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1.  Changes in Molecular Epidemiology of Streptococcus pneumoniae Causing Meningitis following Introduction of Pneumococcal Conjugate Vaccination in England and Wales 
Journal of Clinical Microbiology  2013;51(3):820-827.
The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in September 2006 has markedly reduced the burden of invasive pneumococcal disease (IPD) including meningitis in England and Wales. This study examined changes in the molecular epidemiology of pneumococcal isolates causing meningitis from July 2004 to June 2009. The Health Protection Agency conducts enhanced pneumococcal surveillance in England and Wales. In addition to serotyping, pneumococcal isolates causing meningitis were genotyped by multilocus sequence typing (MLST). A total of 1,030 isolates were both serotyped and genotyped over the 5-year period. Fifty-two serotypes, 238 sequence types (STs), and 87 clonal complexes were identified, with no significant difference in the yearly Simpson's diversity index values (range, 0.974 to 0.984). STs commonly associated with PCV7 serotypes declined following PCV implementation, with a proportionally greater decline in ST124 (commonly associated with serotype 14). No other ST showed significant changes in distribution, even within individual serotypes. Replacement disease following PCV7 introduction was mainly due to serotypes 1, 3, 7F, 19A, 22F, and 33F through clonal expansion. A single instance of possible capsule switching was identified where one ST4327 clone expressed a serotype 14 capsule in 2005 and a serotype 28A capsule in 2009. In 2008 to 2009, ST191 (7F) became the most prevalent clone causing meningitis (10.3%). Case fatality (145 fatalities/1,030 cases; 14.1%) was high across all age groups and serotype groups. Thus, the introduction of PCV7 resulted in an increase in non-PCV7 serotypes, including some not covered by the 13-valent vaccine, such as serotypes 22F and 33F, emphasizing the importance of long-term epidemiological and molecular surveillance.
doi:10.1128/JCM.01917-12
PMCID: PMC3592052  PMID: 23269742
2.  Receptor Subtype-Dependent Galanin Actions on GABAergic Neurotransmission and Ethanol Responses in the Central Amygdala 
Addiction Biology  2011;17(4):694-705.
The neuropeptide galanin and its three receptor subtypes (GalR1–3) are expressed in the central amygdala (CeA), a brain region involved in stress- and anxiety-related behaviors, as well as alcohol dependence. Galanin also has been suggested to play a role in alcohol intake and alcohol dependence. We examined the effects of galanin in CeA slices from wild type (WT) and knockout (KO) mice deficient of GalR2 and both GalR1 and GalR2 receptors. Galanin had dual effects on GABAergic transmission, decreasing the amplitudes of pharmacologically-isolated GABAergic inhibitory postsynaptic potentials (IPSPs) in over half of CeA neurons but augmenting IPSPs in the others. The increase in IPSP size was absent after superfusion of the GalR3 antagonist SNAP 37889, whereas the IPSP depression was absent in CeA neurons of GalR1 × GalR2 double KO and GalR2 KO mice. Paired-pulse facilitation studies showed weak or infrequent effects of galanin on GABA release. Thus, galanin may act postsynaptically through GalR3 to augment GABAergic transmission in some CeA neurons, whereas GalR2 receptors likely are involved in the depression of IPSPs. Co-superfusion of ethanol, which augments IPSPs presynaptically, together with galanin caused summated effects of ethanol and galanin in those CeA neurons showing galanin-augmented IPSPs, suggesting the two agents act via different mechanisms in this population. However, in neurons showing IPSP-diminishing galanin effects, galanin blunted the ethanol effects, suggesting a preemptive effect of galanin. These findings may increase understanding of the complex cellular mechanisms that underlie the anxiety-related behavioral effects of galanin and ethanol in CeA.
doi:10.1111/j.1369-1600.2011.00360.x
PMCID: PMC3252398  PMID: 21955024
electrophysiology; antidepressant; anxiety; alcohol; IPSP; synapse
3.  Synovial Angioma of the FDP Flexor Sheath: A Rare Cause of Carpal Tunnel Syndrome 
It has been previously noted that synovial haemangiomas in the hand and wrist are very rare pathological entities. We report the case of a 34-year-old right hand dominant male who presented to his general practitioner with an enlarging left volar wrist/ palmar mass, who further developed symptoms consistent with carpal tunnel syndrome. An MRI scan subsequently confirmed a large, complex mass with area of necrosis and peripheral enhancement. The rate of mass growth and radiological features raised the possibility of a soft tissue malignancy, and the gentleman was urgently referred to our unit for surgical exploration and removal of tumour. Surgical exploration demonstrated a tan-coloured soft tissue mass on the ulnar aspect of the median nerve. It appeared to arise from, and marginally infiltrated, the tendon sheath of the FDP tendon to the ring finger and the lumbrical muscle of the fourth ray; the distal and proximal extent of the tumour was difficult to define due to the diffuse growth of the tumour. Resection was achieved with macroscopic margins, with excellent functional recovery immediately and at 6 month follow-up. Histological analysis was consistent with a synovial haemangioma, comprising of numerous thin-walled blood vessels with a central cystic cavity containing blood and fibrin. Our case further demonstrates the diagnostic challenges posed by compressive neuropathy due to soft tissue masses, even with thorough clinical and radiological assessment. In the context of a rapidly growing tumour, malignancy must always be suspected and might highlight a role for pre-operative biopsy.
doi:10.2174/1874325001307010072
PMCID: PMC3617547  PMID: 23569470
Carpal tunnel; synovial angioma; median nerve compression; tumour.
4.  Neuroadaptation of GABAergic Transmission in the Central Amygdala During Chronic Morphine Treatment 
Addiction biology  2010;16(4):551-564.
We investigated possible alterations of pharmacologically-isolated, evoked GABAA inhibitory postsynaptic potentials (eIPSPs) and miniature GABAA inhibitory postsynaptic currents (mIPSCs) in the rat central amygdala (CeA) elicited by acute application of μ-opioid receptor (MOR) agonists (DAMGO and morphine; 1 μM) and by chronic morphine treatment with morphine pellets. The acute activation of MORs decreased the amplitudes of eIPSPs, increased paired-pulse facilitation (PPF) of eIPSPs and decreased the frequency (but not the amplitude) of mIPSCs in a majority of CeA neurons, suggesting that acute MOR-dependent modulation of this GABAergic transmission is mediated predominantly via presynaptic inhibition of GABA release. We observed no significant changes in the membrane properties, eIPSPs, PPF or mIPSCs of CeA neurons during chronic morphine treatment compared to CeA of naïve or sham rats. Superfusion of the MOR antagonist CTOP (1 μM) increased the mean amplitude of eIPSPs in a majority of CeA neurons to the same degree in both naïve/sham and morphine-treated rats, suggesting a tonic activation of MORs in both conditions. Superfusion of DAMGO decreased eIPSP amplitudes and the frequency of mIPSCs equally in both naïve/sham and morphine-treated rats but decreased the amplitude of mIPSCs only in morphine treated rats, an apparent postsynaptic action. Our combined findings suggest the development of tolerance of the CeA GABAergic system to inhibitory effects of acute activation of MORs on presynaptic GABA release and possible alteration of MOR-dependent postsynaptic mechanisms that may represent important neuroadaptations of the GABAergic and MOR systems during chronic morphine treatment.
doi:10.1111/j.1369-1600.2010.00269.x
PMCID: PMC3117063  PMID: 21182569
addiction; drug abuse; electrophysiology; extended amygdala; opiate; tolerance
5.  Effect of Serotype on Focus and Mortality of Invasive Pneumococcal Disease: Coverage of Different Vaccines and Insight into Non-Vaccine Serotypes 
PLoS ONE  2012;7(7):e39150.
Background
Differences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13).
Method
Serotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients’ diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5–64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines.
Results
The linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines’ coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals.
Conclusion
Marked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss.
doi:10.1371/journal.pone.0039150
PMCID: PMC3398022  PMID: 22815698
6.  Accelerating Control of Pertussis in England and Wales 
Emerging Infectious Diseases  2012;18(1):38-47.
Pertussis incidence among infants can be reduced by early completion of the primary vaccination schedule.
doi:10.3201/eid1801.110784
PMCID: PMC3381681  PMID: 22260989
whooping cough; Bordetella pertussis; epidemiology; pertussis vaccine; program evaluation; bacteria; disease control; infants; England; Wales
7.  Streptococcus pneumoniae Isolates Expressing a Capsule with Epitopes of Both Serotypes 6A and 6B▿  
Clinical and Vaccine Immunology : CVI  2010;17(11):1820-1822.
Four Streptococcus pneumoniae isolates expressing both 6A and 6B capsular serotypes were detected by a multiplex immunoassay. The sequence of WciP, a GT2-family glycosyltransferase, indicates that point mutation has compromised linkage specificity, allowing two alternative oligosaccharides to be synthesized. This finding highlights that mutation as well as recombination can mediate serotype change.
doi:10.1128/CVI.00335-10
PMCID: PMC2976087  PMID: 20876824
8.  Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study 
PLoS Medicine  2011;8(4):e1001017.
A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.
Background
We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines.
Methods and Findings
Nasopharyngeal swabs were taken from children <5 y old and family members (n = 400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case∶carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76–1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence.
Conclusion
Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases—major causes of illness and death in children and adults worldwide—are caused by Streptococcus pneumoniae, a bacterium that often colonizes the nasopharynx (the area of the throat behind the nose). Carriage of S. pneumoniae bacteria does not necessarily cause disease. However, these bacteria can cause local, noninvasive diseases such as ear infections and sinusitis and, more rarely, they can spread into the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, and meningitis, respectively. Although these invasive pneumococcal diseases (IPDs) can be successfully treated if administered early, they can be fatal. Consequently, it is better to protect people against IPDs through vaccination than risk infection. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules (antigens) that it recognizes as foreign.
Why Was This Study Done?
There are more than 90 S. pneumoniae variants or “serotypes” characterized by different polysaccharide (complex sugar) coats, which trigger the immune response against S. pneumoniae and determine each serotype's propensity to cause IPD. The pneumococcal conjugate vaccine PCV7 contains polysaccharides (linked to a protein carrier) from the seven serotypes mainly responsible for IPD in the US in 2000 when routine childhood PCV7 vaccination was introduced in that country. PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes, which means that, after vaccination, previously uncommon, nonvaccine serotypes can colonize the nasopharynx. If these serotypes have a high invasiveness potential, then “serotype replacement” could reduce the benefits of vaccination. In this cross-sectional study (a study that investigates the relationship between a disease and an intervention in a population at one time point), the researchers investigate the effect of the UK PCV7 vaccination program (which began in 2006) on serotype-specific carriage and IPD in England to understand the role of PCV7 in serotype replacement and to predict the likely impact of vaccines containing additional serotypes (higher valency vaccines).
What Did the Researchers Do and Find?
The researchers examined nasopharyngeal swabs taken from PCV7-vaccinated children and their families for S. pneumoniae, determined the serotype of any bacteria they found, and compared the proportion of people carrying S. pneumoniae (carrier prevalence) and the distribution of serotypes in this study population and in a similar population that was studied in 2000/2001, before the PCV vaccination program began. Overall, there was no statistically significant change in carrier prevalence, but carriage of vaccine serotypes decreased in vaccinated children and their contacts whereas carriage of nonvaccine serotypes increased. The serotype-specific case-to-carrier ratios (CCRs; a measure of serotype invasiveness that was estimated using national IPD data) of the replacing serotypes were generally lower than those of the original serotypes, which resulted in a net reduction in IPD in children. Moreover, before PCV7 vaccination began, PCV7-included serotypes were responsible for similar proportions of pneumococcal carriage and disease; afterwards, the additional serotypes present in the higher valency vaccines PVC10 and PVC13 were responsible for a higher proportion of disease than carriage. Finally, three serotypes not present in the higher valency vaccines with outstandingly high CCRs (high invasiveness potential) are identified.
What Do These Findings Mean?
These findings document the serotype replacement of S. pneumoniae that has occurred in England since the introduction of PCV7 vaccination and highlight the importance of assessing the effects of pneumococcal vaccines on carriage as well as on IPDs. Because the additional serotypes included in PCV10 and PCV13 have high CCRs but low carriage prevalence and because most of the potential replacement serotypes have low CCRs, these findings suggest that the introduction of higher valency vaccines should further reduce the occurrence of invasive disease with limited risk of additional serotype replacement. However, the emergence of a few serotypes that have high CCRs but are not included in PCV10 and PCV13 might mitigate the benefits of higher valency vaccines. In other words, although the recent introduction of PCV13 into UK vaccination schedules is likely to have an incremental benefit on the reduction of IPD compared to PCV7, this benefit might be offset by increases in the carriage of some high CCR serotypes. These serotypes should be considered for inclusion in future vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001017.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal diseases
The UK Health Protection Agency provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
doi:10.1371/journal.pmed.1001017
PMCID: PMC3071372  PMID: 21483718
9.  Presynaptic CRF1 Receptors Mediate the Ethanol Enhancement of GABAergic Transmission in the Mouse Central Amygdala 
Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide involved in stress responses initiated from several brain areas, including the amygdala formation. Research shows a strong relationship between stress, brain CRF, and excessive alcohol consumption. Behavioral studies suggest that the central amygdala (CeA) is significantly involved in alcohol reward and dependence. We recently reported that the ethanol augmentation of GABAergic synaptic transmission in rat CeA involves CRF1 receptors, because both CRF and ethanol significantly enhanced the amplitude of evoked GABAergic inhibitory postsynaptic currents (IPSCs) in CeA neurons from wild-type (WT) and CRF2 knockout (KO) mice, but not in neurons of CRF1 KO mice. The present study extends these findings using selective CRF receptor ligands, gene KO models, and miniature IPSC (mIPSC) analysis to assess further a presynaptic role for the CRF receptors in mediating ethanol effects in the CeA. In whole-cell patch recordings of pharmacologically isolated GABAAergic IPSCs from slices of mouse CeA, both CRF and ethanol augmented evoked IPSCs in a concentration-dependent manner, with low EC50s. A CRF1 (but not CRF2) KO construct and the CRF1-selective nonpeptide antagonist NIH-3 (LWH-63) blocked the augmenting effect of both CRF and ethanol on evoked IPSCs. Furthermore, the new selective CRF1 agonist stressin1, but not the CRF2 agonist urocortin 3, also increased evoked IPSC amplitudes. Both CRF and ethanol decreased paired-pulse facilitation (PPF) of evoked IPSCs and significantly enhanced the frequency, but not the amplitude, of spontaneous miniature GABAergic mIPSCs in CeA neurons of WT mice, suggesting a presynaptic site of action. The PPF effect of ethanol was abolished in CeA neurons of CRF1 KO mice. The CRF1 antagonist NIH-3 blocked the CRF- and ethanol-induced enhancement of mIPSC frequency in CeA neurons. These data indicate that presynaptic CRF1 receptors play a critical role in permitting or mediating ethanol enhancement of GABAergic synaptic transmission in CeA, via increased vesicular GABA release, and thus may be a rational target for the treatment of alcohol abuse and alcoholism.
doi:10.1100/tsw.2009.1
PMCID: PMC3053445  PMID: 19151899
electrophysiology; alcohol; gamma aminobutyric acid; corticotrophin-releasing factor; corticotropin-releasing hormone; CRH; urocortin; stresscopin; whole-cell patch; IPSC
10.  Molecular Typing of Pneumococci for Investigation of Linked Cases of Invasive Pneumococcal Disease ▿  
Journal of Clinical Microbiology  2010;48(5):1926-1928.
In winter 2007-2008, an outbreak of pediatric pneumonia caused by serotype 5 pneumococci was identified in a northeast London suburb. Variable number of tandem repeat analyses clustered these pneumococci from the other serotype 5 pneumococci in the United Kingdom, highlighting the importance of this discriminative typing method in supporting epidemiological investigations.
doi:10.1128/JCM.02054-09
PMCID: PMC2863872  PMID: 20164267
11.  Pediatric Pneumococcal Serotypes in 4 European Countries 
Emerging Infectious Diseases  2010;16(9):1428-1439.
TOC Summary: Non–heptavalent pneumococcal conjugate vaccine serotypes have increased in Spain, France, Belgium, and England and Wales.
After heptavalent pneumococcal conjugate vaccine (PCV7) was marketed in France, Spain, Belgium, and England and Wales (United Kingdom), invasive disease from non-PCV7 serotypes (NVT) increased. Adjusted serotype-specific incidences among children <15 years of age were compared between 1999–2002 (prevaccine) and 2005–2006 (postmarketing). Vaccine coverage increased to ≈32%–48% in France, Spain, and Belgium but remained <1% in England and Wales. Serotype 1 incidence rose in all age groups and countries (incidence rate ratio [IRR] 1.3–4.2; p<0.004), independently of PCV7 use, but incidence of serotypes 7F and 19A increased most in France, Spain, and Belgium (IRR 1.9–16.9 in children <5 years; p<0.001), where PCV7 coverage was greater. Vaccine-induced replacement of PCV7 serotypes possibly contributed to NVT increases, as did secular trends. New vaccines targeting these serotypes are available, but serotype dynamics needs further exploration that accounts for underreporting and prevaccine trends.
doi:10.3201/eid1609.100102
PMCID: PMC3294971  PMID: 20735928
Invasive pneumococcal disease; pneumococcal conjugate vaccines; serotype; bacteria; France; Spain; Belgium; England; Wales; research
12.  Dynamic models of pneumococcal carriage and the impact of the Heptavalent Pneumococcal Conjugate Vaccine on invasive pneumococcal disease 
Background
The 7-valent pneumococcal conjugate vaccine has been introduced in national immunisation programmes of most industrialised countries and recently in two African GAVI eligible countries (Rwanda and The Gambia). However the long term effects of PCV are still unclear, as beneficial direct and herd immunity effects might be countered by serotype replacement.
Method
A dynamic, age-structured, compartmental model of Streptococcus pneumoniae transmission was developed to predict the potential impact of PCV7 on the incidence of invasive disease accounting for both herd immunity and serotype replacement effects. The model was parameterised using epidemiological data from England and Wales and pre and post-vaccination surveillance data from the US.
Results
Model projections showed that serotype replacement plays a crucial role in determining the overall effect of a PCV7 vaccination programme and could reduce, negate or outweigh its beneficial impact. However, using the estimate of the competition parameter derived from the US post-vaccination experience, an infant vaccination programme would prevent 39,000 IPD cases in the 20 years after PCV7 introduction in the UK. Adding a catch-up campaign for under 2 or under 5 year olds would provide a further reduction of 1,200 or 3,300 IPD cases respectively, mostly in the first few years of the programme.
Conclusions
This analysis suggests that a PCV vaccination programme would eradicate vaccine serotypes from circulation. However, the increase in carriage of non-vaccine serotypes, and the consequent increase in invasive disease, could reduce, negate or outweigh the benefit. These results are sensitive to changes in the protective effect of the vaccine, and, most importantly, to the level of competition between vaccine and non-vaccine types. The techniques developed here can be used to assess the introduction of vaccination programmes in developing countries and provide the basis for cost-effectiveness analyses.
doi:10.1186/1471-2334-10-90
PMCID: PMC2867993  PMID: 20377886
13.  Diagnosis of Streptococcus pneumoniae Infections in Adults with Bacteremia and Community-Acquired Pneumonia: Clinical Comparison of Pneumococcal PCR and Urinary Antigen Detection▿  
Journal of Clinical Microbiology  2009;47(4):1046-1049.
The diagnosis of severe Streptococcus pneumoniae infection relies heavily on insensitive culture techniques. To improve the usefulness of PCR assays, we developed a dual-PCR protocol (targeted at pneumolysin and autolysin) for EDTA blood samples. This was compared to the Binax NOW S. pneumoniae urine antigen test in patients with bacteremic pneumococcal infections. Patients with nonbacteremic community-acquired pneumonia also were tested by these methods to determine what proportion could be confirmed as pneumococcal infections. A direct comparison was made in a group of patients who each had both tests performed. The Binax NOW S. pneumoniae urine antigen test was positive in 51 of 58 bacteremic pneumococcal cases (sensitivity, 88%; 95% confidence interval [CI], 77 to 95%), whereas the dual PCR was positive in 31 cases (sensitivity, 53.5%; 95% CI, 40 to 67%; P < 0.0001), and all of these had detectable urinary antigens. Both tests gave positive results in 2 of 51 control patients (referred to as other-organism septicemia), giving a specificity of 96% (95% CI, 86.5 to 99.5%). In 77 patients with nonbacteremic community-acquired pneumonia, urinary antigen was detected significantly more often (in 21 patients [27%]) than a positive result by the dual-PCR protocol (6 [8%]) (P = 0.002). The development of a dual-PCR protocol enhanced the sensitivity compared to that of the individual assays, but it is still significantly less sensitive than the Binax NOW urine antigen test, as well as being more time-consuming and expensive. Urinary antigen detection is the nonculture diagnostic method of choice for patients with possible severe pneumococcal infection.
doi:10.1128/JCM.01480-08
PMCID: PMC2668348  PMID: 19225103
14.  Observed smoking in cars: a method and differences by socioeconomic area 
Tobacco Control  2006;15(5):409-411.
Objectives
To establish a reproducible method to estimate he point prevalence of smoking and second‐hand smoke (SHS) exposure in cars, and to compare this prevalence between two areas of contrasting socioeconomic status.
Method
A method involving two teams of observers was developed and evaluated. It involved observing 16 055 cars in Wellington, New Zealand. Two of the observation sites represented a high and a low area of deprivation (based on a neighbourhood deprivation index) and three were in the central city.
Results
A 4.1% point prevalence of smoking in cars was observed (95% confidence interval (CI) 3.8% to 4.4%). There was a higher prevalence of smoking in cars in the high deprivation area relative to the other sites, and particularly compared to the low deprivation area (rate ratio relative to the latter 3.2, 95% CI 2.6 to 4.0). Of cars with smoking, 23.7% had other occupants being exposed to SHS. Cars with smoking and other occupants were significantly more likely to have a window open (especially if the smoker was not the driver). The observation method developed was practical, and inter‐observer agreement was high (κ value for the “smoking seen in car” category 0.95).
Conclusions
Observational studies can be an effective way of investigating smoking in cars. The data from this survey suggest that smoking in cars occurs at a higher rate in relatively deprived populations and hence may contribute to health inequalities. Fortunately, there are a number of policy options for reducing SHS exposure in cars including mass media campaigns and laws for smoke‐free cars.
doi:10.1136/tc.2006.015974
PMCID: PMC2563644  PMID: 16998177
tobacco smoking; second‐hand smoke; cars; motor vehicles; observational study
15.  Serotype-Specific Immune Unresponsiveness to Pneumococcal Conjugate Vaccine following Invasive Pneumococcal Disease▿  
Infection and Immunity  2008;76(11):5305-5309.
Following the introduction of the pneumococcal 7-valent conjugate vaccine (PCV7) into the routine infant immunization schedule in England, Wales, and Northern Ireland, pneumococcal serotype-specific immunoglobulin G (IgG) antibody testing was offered as a clinical service to all children within the program with invasive pneumococcal disease (IPD) to confirm an adequate antibody response to PCV7. As of March 2008, serum samples taken within 14 to 90 days of vaccination had been submitted from 107 children who had received one or more doses in the second year of life. Sera were assayed by a multiplexed microsphere assay incorporating both cell wall polysaccharide and serotype 22F adsorption. A protective serotype-specific antibody level was defined as a concentration of ≥0.35 μg/ml. Eight children failed to develop a response to their infecting serotype (6B [n = 4], 18C [n = 2], 4 [n = 1], and 14 [n = 1]), despite receiving at least three doses of PCV7 in the second year of life or two doses in the second and two or three in the first year of life. A further two children were nonresponsive to a serotype (6B) different than that causing disease. None of the 10 children had a clinical risk factor for IPD. Two had marginally low levels of total serum IgG but mounted adequate responses to the other six PCV serotypes. This serotype-specific unresponsiveness may reflect immune paralysis due to large pneumococcal polysaccharide antigen loads and/or a potential genetic basis for nonresponse to individual pneumococcal serotypes.
doi:10.1128/IAI.00796-08
PMCID: PMC2573380  PMID: 18779338
16.  Bacterial Pneumonia and Pandemic Influenza Planning 
Emerging Infectious Diseases  2008;14(8):1187-1192.
Prevention and treatment of secondary bacterial complications are important but neglected areas of planning.
Pandemic influenza planning is well under way across the globe. Antiviral drugs and vaccines have dominated the therapeutic agenda. Far less work has been conducted on stockpiling and planning for deployment of antimicrobial drugs against secondary bacterial pneumonia, a cause of substantial illness and death in previous pandemics and epidemics. In the event of a pandemic, effective antimicrobial drug measures are expected to substantially benefit public health. We address issues regarding use of antimicrobial drugs as stocks of individual agents are diminished and the role of resistance surveillance in informing such policy. Furthermore, vaccination with polysaccharide and conjugate pneumococcal vaccines is considered as part of a pandemic strategy. Most illness and death from influenza are likely to occur in developing countries, where neuraminidase inhibitors and vaccines may be neither affordable nor available; thus, compared with industrialized countries, the benefits of treating bacterial complications in developing countries may be substantially greater.
doi:10.3201/eid1408.070751
PMCID: PMC2600366  PMID: 18680640
Pandemic influenza; secondary bacterial pneumonia; antibiotic stockpiles; pneumococcal vaccination; emergency planning; perspective
17.  Increasing Hospital Admissions for Pneumonia, England 
Emerging Infectious Diseases  2008;14(5):727-733.
This rise in recorded incidence from 2001 to 2005 was particularly marked among the elderly.
Pneumonia is an important cause of illness and death in England. To describe trends in pneumonia hospitalizations, we extracted information on all episodes of pneumonia that occurred from April 1997 through March 2005 recorded in the Hospital Episode Statistics (HES) database by searching for International Classification of Diseases 10th revision codes J12–J18 in any diagnostic field. The age-standardized incidence of hospitalization with a primary diagnosis of pneumonia increased by 34% from 1.48 to 1.98 per 1,000 population between 1997–98 and 2004–05. The increase was more marked in older adults, in whom the mortality rate was also highest. The proportion of patients with recorded coexisting conditions (defined by using the Charlson Comorbidity Index score) increased over the study period. The rise in pneumonia hospital admissions was not fully explained by demographic change or increasing coexisting conditions. It may be attributable to other population factors, changes in HES coding, changes to health service organization, other biologic phenomenon, or a combination of these effects.
doi:10.3201/eid1405.071011
PMCID: PMC2600241  PMID: 18439353
Pneumonia; hospital; patient admission; epidemiology; trends; England; research
18.  Age-Stratified Prevalences of Pneumococcal-Serotype-Specific Immunoglobulin G in England and Their Relationship to the Serotype-Specific Incidence of Invasive Pneumococcal Disease Prior to the Introduction of the Pneumococcal 7-Valent Conjugate Vaccine▿  
Clinical and Vaccine Immunology : CVI  2007;14(11):1442-1450.
Recent changes to the childhood immunization schedule in the United Kingdom have resulted in the inclusion of the 7-valent pneumococcal conjugate vaccine. However, the seroprevalence of pneumococcal antibodies in the population was unknown. To address this, we measured pneumococcal, age-specific immunoglobulin G (IgG) concentrations specific for nine serotypes by an assay run on the Bioplex platform, using 2,664 serum samples collected in England from 2000 to 2004. The lowest concentrations of IgG specific to all serotypes and the proportions of serotype-specific IgG concentrations of ≥0.35 μg/ml were observed in children aged <1 year. From 1 year on, there was a general increase in antibody levels with increasing age, and they remained high in adults. Maternal antibody was detected in young children aged <36 days but waned rapidly. Comparison of the age-specific seroprevalence of serotype-specific IgG to the serotype-specific incidence of invasive pneumococcal disease demonstrated a general inverse relationship for all age groups except the elderly. These data provide a baseline for natural immunity to the pneumococcal serotypes analyzed prior to the introduction of pneumococcal conjugate vaccine in the United Kingdom.
doi:10.1128/CVI.00264-07
PMCID: PMC2168168  PMID: 17881503
19.  Severe Streptococcus pyogenes Infections, United Kingdom, 2003–2004 
Emerging Infectious Diseases  2008;14(2):202-209.
Epidemiology of severe disease caused by this organism has changed, with increased incidence and different risk groups.
As part of a Europe-wide initiative to explore current epidemiologic patterns of severe disease caused by Streptococcus pyogenes, the United Kingdom undertook enhanced population-based surveillance during 2003–2004. A total of 3,775 confirmed cases of severe S. pyogenes infection were identified over 2 years, 3.33/100,000 population, substantially more than previously estimated. Skin/soft tissue infections were the most common manifestation (42%), followed by respiratory tract infections (17%). Injection drug use was identified as a risk factor for 20% of case-patients. One in 5 infected case-patients died within 7 days of diagnosis; the highest mortality rate was for cases of necrotizing fasciitis (34%). Nonsteroidal antiinflammatory drugs, alcoholism, young age, and infection with emm/M3 types were independently associated with increased risk for streptococcal toxic shock syndrome. Understanding the pattern of these diseases and predictors of poor patient outcome will help with identification and assessment of the potential effect of targeted interventions.
doi:10.3201/eid1402.070888
PMCID: PMC2600190  PMID: 18258111
Streptococcus pyogenes; population surveillance; bacteremia; shock; septic; United Kingdom; research
20.  EP4 mediates PGE2 dependent cell survival through the PI3 Kinase/AKT pathway 
The anti-apoptotic effect of PGE2 was examined in Jurkat cells (human T-cell leukemia) by incubation with PGE2 (5nM) prior to treatment with the cancer chemotherapeutic agent camptothecin. Apoptosis was evaluated by caspase-3 activity in cell extracts and flow cytometry of propidium iodide-labeled cells. Pre-incubation with PGE2 reduced camptothecin-induced caspase activity by 30% and apoptosis by 35% respectively. Pharmacological data demonstrate that the EP4 receptor is responsible for mediating the protection from camptothecin–induced apoptosis. Pre-treatment of the cells with the EP4 antagonist (EP4A) prior to PGE2 and camptothecin abolished the increased survival effect of PGE2. Specific inhibition of the downstream of PI3 kinase or AKT/protein kinase but not protein kinase A prevents the observed increase in cell survival elicited by PGE2. These findings have critical implications regarding the mechanism and potential application of PGE2 receptor specific inhibition in cancer therapy.
doi:10.1016/j.prostaglandins.2006.10.005
PMCID: PMC1886004  PMID: 17259077
Prostaglandin; EP4 receptor; Apoptosis; Survival; PI3 Kinase
21.  On the Origin of the Treponematoses: A Phylogenetic Approach 
Background
Since the first recorded epidemic of syphilis in 1495, controversy has surrounded the origins of the bacterium Treponema pallidum subsp. pallidum and its relationship to the pathogens responsible for the other treponemal diseases: yaws, endemic syphilis, and pinta. Some researchers have argued that the syphilis-causing bacterium, or its progenitor, was brought from the New World to Europe by Christopher Columbus and his men, while others maintain that the treponematoses, including syphilis, have a much longer history on the European continent.
Methodology/Principal Findings
We applied phylogenetics to this problem, using data from 21 genetic regions examined in 26 geographically disparate strains of pathogenic Treponema. Of all the strains examined, the venereal syphilis-causing strains originated most recently and were more closely related to yaws-causing strains from South America than to other non-venereal strains. Old World yaws-causing strains occupied a basal position on the tree, indicating that they arose first in human history, and a simian strain of T. pallidum was found to be indistinguishable from them.
Conclusions/Significance
Our results lend support to the Columbian theory of syphilis's origin while suggesting that the non-sexually transmitted subspecies arose earlier in the Old World. This study represents the first attempt to address the problem of the origin of syphilis using molecular genetics, as well as the first source of information regarding the genetic make-up of non-venereal strains from the Western hemisphere.
Author Summary
For 500 years, controversy has raged around the origin of T. pallidum subsp. pallidum, the bacterium responsible for syphilis. Did Christopher Columbus and his men introduce this pathogen into Renaissance Europe, after contracting it during their voyage to the New World? Or does syphilis have a much older history in the Old World? This paper represents the first attempt to use a phylogenetic approach to solve this question. In addition, it clarifies the evolutionary relationships between the pathogen that causes syphilis and the other T. pallidum subspecies, which cause the neglected tropical diseases yaws and endemic syphilis. Using a collection of pathogenic Treponema strains that is unprecedented in size, we show that yaws appears to be an ancient infection in humans while venereal syphilis arose relatively recently in human history. In addition, the closest relatives of syphilis-causing strains identified in this study were found in South America, providing support for the Columbian theory of syphilis's origin.
doi:10.1371/journal.pntd.0000148
PMCID: PMC2217670  PMID: 18235852
22.  Diagnosis of Gastric Syphilis by Direct Immunofluorescence Staining and Real-Time PCR Testing 
Journal of Clinical Microbiology  2006;44(9):3452-3456.
We report on a case of gastric syphilis in a patient with chronic dyspepsia. The diagnosis was established by serology and the demonstration of spirochetes in diffusely inflammed gastric mucosa by staining with a fluorescent monoclonal antibody specific for pathogenic treponemes and by the detection of specific treponemal DNA sequences by a real-time PCR.
doi:10.1128/JCM.00721-06
PMCID: PMC1594693  PMID: 16954299
23.  Tetanus in Injecting Drug Users, United Kingdom 
Emerging Infectious Diseases  2006;12(4):709-710.
doi:10.3201/eid1204.050599
PMCID: PMC3294684  PMID: 16715588
Tetanus; heroin; street drugs; substance abuse; intravenous; immunization; Clostridium tetani; letter
24.  Screening and Toxigenic Corynebacteria Spread 
Emerging Infectious Diseases  2006;12(3):520-521.
doi:10.3201/eid1203.050601
PMCID: PMC3291432  PMID: 16710980
diphtheria; secondary cases; surveillance; corynebacteria
25.  Characterization of Toxigenic Corynebacterium ulcerans Strains Isolated from Humans and Domestic Cats in the United Kingdom 
Journal of Clinical Microbiology  2005;43(9):4377-4381.
In the United Kingdom there has been a marked increase in the number of human infections caused by toxigenic Corynebacterium ulcerans. During 2002 and 2003 the organism was also isolated from several domestic cats with bilateral nasal discharge. As C. ulcerans has never previously been isolated from cats, the 16S rRNA gene from three cat isolates was sequenced to confirm their species identities. Fifty clinical isolates from the United Kingdom isolated from 1986 to 2003 and seven cat isolates were characterized by ribotyping to determine whether the ribotypes of the cat isolates were genotypically related to those found for human clinical isolates. For comparison, the genotypes of 11 overseas isolates and 13 isolates from H. R. Carne's collection isolated between 1933 and 1979 were also determined. Strains isolated from domestic cats were found to exhibit the predominant ribotypes observed among human clinical isolates, suggesting that C. ulcerans isolated from cats could be a potential reservoir for human infection.
doi:10.1128/JCM.43.9.4377-4381.2005
PMCID: PMC1234052  PMID: 16145080

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