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Biomedical subjects

S Cox

Publications and source records attributed to S Cox.

At least 55 records · Page 3Linked to original sources
PubMed2000

Oral cancer in Australia--risk factors and disease distribution.

There are approximately 2500 new cases of oral and pharyngeal cancer registered in Australia each year (Australian Institute of Health and Welfare). The life-time risk of developing oral cancer is approximately 1 in 90 for men and 1 in 200 for women (NHMRC 1996). In common with that of other developed countries, the incidence of oral and pharyngeal cancer in NSW showed a disturbing increase in recent decades although it has now levelled off, affecting primarily middle-aged men, (45-49 years). The highest incidence rates for males were in the western half of the State of New South Wales, sections of the Central Coast and in the inner and eastern suburbs of Sydney. Oral cancer accounts for up to 40% of all malignancies in parts of India and South East Asia. Recognized aetiological agents for oral cancer include tobacco, alcohol and use of the areca nut. The incidence of oral cancer amongst immigrant communities is examined. The easy availability of the areca nut and chewing tobacco in Australia suggests that there is a significant group at risk of developing oral cancer.

Age Factors↗
PubMed1999

600 ps molecular dynamics reveals stable substructures and flexible hinge points in cAMP dependent protein kinase.

Molecular dynamics simulations of the catalytic subunit of cAMP dependent protein kinase (cAPK) have been performed in an aqueous environment. The relations among the protein hydrogen-bonding network, secondary structural elements, and the internal motions of rigid domains were examined. The values of fluctuations of protein dihedral angles during dynamics show quite distinct maxima in the regions of loops and minima in the regions of alpha-helices and beta-strands. Analyses of conformation snapshots throughout the run show stable subdomains and indicate that these rigid domains are constrained during the dynamics by a stable network of hydrogen bonds. The most stable subdomain during the dynamics was in the small lobe including part of the carboxy-terminal tail. The most significant flexible region was the highly conserved glycine-rich loop between beta strands 1 and 2 in the small lobe. Many of the main chain dihedral angle changes measured in a comparison of the crystallographic structures of "open" and "closed" conformations of cAPK correspond to the highly flexible residues found during dynamics.

Animals↗
PubMed1999

Dissection of the nucleotide and metal-phosphate binding sites in cAMP-dependent protein kinase.

The catalytic (C) subunit of cAMP-dependent protein kinase (cAPK) is more stable by several criteria when it is part of a holoenzyme complex. By measuring the thermal stability of the free C subunit in the presence and absence of nucleotides and/or divalent metal ions, it was found that most of the stabilizing effects associated with the type I holoenzyme could be attributed to the nucleotide. The specific requirements for this enhanced stability were further dissected: Adenosine stabilized the C subunit up to 5 degrees C; however, divalent cations (i.e., Mg2+, Ca2+, and Mn2+) do not increase heat stability in combination with adenosine and adenine (1). Divalent cations as well as ATP and ADP have no effect by themselves (2). The enhanced stability derived from both ATP and ADP requires divalent cations. MnATP (12 degrees C) shows a much stronger effect than CaATP (7 degrees C) and MgATP (5 degrees C) (3). In the holoenzyme complex or the protein kinase inhibitor/C subunit complex, metal/ATP is also required for enhanced stability; neither the RI or RII subunits nor PKI alone stabilize the C subunit significantly (4). For high thermal stability, the occupation of the second, low-affinity metal-binding site is necessary (5). From these results, we concluded that the adenine moiety works independently from the metal-binding sites, stabilizing the free C subunit by itself. When the beta- and gamma-phosphates are present, divalent metals are required for positioning these phosphates, and two metals are required to achieve thermostability comparable to adenosine alone. The complex containing two metals is the most stable. A comparison of several conformations of the C subunit derived from different crystal structures is given attributing open and closed forms of the C subunit to less and more thermostable enzymes, respectively.

Binding Sites↗
PubMed1999

Percutaneous revascularization of atherosclerotic obstruction of aortic arch vessels.

OBJECTIVES: To compare stenting of aortic arch vessel obstruction with surgical therapy and to establish recommendations for treatment. BACKGROUND: Though surgery has been considered to be the procedure of choice for subclavian and brachiocephalic obstruction, little work has been done to compare it with stenting. METHODS: Eighteen patients with symptomatic aortic arch vessel stenosis or occlusion were treated with stenting, followed by periodic clinical follow-up and noninvasive arterial Doppler studies. Data were compared with the results as shown in a systematic review of a published series of surgery and stenting procedures which included comparison of technical success, complications, mortality and patency. RESULTS: Primary success in our series was 100% with improvement in mean stenosis from 84+/-11% to 1+/-5% and mean arm systolic blood pressure difference from 44+/-16 mm Hg to 3+/-3 mm Hg. There were no major complications (death, stroke, TIA, stent thrombosis or myocardial infarction). At follow-up (mean 17 months), all patients were asymptomatic with 100% primary patency. Literature review demonstrates equivalent patency and complications in the other published series of stenting. In contrast, there was a similar patency but overall incidence of stroke of 3+/-4% and death of 2+/-2% in the published surgical series. CONCLUSIONS: Subclavian or brachiocephalic artery obstruction can be effectively treated by primary stenting or surgery. Comparison of stenting and the surgical experience demonstrates equal effectiveness but fewer complications and suggests that stenting should be considered as first line therapy for subclavian or brachiocephalic obstruction.

Aged↗
PubMed1999

Prevalence of herpes simplex virus types 1 and 2, cytomegalovirus, and varicella-zoster virus infections in Eritrea.

BACKGROUND: Herpesviruses establish latent infections in their hosts for life. The scarcity of data that exists in regard to herpesvirus infections in many African regions, could partly be due to the mild nature of their primary infections and the lack of means for their proper diagnosis. However, in recent decades the alarming spread of HIV infection in Africa and associated frequent reactivation of herpesvirus infections is leaving less room for neglect. This seroprevalence study is intended to help in the evaluation of the prevalence of herpesvirus infections in Eritrea. OBJECTIVE: To evaluate the spread of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), and varicella-zoster virus (VZV) infections. STUDY DESIGN: The study population groups comprise female sex workers (FSW), former guerrilla fighters, truck drivers, port workers, a tribe called Rashaida, pregnant women, children under 5 years of age, and children over 5 years of age. The groups of pregnant women and children under and over 5 years of age were included to form a background for the evaluation of groups considered at risk for sexually transmitted or blood borne infections. RESULTS: All study groups had a high seroprevalence of HSV-1 infections ( > 80%), except for the children under 5 years of age. The FSW had the highest prevalence of HSV-2 infections, 80%, followed by guerrilla fighters, truck drivers, port workers, pregnant women, children, and the Rashaidas. Positivity for antibodies against CMV was > 90% in all studied populations. The prevalence of VZV infections was surprisingly low in the tribe of Rashaida, 44% compared to more than 90% in the other adult groups tested for VZV (P = 0.0001). CONCLUSION: The study shows that the prevalence of HSV-2 in the risk group of FSW was high, which could partly be explained by their sexual behaviours. HSV-2 was particularly low in the Rashaida group and, as expected, in the children. The low prevalence of VZV observed in the Rashaida is of importance since it makes them vulnerable to infection with varicella during their inevitable integration with the other tribes in their society.

Adult↗
PubMed1999

Estimating the prevalence of problem drug use in inner London: a discussion of three capture-recapture studies.

AIMS: To provide an evidence base of estimates of the prevalence of problem drug use in inner London. DESIGN: Re-analysis of three capture-recapture studies using subjects aged 15-49 years, that aim to estimate the hidden population from analysing the overlaps between three data sources. SETTING: Newham (1995) Camden and Islington (C&I) (1993/4) and Lambeth, Southwark and Lewisham (LSL) (1992). PARTICIPANTS: Each study collected data from three sources of problem drug users including: the Regional Drug Misuse Database, specialist drug agencies, HIV tests, social services, police arrests and court records. In LSL opiate users were analysed separately. The studies identified 1832 individuals in LSL, 543 in Newham, and 1321 in C&I. MEASUREMENTS: Poisson models were fitted to the data testing different interactions between the data sources representing potential dependencies. The simplest model was selected on the basis of its AIC score and log-likelihood ratio tests. FINDINGS: The number of hidden problem drug users were estimated to be 12,500 (95% CI 9600-16,100) in LSL with 4400 (3200-6100) opiate users; 7000 (5000-10,000) in C&I and 3800 (2000-7200) in Newham. The prevalence of problem drug use in those aged 15-49 was estimated to be 3.1% (2.5-3.9%) in LSL with 1.3% (1.0-1.6%) opiate users; and 3.6% (2.7-4.9%) and 3.3% (1.9-5.7%) in C&I and Newham, respectively. CONCLUSIONS: Despite the inherent problems with capture-recapture methods, our three studies establish an evidence base for estimates of problem drug use in London. It is important that a larger study is carried out in London.

Adolescent↗
PubMed1999

Improving the repeat prescribing process in a busy general practice. A study using continuous quality improvement methodology.

PROBLEM: A need to improve service to patients by reducing the time wasted by reception staff so that the 48 hour target for processing repeat prescription requests for patient collection could be achieved. DESIGN: An interprofessional team was established within the practice to tackle the area of repeat prescribing which had been identified as a priority by practice reception staff. The team met four times in three months and used continuous quality improvement (CQI) methodology (including the Plan-Do-Study-Act cycle) with the assistance of an external facilitator. BACKGROUND AND SETTING: A seven partner practice serving the 14,000 patients on the northern outskirts of Bournemouth including a large council estate and a substantial student population from Bournemouth University. The repeat prescribing process is computerised. KEY MEASURES FOR IMPROVEMENT: Reducing turn around times for repeat prescription requests. Reducing numbers of requests which need medical records to be checked to issue the script. Feedback to staff about the working of the process. STRATEGIES FOR CHANGE: Using a Plan-Do-Study-Act cycle for guidance, the team decided to (a) coincide repeat medications and to record on the computer drugs prescribed during visits; (b) give signing of prescriptions a higher priority and bring them to doctors' desks at an agreed time; and (c) move the site for printing prescriptions to the reception desk so as to facilitate face to face queries. EFFECTS OF CHANGE: Prescription turnaround within 48 hours increased from 95% to 99% with reduced variability case to case and at a reduced cost. The number of prescriptions needing records to be looked at was reduced from 18% to 8.6%. This saved at least one working day of receptionist time each month. Feedback from all staff within the practice indicated greatly increased satisfaction with the newly designed process. LESSONS LEARNT: The team's experience suggests that a combination of audit and improvement methodology offers a powerful way to learn about, and improve, practice. The interventions used by the team not only produced measurable and sustainable improvements but also helped the team to learn about the cost of achieving the results and provided them with tools to accomplish the aims. The importance of feedback to all staff about CQI measures was also recognised.

Accounts Payable and Receivable↗
PubMed1999

An analysis of breastfeeding initiation in Tasmania by demographic and socioeconomic factors for the period 1981-1995.

Breastfeeding initiation and duration trend data is an important component of infant health and nutrition monitoring and surveillance systems. It is also an important basis for identifying breastfeeding promotion needs, prioritising target groups and strategies and in evaluating the effectiveness of breastfeeding promotion efforts. A collation and analysis of available Tasmanian breastfeeding initiation data was undertaken in order to help direct statewide breastfeeding promotion planning and evaluation and to begin the development of a minimum data set for statewide breastfeeding monitoring and surveillance. Perinatally collected breastfeeding initiation data (breastfeeding at discharge from hospital) was analysed against available demographic and socioeconomic variables and compared with initiation rates from interstate Australian populations. Data suggest that breastfeeding initiation rates in Tasmania have been static over the 15 years to 1995 (a three percent increase from 1981 to 1995) and that the associations between breastfeeding initiation and occupational classification, maternal age and parity in Tasmania are consistent with those reported elsewere. Whilst caution needs to be applied to between-population comparisons, breastfeeding initiation rates in Tasmania appear to be considerably lower than that reported in other states. This suggests relatively greater efforts are required to influence breastfeeding initiation. Further research is required to investigate reasons for this difference.

Adult↗
PubMed1998

Analysis of HIV-1 reverse transcriptase gene mutations in infected children treated with zidovudine.

Prolonged treatment with antiretroviral agents directed against reverse transcription (RT) in patients with HIV-1 infection results in the emergence of virus variants with reduced sensitivity containing mutations in the HIV-1 RT gene. Development of zidovudine (ZDV)-related mutations was studied in a cohort of 24 vertically infected pediatric patients receiving ZDV therapy. Monthly clinical and immunologic evaluation was accompanied by direct sequencing of the HIV-1 RT gene every 4 months. A correlation was observed between the emergence of mutations and the duration of therapy. Mutation at codon 41 was found only in the presence of mutation at codon 215. The presence of the mutations Met41-->Leu and Thr215-->Tyr/Phe did not appear to be related to disease progression. These findings suggest that the mere presence of mutations in the HIV-1 RT gene alone during ZDV monotherapy is not a reliable prognostic marker in the absence of other clinical and virologic information.

Anti-HIV Agents↗
PubMed1998

Backbone flexibility of five sites on the catalytic subunit of cAMP-dependent protein kinase in the open and closed conformations.

To develop an alternative approach to measure peptidyl backbone flexibility and to expand our understanding of the segmental flexibility of cAMP-dependent protein kinase (cAPK), the effect of protein kinase inhibitor peptide, PKIalpha(5-24), and MgATP on the mobility of fluorescein selectively conjugated to five sites on the catalytic subunit of cAPK was examined. Specifically, five full-length, single-site catalytic subunit mutants (K16C, K81C, I244C, C199A, and N326C) were prepared, and fluorescein maleimide was selectively attached to the side chains of each substituted cysteine or, in the case of the C199A mutant, to the unprotected native C343. The time-resolved anisotropy decay profiles of the five fluorescein maleimide-conjugated mutants were well fit to a biexponential equation. The fast rotational correlation times of the fluorescein conjugates ranged between 1.9 and 2.8 ns and were inversely correlated (r = -0.87) to the averaged crystallographic main-chain atom B factors around each site of conjugation. The slow correlation times ranged between 25 and 28 ns and were about the same magnitude as the value of 21 ns estimated from the Stokes-Einstein equation. The presence of MgATP and PKIalpha(5-24), which induces the closed conformation of cAPK, was associated with a reduction of the fast rotational correlation time of the K81C conjugate, indicating that the peptidyl backbone around K81 is measurably less flexible when the C subunit is in the closed compared with the open conformation. The results suggest (i) that time-resolved fluorescence anisotropy can assess the nanosecond flexibility of short segments of the peptidyl backbone around each site of labeling and (ii) that the substrate/pseudosubstrate binding differentially affects the backbone flexibility of cAPK.

Animals↗
PubMed1998

Conserved water molecules contribute to the extensive network of interactions at the active site of protein kinase A.

Protein kinases constitute a large family of regulatory enzymes, each with a distinct specificity to restrict its action to its physiological target(s) only. The catalytic (C) subunit of protein kinase A, regarded as a structural prototype for this family, is composed of a conserved core flanked by two nonconserved segments at the amino and carboxyl termini. Here we summarize evidence to show that (i) the active site consists of an extended network of interactions that weave together both domains of the core as well as both segments that flank the core; (ii) the opening and closing of the active site cleft, including the dynamic and coordinated movement of the carboxyl terminal tail, contributes directly to substrate recognition and catalysis; and (iii) in addition to peptide and ATP, the active site contains six structured water molecules that constitute a conserved structural element of the active site. One of these active-site conserved water molecules is locked into place by its interactions with the nucleotide, the peptide substrate/inhibitor, the small and large domains of the conserved core, and Tyr-330 from the carboxyl-terminal "tail."

Animals↗
PubMed1998

Drug susceptibility of subtypes A,B,C,D, and E human immunodeficiency virus type 1 primary isolates.

We determined the susceptibility to antiviral drugs of clinical isolates of human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C, D, and E. Isolates from treated and untreated patients were tested for sensitivity to zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), nevirapine (NVP), foscarnet (PFA), and ritonavir (RNV). The susceptibility to these different drugs was broadly similar between the different subtypes of HIV-1. Isolates of subtype D showed a tendency toward slightly lower susceptibility to all the antiviral drugs, which could be related to the rapid growth characteristics of these isolates.

Anti-HIV Agents↗
PubMed1998

Solid phase ELISA for determination of the virus dose dependent sensitivity of human cytomegalovirus to antiviral drugs in vitro.

The main problems in determining the true in vivo susceptibility of human cytomegalovirus (CMV) to antiviral compounds are the influence of the size of the viral inoculum, the variation in the replication capacity of different CMV strains and the subjective evaluation of the inhibition of viral growth in the plaque assay. In this study, a specific assay was developed which reproducibly determines the sensitivity of primary isolates of CMV. The assay includes simultaneous virus titration and determination of the antiviral sensitivity. When individual virus doses were evaluated, the IC50 was generally dependent on the virus dose, except for resistant isolates, where the IC50 did not change irrespective of the dose of virus. The novel method of IC50 calculation takes into account all values derived from the linear part of the inhibition curve. This may better reflect the in vivo conditions, where the antiviral drug encounters different amounts of virus in different organs. Two human fibroblast-derived cell lines showed similar results.

Antiviral Agents↗
PubMed1998

Prevalence of infection with HIV, hepatitis B and C viruses, in four high risk groups in Eritrea.

BACKGROUND: Little is known about the prevalence of infections in different population groups in Africa, and about the influence of living conditions on the spread of infections. This study is the first of its kind in the state of Eritrea and is expected to serve as an evaluation of the situation in the country. OBJECTIVE: A serosurvey for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) was carried out during the summer of 1995 in Massawa, a small sea port in Eritrea (East Africa) in four groups considered to be at risk for these infections. STUDY DESIGN: The study subjects were former Guerrilla Fighters, Female Sex Workers, Truck Drivers, and Port Workers. Participants from a tribe called Rashaida were believed to be at low risk, and thus served as a control. RESULTS: The Female Sex Workers had the highest incidence of HIV-1 infection, 29%, compared to 10% for Port Workers, and 3% for Guerrilla Fighters. On the other hand presence of HBsAg, indicating a high prevalence of hepatitis B carrier status, was highest in the Guerrilla Fighters, followed by the Rashaidas, and lowest in the Female Sex Workers. The Female Sex Workers were further tested for antibodies against HBV and the results revealed that 53% of them, 5%, had antibodies against HBcoreAg. Excluding the possibility of an acute infection at sampling time, three of them became HBsAg carriers. Surprisingly, our group of Truck Drivers did not show HIV-1 infection, and no HIV-2 infections were seen in the whole cohort. CONCLUSION: The study shows that the described groups have different prevalences of infection with HIV, hepatitis B and C which can partly be explained by their living conditions.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Pharmacokinetics and safety of tobramycin after once-daily administration in patients with cystic fibrosis.

STUDY OBJECTIVE: Tobramycin is commonly used to treat respiratory tract infections in patients with cystic fibrosis. We designed a study to determine the pharmacokinetics and safety of once-daily dosing of tobramycin in this population. DESIGN: Multiple blood samples were collected from each patient, and serum concentrations of tobramycin were determined by a fluorescence polarization immunoassay. Blood urea nitrogen and serum creatinine levels were measured every 2 to 3 days, and audiometric evaluations were performed at the start and end of therapy. MEASUREMENTS AND RESULTS: Eighteen patients (mean age, 24.6 years) received tobramycin at doses of 7 to 15 mg/kg/d as a single-dose infusion over 20 min. The maximum serum concentration of tobramycin ranged from 40.1 to 64.6 mg/L. A mean dose of 11.9+/-1.9 mg/kg was needed to obtain a theoretical mean peak serum concentration of 42.4+/-4.5 mg/L. The mean total body clearance, apparent volume of distribution, and elimination half-life was 1.7+/-0.4 mL/min/kg, 0.27+/-0.06 L/kg, and 1.8+/-0.3 h, respectively. The period of time that the serum concentration exceeded eight times the theoretical minimum inhibitory concentration of 1 mg/L ranged from 2.1 to 4.4 h, which was nearly five times longer compared with the use of divided daily doses in the same patients during previous hospitalizations. No nephrotoxicity, ototoxicity, or adverse effects occurred in any patient. CONCLUSION: Based on our data, tobramycin may be used safely in once-daily doses to treat exacerbations of respiratory tract infections in patients with cystic fibrosis.

Adolescent↗
PubMed1997

A binary complex of the catalytic subunit of cAMP-dependent protein kinase and adenosine further defines conformational flexibility.

BACKGROUND: cAMP-dependent protein kinase (cAPK), a ubiquitous protein in eukaryotic cells, is one of the simplest members of the protein kinase family. It was the first protein kinase to be crystallized and continues to serve as a biochemical and structural prototype for this family of enzymes. To further understand the conformational changes that occur in different liganded and unliganded states of cAPK, the catalytic subunit of cAPK was crystallized in the absence of peptide inhibitor. RESULTS: The crystal structure of the catalytic subunit of mouse recombinant cAPK (rC) complexed with adenosine was solved at 2.6 A resolution and refined to a crystallographic R factor of 21.9% with good stereochemical parameters. This is the first structure of the rC subunit that lacks a bound inhibitor or substrate peptide. The structure was solved by molecular replacement and comprises two lobes (large and small) which contain a number of conserved loops. CONCLUSIONS: The binary complex of rC and adenosine adopts an 'intermediate' conformation relative to the previously described 'closed' and 'open' conformations of other rC complexes. Based on a comparison of these structures, the induced fit that is necessary for catalysis and closing of the active-site cleft appears to be confined to the small lobe, as in the absence of the peptide the conformation of the large lobe, including the peptide-docking surface, does not change. Three specific components contribute to the closing of the cleft: rotation of the small lobe; movement of the C-terminal tail; and closing of the so-called glycine-rich loop. There is no induced fit in the large lobe to accommodate the peptide and the closing of the cleft. A portion of the C-terminal tail, residues 315-334, serves as a gate for the entry or exit of the nucleotide into the hydrophobic active-site cleft.

Adenosine↗
PubMed1997

Structure of poliovirus type 2 Lansing complexed with antiviral agent SCH48973: comparison of the structural and biological properties of three poliovirus serotypes.

BACKGROUND: Polioviruses are human pathogens and the causative agents of poliomyelitis. Polioviruses are icosahedral single-stranded RNA viruses, which belong to the picornavirus family, and occur as three distinct serotypes. All three serotypes of poliovirus can infect primates, but only type 2 can infect mice. The crystal structures of a type 1 and a type 3 poliovirus are already known. Structural studies of poliovirus type 2 Lansing (PV2L) were initiated to try to enhance our understanding of the differences in host range specificity, antigenicity and receptor binding among the three serotypes of poliovirus. RESULTS: The crystal structure of the mouse neurovirulent PV2L complexed with a potent antiviral agent, SCH48973, was determined at 2.9 A resolution. Structural differences among the three poliovirus serotypes occur primarily in the loop regions of the viral coat proteins (VPs), most notably in the loops of VP1 that cluster near the fivefold axes of the capsid, where the BC loop of PV2L is disordered. Unlike other known structures of enteroviruses, the entire polypeptide chain of PV2L VP4 is visible in the electron density and RNA bases are observed stacking with conserved aromatic residues (Tyr4020 and Phe4046) of VP4. The broad-spectrum antiviral agent SCH48973 is observed binding in a pocket within the beta-barrel of VP1, in approximately the same location that natural 'pocket factors' bind to polioviruses. SCH48973 forms predominantly hydrophobic interactions with the pocket residues. CONCLUSIONS: Some of the conformational changes required for infectivity and involved in the control of capsid stability and neurovirulence in mice may occur in the vicinity of the fivefold axis of the poliovirus, where there are significant structural differences among the three poliovirus serotypes in the surface exposed loops of VP1 (BC, DE, and HI). A surface depression is located at the fivefold axis of PV2L that is not present in the other two poliovirus serotypes. The observed interaction of RNA with VP4 supports the observation that loss of VP4 ultimately leads to the loss of viral RNA. A model is proposed that suggests dual involvement of the virion fivefold and pseudo-threefold axes in receptor-mediated initiation of infection by picornaviruses.

Adaptation, Physiological↗