis, 32% panuveitis, and 22% posterior uveitis. The visual acuity, disease activity, and the requirement for medications to control it were recorded for 12 months pre- and postoperatively. RESULTS: Overall, 61% of the eyes gained more than 2 Snellen lines (P<0.001) and the incidence of cystoid macular oedema (CMO) significantly reduced from 44 to 20% (P<0.05). Postoperatively, there was a significant decrease in the recurrence rate of intermediate uveitis, posterior uveitis, and panuveitis (P<0.001). The use of systemic and local depot immunosuppressive agents did not change over the study period, although the use of topical agents increased (P<0.05). CONCLUSION: PPV appears to have a beneficial effect on the clinical course of EPU in selected cases. This may be mediated by the physical clearance of inflammatory debris, the anti-inflammatory effect of replacing vitreous by aqueous humour, by a reduction of CMO and/or the anatomical correction of sight-threatening retinal pathology.

Adolescent↗
PubMed2001

Structural evidence that the methionyl aminopeptidase from Escherichia coli is a mononuclear metalloprotease.

The Co and Fe K-edge extended X-ray absorption fine structure (EXAFS) spectra of the methionyl aminopeptidase from Escherichia coli (EcMetAP) have been recorded in the presence of 1 and 2 equiv of either Co(II) or Fe(II) (i.e., [Co(II)_(EcMetAP)], [Co(II)Co(II)(EcMetAP)], [Fe(II)_(EcMetAP)], and [Fe(II)Fe(II)(EcMetAP)]). The Fourier transformed data of both [Co(II)_(EcMetAP)] and [Co(II)Co(II)(EcMetAP)] are dominated by a peak at ca. 2.05 A, which can be fit assuming 5 light atom (N,O) scatterers at 2.04 A. Attempts to include a Co-Co interaction (in the 2.4-4.0 A range) in the curve-fitting parameters were unsuccessful. Inclusion of multiple-scattering contributions from the outer-shell atoms of a histidine-imidazole ring resulted in reasonable Debye-Waller factors for these contributions and a slight reduction in the goodness-of-fit value (f '). These data suggest that a dinuclear Co(II) center does not exist in EcMetAP and that the first Co atom is located in the histidine-ligated side of the active site. The EXAFS data obtained for [Fe(II)_(EcMetAP)] and [Fe(II)Fe(II)(EcMetAP)] indicate that Fe(II) binds to EcMetAP in a similar site to Co(II). Since no X-ray crystallographic data are available for any Fe(II)-substituted EcMetAP enzyme, these data provide the first glimpse at the Fe(II) active site of MetAP enzymes. In addition, the EXAFS data for [Co(II)Co(II)(EcMetAP)] incubated with the antiangiogenesis drug fumagillin are also presented.

Absorptiometry, Photon↗
PubMed2001

Spectroscopic properties of the metalloregulatory Cd(II) and Pb(II) sites of S. aureus pI258 CadC.

Staphylococcus aureus pI258 CadC is an extrachromosomally encoded metalloregulatory repressor protein from the ArsR superfamily which negatively regulates the expression of the cad operon in a metal-dependent fashion. The metalloregulatory hypothesis holds that direct binding of thiophilic divalent cations including Cd(II), Pb(II), and Zn(II) by CadC allosterically regulates the DNA binding activity of CadC to the cad operator/promoter (O/P). This report presents a detailed characterization of the metal binding and DNA binding properties of wild-type CadC. The results of analytical ultracentrifugation experiments suggest that both apo- and Cd(1)-CadC are stable or weakly dissociable homodimers characterized by a K(dimer) = 3.0 x 10(6) M(-1) (pH 7.0, 0.20 M NaCl, 25.0 degrees C) with little detectable effect of Cd(II) on the dimerization equilibrium. As determined by optical spectroscopy, the stoichiometry of Cd(II) and Pb(II) binding is approximately 0.7-0.8 mol/mol of wild-type CadC monomer. Chelator (EDTA) competition binding isotherms reveal that Cd(II) binds very tightly, with K(Cd) = 4.3 (+/-1.8) x 10(12) M(-1). The results of UV-Vis and X-ray absorption spectroscopy of the Cd(1) complex are consistent with a tetrathiolate (S(4)) complex formed by four cysteine ligands. The (113)Cd NMR spectrum reveals a single resonance of delta = 622 ppm, consistent with an S(3)(N,O) or unusual upfield-shifted S(4) complex. The Pb(II) complex reveals two prominent absorption bands at 350 nm (epsilon = 4000 M(-1) cm(-1)) and 250 nm (epsilon = 41 000 M(-1) cm(-1)), spectral properties consistent with three or four thiolate ligands to the Pb(II) ion. The change in the anisotropy of a fluorescein-labeled oligonucleotide containing the cad O/P upon binding CadC and analyzed using a dissociable CadC dimer binding model reveals that apo-CadC forms a high-affinity complex [K(a) = (1.1 +/- 0.3) x 10(9) M(-1); pH 7.0, 0.40 M NaCl, 25 degrees C], the affinity of which is reduced approximately 300-fold upon the binding of a single molar equivalent of Cd(II) or Pb(II). The implications of these findings on the mechanism of metalloregulation are discussed.

Allosteric Regulation↗
PubMed2001

Expression, purification, and characterization of NosL, a novel Cu(I) protein of the nitrous oxide reductase (nos) gene cluster.

NosL, one of the accessory proteins of the nos (nitrous oxide reductase) gene cluster, has been heterologously expressed, purified, and characterized. NosL is a monomeric protein of 18,540 MW that specifically and stoichiometrically binds Cu(I). The copper ion in NosL is ligated by a Cys residue, and one Met and one His are thought to serve as the other ligands. While it is possible to oxidize Cu(I)-NosL with ferricyanide, the Cu(II) ion thus formed appears to dissociate from the protein. The function of Cu(I)NosL is not yet known, but the data indicate that NosL does not act as an electron transfer partner to nitrous oxide reductase. NosL is encoded on the same transcript as three other gene products (NosD, NosF, and NosY). These have been shown to be required for assembly of the active site in nitrous oxide reductase, which is thought to be a copper cluster. Accordingly, it is possible that NosL is a copper chaperone involved in metallocenter assembly.

Alcaligenes↗
PubMed2001

The treatment gap in epilepsy: the current situation and ways forward.

This article is a summary of a workshop held by the ILAE concerning the issue of the epilepsy treatment gap in developing countries. The gap is defined in terms of those people with epilepsy who are not being appropriately treated and is the result of an array of medical, political, social, economic, and cultural factors. The situation regarding the treatment gap for various countries is reviewed, along with some of its causes. Although the overall gap is estimated to be large, a number of recent projects and interventions have been effective in delivering appropriate treatment to people with epilepsy in underresourced countries of the developing world. It is hoped that these may be transferable elsewhere and that, combined with the ILAE/IBE/WHO Global Campaign against Epilepsy and increased support from the worldwide epilepsy community, the treatment gap will begin to be bridged.

Anticonvulsants↗
PubMed2001

The long-term benefits of a single scan for abdominal aortic aneurysm (AAA) at age 65.

AIM: To investigate the efficacy of a single ultrasonic scan at age 65 to identify patients at risk from ruptured abdominal aortic aneurysm (AAA). METHOD: A total of 6058 men aged 64-81 were recruited to a randomised trial, and 3000 were invited to attend a single screening test. An additional population of 1011 men was offered screening as they reached age 65. If a normal aorta was identified in this sub-group, further scans were offered at two-yearly intervals. Follow up and treatment of those identified as having an aortic dilatation of 3 cm or greater was undertaken. All subject groups were monitored for deaths occurring over the study period, and date and cause of death were recorded. RESULTS: A total of 2212 men attended screening in the randomised trial; the overall compliance was 74%, and prevalence of AAA was 7.7%. Compliance decreased, and prevalence increased, with age. Mortality from ruptured AAA was reduced by 68% at 5 years (screened group compared to the age-matched control population), and by 42% in the study arm (screened and refusers) compared with controls. The benefit persisted at ten years (53% and 21% respectively). Of the uncontrolled sample of 1011 men offered a scan at age 65, 681 attended and 649 of these were found to have a normal aortic diameter; re-screening demonstrated new aneurysm development in 4% over ten years. The aortic diameters of the new AAAs were under 4 cm and would therefore have a low risk of rupture.1 Mortality from rupture in all those with an initially normal aortic diameter was low, at 1 case per 1000 scans over ten years. CONCLUSION: Screening once for AAA at age 65 can identify the majority of AAA that are of clinical significance and can identify a large population at low risk from rupture who do not require surveillance. This policy has been effective when combined with selective treatment in reducing the risk of rupture for ten years in those who attend the screening programme.

Aged↗
PubMed2001

Serum elastin peptides in the preoperative evaluation of abdominal aortic aneurysms.

OBJECTIVE: Serum elastin peptides (SEP) have been reported to be associated with the expansion of small abdominal aortic aneurysms (AAA). Consequently, SEP-measurements may predict future rupture, and allow further selection for surgery in cases referred for surgery due to size. MATERIAL AND METHODS: SEP was measured in 90 men and 10 women with AAA, who were considered for surgery as part of the Chichester aneurysm screening programme. Sixty-one patients were electively operated and four because of symptoms. The rest were followed up further. Twelve of these experienced ruptured AAA later. RESULTS: No correlation between last measured AAA-diameter, annual expansion rate and SEP was noticed. However, SEP levels were significantly higher in cases rupturing later, persisting after adjustment for age, sex, and last measured AAA-size. ROC curve analysis concerning SEP as a predictor of rupture later showed an optimal sensitivity and specificity of 67% and 60%, respectively, similar with last measured AAA-size. By combining AAA-size and SEP, the optimal sensitivity and specificity reached 83% and 66%, respectively. CONCLUSION: One sampling of SEP combined with AAA-size in patients referred for AAA surgery may be a clinical useful indicator of high rupture risk.

Aged↗
PubMed2001

Indicators of infection with Chlamydia pneumoniae are associated with expansion of abdominal aortic aneurysms.

PURPOSE: Chlamydia Pneumoniae has been shown to be associated with atherosclerosis, myocardial infarction, and abdominal aortic aneurysms (AAAs). The possible association between AAA expansion and C pneumoniae infection was therefore assessed. METHODS: Blood samples were taken from patients with an AAA that was considered for surgical repair after having been diagnosed by means of the Chichester aneurysm screening program (UK) as having an initially infrarenal aortic diameter of 3.0 to 5.9 cm. The patients were examined prospectively for as long as 11.5 years (mean, 4.1 years) with ultrasound scanning. Of 110 patients considered for surgery, 90 men and 10 women had blood samples taken. Their IgG and IgA antibodies against C pneumoniae were measured by means of a microimmunofluorescence test. Unpaired t tests, multiple linear regression analyses, and logistic regression analyses were used for statistical analysis. RESULTS: A total of 44% (95% CI, 31%-55%) of the men with an AAA had an IgA titer of 64 or more, an IgG titer of 128 or more, or both, compared with 10% of the women with an AAA (OR = 7.2; 95% CI, 1.05-160.8). A titer of IgG of 128 or more was significantly associated with higher expansion (5.3 vs 2.6 mm per year), even after adjustment for initial AAA size and age. A significant positive correlation between both IgA and IgG titers and mean annual expansion was observed (r = 0.28; 95% CI, 0.05-0.49; and r = 0.45; 95% CI, 0.24-0.62, respectively), persisting after adjusting for initial AAA size and age. An IgG titer of 128 or more was present significantly more often in cases with an expansion greater than 1 cm annually (adjusted OR = 12.6; 95% CI, 1.37-293). CONCLUSION: A high proportion of men with an AAA has signs of infection with C pneumoniae. The progression of their AAAs was positively correlated with the presence of indicators of C pneumoniae infection.

Aged↗
PubMed2001

X-ray absorption spectroscopic analysis of the high-spin ferriheme site in substrate-bound neuronal nitric-oxide synthase.

Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to citrulline and nitric oxide through two stepwise oxygenation reactions involving N(omega)-hydroxy-L-arginine, an enzyme-bound intermediate. The N(omega)-hydroxy-L-arginine- and arginine-bound NOS ferriheme centers show distinct, high-spin electron paramagnetic resonance signals. Iron X-ray absorption spectroscopy (XAS) has been used to examine the structure of the ferriheme site in the N(omega)-hydroxy-L-arginine-bound full-length neuronal NOS in the presence of (6R)-5,6,7,8-tetrahydro-L-biopterin. Iron XAS shows that the high-spin ferriheme sites in the N(omega)-hydroxy-L-arginine- and arginine-bound forms are strikingly similar, both being coordinated by the heme and an axial thiolate ligand, with an Fe-S distance of ca. 2.29 A. Cu(2+) inhibition slightly affects the spin-state equilibrium, but causes no XAS-detectable changes in the immediate ferriheme coordination environment of neuronal NOS. The structure and ligand geometry of the high-spin ferriheme in arginine-bound neuronal NOS are essentially identical to those of the N(omega)-hydroxy-L-arginine-bound form and only slightly affected by the divalent cation inhibitor of constitutive NOS.

Animals↗
PubMed2001

The effect of pars plana vitrectomy in the management of Fuchs heterochromic cyclitis.

PURPOSE: Fuchs heterochromic cyclitis (FHC) is characterized by a unilateral chronic iridocyclitis of insidious onset and uncertain cause. Our aim was to evaluate the effect of vitreous surgery in patients with FHC and clinically significant visual symptoms caused by inflammatory vitreous debris. METHODS: This study was a review of 12 eyes of 12 consecutive patients with FHC who underwent pars plana vitrectomy for visually significant vitreous opacities. Cataract extraction with posterior chamber lens implantation had been performed on four eyes preoperatively. Four eyes had a concomitant lensectomy for cataracts, and one had a surgical posterior capsulotomy. Visual and anatomic data were recorded before surgery and for at least 6 months after surgery. RESULTS: Visual acuity improved in all patients from an average logMAR of 0.57 to 0.007 (P = 0.0004) and by more than 2 Snellen lines in 8 of 12 of the eyes (P < 0.05). Symptoms of floaters resolved in all 11 patients in whom they were a symptom. Vitreous haze was cleared completely from an average Nussenblatt grade of 1.7 to 0 after 1 week (P = 0.0001). CONCLUSIONS: Pars plana vitrectomy is a safe and effective treatment for the visual symptoms associated with FHC and can be combined safely with a lensectomy if required.

Adult↗
PubMed2000

Direct FeS cluster involvement in generation of a radical in lysine 2,3-aminomutase.

Lysine 2,3-aminomutase (KAM) belongs to a class of enzymes that use FeS clusters and S-adenosyl-L-methionine to initiate radical-dependent chemistry. Selenium K-edge X-ray absorption spectroscopic analysis of KAM poised at various stages of catalysis, in the presence of selenomethionine or Se-adenosyl-L-selenomethionine, reveals that the cofactor is cleaved only in the presence of dithionite and the substrate analogue trans-4,5-dehydrolysine. A new Fourier transform peak at 2.7 A, assigned as a Se-Fe interaction, appears concomitant with this cleavage. This is the first demonstration of a direct interaction of S-adenosyl-L-methionine, or its cleavage products, with the FeS cluster in this class of enzymes.

Deoxyadenosines↗
PubMed2000

The zinc metalloregulatory protein Synechococcus PCC7942 SmtB binds a single zinc ion per monomer with high affinity in a tetrahedral coordination geometry.

The Synechococcus PCC7942 SmtB is a zinc-responsive transcriptional repressor and a member of the ArsR superfamily of prokaryotic metalloregulatory transcription factors. The mechanism of negative regulation by Zn(II) and other metals as well as the coordination chemistry (stoichiometry, affinity, and specificity) of SmtB is poorly understood. In contrast to previous results [Kar, S. R., Adams, A. C., Lebowitz, J., Taylor, K. B., and Hall, L. M. (1997) Biochemistry 36, 15343-15348], we find that fully reduced SmtB binds 1 mol equiv of Zn(II) with a very high affinity, K(Zn) in excess of 10(11) M(-1) (pH 7.4, 0.15 M KCl, 22 degrees C). Optical spectroscopic experiments reveal that SmtB binds 1 mol equiv of Co(II) in a tetrahedral or distorted tetrahedral environment with one or two cysteine thiolate ligands in the first coordination shell. Zn(II) and Co(II) EXAFS studies are consistent with the optical spectroscopic data, and further suggest the presence of a mixture of carboxylate and imidazole-containing ligands. K(Co) was determined to be 1.7 (+/-0.1) x 10(9) M(-1) in a chelator (EGTA) competition assay; 1 equiv of Zn(II) results in complete displacement of the bound Co(II). SmtB also binds 1 mol equiv of Ni(II), which, when formed at low Ni(II):SmtB molar ratios, adopts a non-native, six-coordinate complex characterized by at least two histidine and no thiolate ligands. The hierarchy of metal binding affinities is Zn(II) >> Co(II) >> Ni(II).

Bacterial Proteins↗
PubMed2000

Spectroscopic investigation of selective cluster conversion of archaeal zinc-containing ferredoxin from Sulfolobus sp. strain 7.

Archaeal zinc-containing ferredoxin from Sulfolobus sp. strain 7 contains one [3Fe-4S] cluster (cluster I), one [4Fe-4S] cluster (cluster II), and one isolated zinc center. Oxidative degradation of this ferredoxin led to the formation of a stable intermediate with 1 zinc and approximately 6 iron atoms. The metal centers of this intermediate were analyzed by electron paramagnetic resonance (EPR), low temperature resonance Raman, x-ray absorption, and (1)H NMR spectroscopies. The spectroscopic data suggest that (i) cluster II was selectively converted to a cubane [3Fe-4S](1+) cluster in the intermediate, without forming a stable radical species, and that (ii) the local metric environments of cluster I and the isolated zinc site did not change significantly in the intermediate. It is concluded that the initial step of oxidative degradation of the archaeal zinc-containing ferredoxin is selective conversion of cluster II, generating a novel intermediate containing two [3Fe-4S] clusters and an isolated zinc center. At this stage, significant structural rearrangement of the protein does not occur. We propose a new scheme for oxidative degradation of dicluster ferredoxins in which each cluster converts in a stepwise manner, prior to apoprotein formation, and discuss its structural and evolutionary implications.

Chromatography, Agarose↗