UK National Guidelines on HIV Testing 2006.
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Ambulatory Care Facilities↗
Biomedical subjects
P Carter
Publications and source records attributed to P Carter.
Diagnosing necrotising fasciitis.
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Clinical Protocols↗
Establishing the National Chlamydia Screening Programme in England: results from the first full year of screening.
BACKGROUND: The phased implementation of the National Chlamydia Screening Programme (NCSP) began in September 2002. The NCSP offers opportunistic screening for chlamydia to women and men under 25 years of age attending clinical and non-clinical screening venues using non-invasive urine or vulvo-vaginal swab samples tested via nucleic acid amplification. This review describes the implementation of the NCSP, reports positivity rates for the first year, and explores risk factors for genital chlamydial infection. METHODS: Cross sectional study of the first year's screening data from the NCSP. A standardised core dataset for each screening test was collected from 302 screening venues, excluding genitourinary medicine (GUM) clinics, across 10 phase 1 programme areas. We estimated chlamydia positivity by demographic and behavioural characteristics, and investigated factors associated with infection through univariate and multivariate analyses. RESULTS: Chlamydia positivity among people under 25 years of age screened in non-GUM settings was 10.1% (1538/15 241) in women and 13.3% (156/1172) in men. Risk factors varied by sex: for women-age 16-19, non-white ethnicity, and sexual behaviours were associated with infection; for men-only age 20-24 and non-white ethnicity were associated with infection. DISCUSSION: In the first phase of the NCSP, 16 413 opportunistic screens among young adults under 25 years of age were performed at non-GUM settings and testing volume increased over time. Rates of disease were similar to those found during the English screening pilot and were comparable to the first year of widespread screening in Sweden and the United States. The screening programme in England will continue to expand as further phases are included, with national coverage anticipated by 2008.
Adolescent↗
A pilot study of the effect of the Queen's Square external bladder stimulator on urinary retention after knee replacement surgery.
Postoperative urinary retention remains an important problem after major orthopaedic surgery and can increase morbidity. External vibration applied to the suprapubic region has improved bladder emptying and urinary symptoms in patients with neurogenic bladders. Forty-three patients undergoing elective major knee surgery were randomly assigned to receive either a Queen's Square bladder stimulator or placebo device for 24 h postoperatively. No statistically significant differences in rates of urinary retention could be demonstrated in the bladder stimulator group compared to the placebo group (41% and 33%, respectively). There were no differences between the two groups when analysed for prostatic symptoms, type and effectiveness of analgesia and fluid balance. We conclude that, while the Queen's Square external bladder stimulator may be effective in treating chronic urinary retention associated with a neurogenic bladder, it does not appear to be effective in preventing postoperative urinary retention.
Aged↗
Study of brain uptake and biodistribution of [11C]toluene in non-human primates and mice.
Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain phamacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [11C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radio-tracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene.
Administration, Inhalation↗
Polynitroxylated starch/TPL attenuates cachexia and increased epithelial permeability associated with TNBS colitis.
Free radicals play an important role in the initiation and progression of inflammatory bowel disease (IBD). Therefore, the reduction or elimination of adverse oxidant effects can provide novel therapy for IBD. Here, the antioxidant capacity and protective effects of a new class of chemically modified hetastarch (polynitroxyl starch, or PNS) plus 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol or TPL) (PNS/TPL) were assessed in a model of colitis. The superoxide scavenging capacity of PNS/TPL-that is, the inhibition of the reduction of cytochrome c in the presence of xanthine/xanthine oxidase (X/XO)-was evaluated in vitro. The effects of PNS/TPL on X/XO-induced neutrophil endothelial adhesion in vitro were investigated. Also, this study tested the protection produced by PNS/TPL in a mouse model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. PNS/TPL was given intravenously immediately before (< 30 min) and intraperitoneally at 24 and 72 hr after TNBS induction. The body weight and survival rate of the mice were checked daily. Colonic mucosal damage was assessed on the 7th day by measuring intestinal permeability to Evans blue (EB) in vivo. The ability of PNS to reoxidize bioreduced TPL was documented by whole-body electron paramagnetic resonance (EPR) detection. We found that PNS or TPL exhibits superoxide dismutase (SOD)-like activity, with approximately 2% of SOD activity occurring on a molar basis. The endothelial-neutrophil adherence induced by X/XO was significantly inhibited by PNS/TPL but not by TPL alone. PNS/TPL protected against cachexia and mortality, both usually induced by TNBS. Epithelial permeability was increased significantly in TNBS mice but was ameliorated by the administration of PNS/TPL. In conclusion, PNS/TPL may be beneficial in the treatment or prevention of IBD through its antioxidant effects, which inhibit oxidant-mediated leukocyte adhesion and injury to endothelial cells.
Adult↗
Submucosal rectal lipoma presenting as rectal prolapse.
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Aged↗
Temporal evolution of the electric field accelerating electrons away from the auroral ionosphere.
The bright night-time aurorae that are visible to the unaided eye are caused by electrons accelerated towards Earth by an upward-pointing electric field. On adjacent geomagnetic field lines the reverse process occurs: a downward-pointing electric field accelerates electrons away from Earth. Such magnetic-field-aligned electric fields in the collisionless plasma above the auroral ionosphere have been predicted, but how they could be maintained is still a matter for debate. The spatial and temporal behaviour of the electric fields-a knowledge of which is crucial to an understanding of their nature-cannot be resolved uniquely by single satellite measurements. Here we report on the first observations by a formation of identically instrumented satellites crossing a beam of upward-accelerated electrons. The structure of the electric potential accelerating the beam grew in magnitude and width for about 200 s, accompanied by a widening of the downward-current sheet, with the total current remaining constant. The 200-s timescale suggests that the evacuation of the electrons from the ionosphere contributes to the formation of the downward-pointing magnetic-field-aligned electric fields. This evolution implies a growing load in the downward leg of the current circuit, which may affect the visible discrete aurorae.
Journal Article↗
Evidence that L-deprenyl treatment for one week does not inhibit MAO A or the dopamine transporter in the human brain.
In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.
Adult↗
Bispecific human IgG by design.
A major obstacle facing the development of bispecific antibodies as therapeutics has been the formidable task of producing these complex molecules in sufficient quantity and purity for clinical trials. These production difficulties have been largely overcome with the advent of efficient methods for the secretion of designer bispecific antibody fragments such as diabodies and miniantibodies from Escherichia coli. In contrast, the creation of bispecific IgG by the coexpression of two different IgG is highly inefficient due to unwanted pairings of the component heavy and light chains. A robust technology for the creation of bispecific IgG has recently been developed that virtually precludes IgG contaminants, as reviewed here. This technology is anticipated to spur the clinical development of bispecific IgG and other bifunctional Fc-containing molecules such as antibody/immunoadhesin hybrids and bispecific immunoadhesins.
Antibodies, Bispecific↗
Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function.
Inflammatory bowel disease (IBD) is associated with Th1/Th2 cytokine dysregulation, leukocyte extravasation, and tissue edema, but the mechanisms for cytokine-mediated vascular dysfunction are not understood. To investigate how cytokines might control edema in IBD, we determined vascular permeability and IFN-gamma expression in two models of murine colitis: SCID mice reconstituted with CD45RB(high T-lymphocytes (CD45RB(high)/SCID mice), and interleukin-10 gene deficient (IL-10(-/-)) mice. We also investigated the in vitro effects of IFN-gamma and IL-10 on human endothelial solute barrier and junction protein expression. Vascular permeability in CD45RB(high)/SCID and IL-10(-/-) mice was quantified using tissue (131)I-IgG accumulation. The IFN-gamma message was quantified using the ribonuclease protection assay. Endothelial barrier integrity in vitro was measured by transmonolayer electrical resistance, and junctional proteins were examined by immunoblotting and fluorescence microscopy. Both CD45RB(high)/SCID and IL-10(-/-) mice exhibit enhanced colonic microvascular leakage and IFN-gamma message levels compared to their respective controls. In vitro, IFN-gamma also reduced endothelial barrier (monolayer electrical resistance, increased albumin permeability) and reduced tight junction (occludin) expression and staining. These effects were reversed by pretreatment of monolayers with IL-10. Therefore, in vivo IFN-gamma and IL-10 may modulate microvascular leakage in IBD partly by controlling the expression of intestinal endothelial tight junctional proteins.
Animals↗
Species differences in [11C]clorgyline binding in brain.
[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.
Animals↗
Improving the efficacy of antibody-based cancer therapies.
A quarter of a century after their advent, monoclonal antibodies have become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases, including cancer. Although antibodies have yet to achieve the ultimate goal of curing cancer, many innovative approaches stand poised to improve the efficacy of antibody-based therapies.
Animals↗
Effects of uremic serum on isolated cardiac myocyte calcium cycling and contractile function.
BACKGROUND: Diastolic dysfunction occurs in patients with chronic renal failure. Moreover, serum from uremic patients contains one or more inhibitors of the plasmalemmal Na,K-ATPase (sodium pump). We hypothesized that a circulating substance present in uremic sera contributes to both sodium pump inhibition and diastolic dysfunction. METHODS: Serum samples were obtained from six patients with chronic renal failure and diastolic dysfunction. RESULTS: Their serum samples caused marked inhibition of Na,K-ATPase purified from dog kidney at all concentrations studied (all P < 0.01) and also impaired ouabain-sensitive rubidium uptake by myocytes isolated from Sprague-Dawley rats (P < 0.01). These cardiac myocytes were studied for their contractile function with video-edge detection and calcium metabolism with indo-1 fluorescence spectroscopy after exposure to these uremic sera. These uremic sera caused increases in myocyte fractional shortening (P < 0.01) as well as an increase in the time constant of relengthening (P < 0.01). Examining the calcium transient, the time constant for calcium recovery was also increased (P < 0.01). Exposure of these cells to sera from age- and sex-matched healthy subjects did not result in significant changes in contraction or calcium cycling. Extracts of uremic serum samples inhibited isolated Na,K-ATPase whereas extracts of normal serum samples did not. The effect of uremic serum extracts on contractile function and calcium cycling were quite similar to that of intact serum or the addition of ouabain. Co-incubation of uremic serum extract with an antibody fragment directed against digoxin markedly attenuated the inhibition of Na,K-ATPase activity and completely prevented any effects on calcium cycling or contractile function. CONCLUSION: These data show that one or more substances are present in uremic sera that acutely cause increased force of contraction and impaired recovery of cardiac myocyte calcium concentration as well as impaired relaxation. As these effects are similar to that seen with ouabain and can be prevented by co-incubation with an antibody fragment to digitalis, which also attenuates the sodium pump inhibitory effect, we suggest that this (these) substance(s) circulating in uremic sera and inhibiting the sodium pump also causes the acute diastolic dysfunction seen in our system.
Adult↗
Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors.
SB-219383 and its analogues are a class of potent and specific inhibitors of bacterial tyrosyl-tRNA synthetases. Crystal structures of these inhibitors have been solved in complex with the tyrosyl-tRNA synthetase from Staphylococcus aureus, the bacterium that is largely responsible for hospital-acquired infections. The full-length enzyme yielded crystals that diffracted to 2.8 A resolution, but a truncated version of the enzyme allowed the resolution to be extended to 2.2 A. These inhibitors not only occupy the known substrate binding sites in unique ways, but also reveal a butyl binding pocket. It was reported that the Bacillus stearothermophilus TyrRS T51P mutant has much increased catalytic activity. The S. aureus enzyme happens to have a proline at position 51. Therefore, our structures may contribute to the understanding of the catalytic mechanism and provide the structural basis for designing novel antimicrobial agents.
Amino Acid Sequence↗
Surfing with spirochaetes: an ongoing syphilis outbreak in Brighton.
BACKGROUND/OBJECTIVES: There has been a recent shift in the epidemiology of early syphilis in the developed world with sporadic outbreaks on a historic low level of background disease. Here we describe an ongoing outbreak of syphilis in Brighton. METHODS: Data collected on all patients with a diagnosis of early infectious syphilis at Brighton GUM clinic. RESULTS: 30 cases of early syphilis were diagnosed over a 25 month period beginning in July 1999. 28 were homosexual or bisexual men, giving a rate of 134 cases per 100 000 homosexual men. The cases reported a median of three sexual contacts (range 1-50) in the preceding 6 months and 77% had concurrent regular and casual partners. 83% of contacts were casual and untraceable. Over one third (11) of these cases reported oral sex as their only risk factor for syphilis acquisition and were unaware of this transmission route. 70% were diagnosed with primary or secondary infection, the remaining 30% being asymptomatic with early latent infection. Eight of the cases were HIV positive and a further eight remain untested for HIV. At least one concurrent STI was found in 40% of cases. Regular outbreak control meetings, involving relevant healthcare professionals, were held to plan appropriate interventions. CONCLUSION: The high rate of casual and untraceable contacts in this outbreak suggest that alternative control measures are necessary, including on-site testing and further health education regarding the oral transmission of syphilis. Continued vigilance for syphilis is essential, especially in those patients who are HIV positive.
Adult↗
Phenotypes Associated with SHOX Deficiency.
Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3-56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.
Adolescent↗
Mass changes and dissolution of platinum during electrical stimulation in artificial perilymph solution.
The electrochemistry of platinum electrodes in artificial perilymph solution subjected to cyclic and steady-state potentials was studied by a quartz crystal electrochemical microbalance and by analysis of electrolyte for dissolved platinum. The effect of amino acid adsorption appears to be one of blocking sites for platinum oxidation and oxide reduction, a process in which the amino acid competes with chloride from phosphate-buffered saline. For amino acids such as cysteine, which are known to interact strongly with platinum, the voltammograms became nearly featureless and only a small change in mass was observed during cycling of the potential. There were no mass changes of an electrode in solution containing human serum albumen, but its presence did inhibit dissolution of platinum. The overall magnitudes of dissolved platinum found in the buffered solutions were low, remaining below 5 ppb in most cases. Dissolution was greatest in solutions containing high concentrations of cysteine. Extrapolation of the results to implanted auditory prosthesis electrodes indicated that platinum dissolution would not lead to toxic concentrations in the body.
Adsorption↗