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1.  Novel technique in managing bronchobiliary fistula in adults: Endobronchial embolization using silicone spigots in 2 cases 
Annals of Thoracic Medicine  2015;10(1):67-68.
Bronchobiliary fistula (BBF) can complicate most hepatic pathologies. This is a challenging group of patients, especially when surgery is precluded. The bronchoscopic application of silicon spigots is a recognized technique for the treatment of massive hemoptysis and the management of patients with bronchopleural fistula following lung resection. Their role in the treatment of BBF has never been described. In this paper we report the successful embolization using silicon spigots in two patients with BBF secondary to malignant disease, when all surgical options were exhausted.
PMCID: PMC4286849  PMID: 25593611
Bronchobiliary fistula; bilioptysis; endobronchial embolization; silicon spigot
2.  Dose-Dependent Hemodynamic, Biochemical, and Tissue Oxygen Effects of OC99 following Severe Oxygen Debt Produced by Hemorrhagic Shock in Dogs 
We determined the dose-dependent effects of OC99, a novel, stabilized hemoglobin-based oxygen-carrier, on hemodynamics, systemic and pulmonary artery pressures, surrogates of tissue oxygen debt (arterial lactate 7.2 ± 0.1 mM/L and arterial base excess −17.9 ± 0.5 mM/L), and tissue oxygen tension (tPO2) in a dog model of controlled severe oxygen-debt from hemorrhagic shock. The dose/rate for OC99 was established from a pilot study conducted in six bled dogs. Subsequently twenty-four dogs were randomly assigned to one of four groups (n = 6 per group) and administered: 0.0, 0.065, 0.325, or 0.65 g/kg of OC99 combined with 10 mL/kg lactated Ringers solution administered in conjunction with 20 mL/kg Hextend IV over 60 minutes. The administration of 0.325 g/kg and 0.65 g/kg OC99 produced plasma hemoglobin concentrations of 0.63 ± 0.01 and 1.11 ± 0.02 g/dL, respectively, improved systemic hemodynamics, enhanced tPO2, and restored lactate and base excess values compared to 0.0 and 0.065 g/kg OC99. The administration of 0.65 g/kg OC99 significantly elevated pulmonary artery pressure. Plasma hemoglobin concentrations of OC99 ranging from 0.3 to 1.1 g/dL, in conjunction with colloid based fluid resuscitation, normalized clinical surrogates of tissue oxygen debt, improved tPO2, and avoided clinically relevant increases in pulmonary artery pressure.
PMCID: PMC4227330  PMID: 25405028
3.  Actions of Acute and Chronic Ethanol on Presynaptic Terminals 
This article presents the proceedings of a symposium entitled “The Tipsy Terminal: Presynaptic Effects of Ethanol” (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a “hot” topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol’s behavioral actions. Such studies could lead to new treatment strategies for alcohol intoxication, alcohol abuse, and alcoholism.
PMCID: PMC4115792  PMID: 16441271
Alcohol; Synapses; GABA; Glutamate; Peptides; Intoxication
4.  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.
PMCID: PMC3592052  PMID: 23269742
5.  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.
PMCID: PMC3252398  PMID: 21955024
electrophysiology; antidepressant; anxiety; alcohol; IPSP; synapse
6.  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.
PMCID: PMC3617547  PMID: 23569470
Carpal tunnel; synovial angioma; median nerve compression; tumour.
7.  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.
PMCID: PMC3117063  PMID: 21182569
addiction; drug abuse; electrophysiology; extended amygdala; opiate; tolerance
8.  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.
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).
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.
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.
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.
PMCID: PMC3398022  PMID: 22815698
9.  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.
PMCID: PMC3381681  PMID: 22260989
whooping cough; Bordetella pertussis; epidemiology; pertussis vaccine; program evaluation; bacteria; disease control; infants; England; Wales
10.  Using the Indirect Cohort Design to Estimate the Effectiveness of the Seven Valent Pneumococcal Conjugate Vaccine in England and Wales 
PLoS ONE  2011;6(12):e28435.
The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2,3 and 13month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD.
Methods and Findings
We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%.
This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine.
PMCID: PMC3229580  PMID: 22164292
11.  7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement? 
PLoS ONE  2011;6(10):e26190.
The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.
Methods and Findings
A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.
Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.
PMCID: PMC3193519  PMID: 22022559
12.  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.
PMCID: PMC2976087  PMID: 20876824
13.  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.
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.
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
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
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)
PMCID: PMC3071372  PMID: 21483718
14.  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.
PMCID: PMC3053445  PMID: 19151899
electrophysiology; alcohol; gamma aminobutyric acid; corticotrophin-releasing factor; corticotropin-releasing hormone; CRH; urocortin; stresscopin; whole-cell patch; IPSC
15.  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.
PMCID: PMC2863872  PMID: 20164267
16.  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.
PMCID: PMC3294971  PMID: 20735928
Invasive pneumococcal disease; pneumococcal conjugate vaccines; serotype; bacteria; France; Spain; Belgium; England; Wales; research
17.  Dynamic models of pneumococcal carriage and the impact of the Heptavalent Pneumococcal Conjugate Vaccine on invasive pneumococcal disease 
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.
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.
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.
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.
PMCID: PMC2867993  PMID: 20377886
18.  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.
PMCID: PMC2668348  PMID: 19225103
19.  Observed smoking in cars: a method and differences by socioeconomic area 
Tobacco Control  2006;15(5):409-411.
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.
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.
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).
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.
PMCID: PMC2563644  PMID: 16998177
tobacco smoking; second‐hand smoke; cars; motor vehicles; observational study
20.  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.
PMCID: PMC2573380  PMID: 18779338
21.  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.
PMCID: PMC2600366  PMID: 18680640
Pandemic influenza; secondary bacterial pneumonia; antibiotic stockpiles; pneumococcal vaccination; emergency planning; perspective
22.  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.
PMCID: PMC2600241  PMID: 18439353
Pneumonia; hospital; patient admission; epidemiology; trends; England; research
23.  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.
PMCID: PMC2168168  PMID: 17881503
24.  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.
PMCID: PMC2600190  PMID: 18258111
Streptococcus pyogenes; population surveillance; bacteremia; shock; septic; United Kingdom; research
25.  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.
PMCID: PMC1886004  PMID: 17259077
Prostaglandin; EP4 receptor; Apoptosis; Survival; PI3 Kinase

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