Experiments in pneumatic chemistry paved the way for medical innovation in the last quarter of the eighteenth century. Thomas Beddoes and James Watt were instrumental in the spread of the use of new gas chemistry in pneumatic therapy, but they were far from alone. There was no shortage of experimental subjects, as the practice was quickly taken up by medics throughout Britain.

OBJECTIVES: To evaluate the clinical effectiveness (including adverse events) and cost-effectiveness of antivirals for the treatment of naturally acquired influenza for 'at-risk' and otherwise healthy populations. DATA SOURCES: Eleven electronic databases (MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Pascal, Science Citation Index, BIOSIS, Latin American and Caribbean Health Sciences, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database) were searched from October 2001 to November 2007. A supplementary search was undertaken in June 2008 for information relating to drug resistance during the 2007-8 influenza season. REVIEW METHODS: Systematic reviews of the evidence on the clinical effectiveness and cost-effectiveness of antivirals for the treatment of influenza were undertaken. Twenty-nine randomised controlled trials comparing antivirals with each other, placebo, or best symptomatic care were included in the evaluation of clinical effectiveness in patients presenting with an influenza-like illness (ILI). Primary outcomes were measures of symptom duration (median time to alleviation of symptoms and median time to return to normal activity). Incidence of complications, mortality, hospitalisations, antibiotic use (as a surrogate for complications) and adverse events was also assessed. In addition, an independent decision model was developed to evaluate the cost-effectiveness of antiviral treatment from the perspective of the UK NHS. RESULTS: Amantadine was excluded at an early stage, owing to a lack of any new trials that met the inclusion criteria and the limitations of the existing evidence. The review therefore focused on the neuraminidase inhibitors (NIs) oseltamivir and zanamivir, both of which were found to be effective in reducing symptom duration (zanamavir by 0.5-1.0 days and oseltamivir by 0.5-1.5 days). However, the effect sizes were often small and unlikely to be clinically significant in many cases, particularly in healthy adults. For the at-risk subgroups, effect sizes for differences in symptom duration were generally larger, and potentially more clinically significant, than those seen in healthy adults (median duration of symptoms reduced by 1-2 days with zanamivir and 0.50-0.75 days with oseltamivir). However, there was greater uncertainty around these results, with estimates often failing to reach statistical significance. The most consistent data and strongest evidence related to antibiotic use, with both zanamivir and oseltamivir resulting in statistically significant reductions in antibiotic use. In general, the estimates from the cost-effectiveness model were more favourable in at-risk populations (including adults and children with comorbid conditions and the elderly) compared with otherwise healthy populations. Zanamivir was the optimal NI treatment in each of the at-risk populations considered, and oseltamivir was optimal for healthy populations (both adults and children). CONCLUSIONS: The clinical effectiveness data for population subgroups used to inform the multiparameter evidence synthesis and cost-effectiveness modelling were, in places, limited and this should be borne in mind when interpreting the findings of this review. Trials were often not designed to determine clinical effectiveness in population subgroups and hence, although the direction of effect was clear, estimates of differences in symptom duration tended to be subject to greater uncertainty in subgroups. Despite some concerns, the use of NIs in at-risk populations appeared to be a cost-effective approach for the treatment of influenza. Well-designed observational studies might also be considered to evaluate the clinical course of influenza in terms of complications, hospitalisation, mortality and quality of life, as well as the impact of NIs.

Elevated C-reactive protein (CRP) is associated with an increased risk of cardiovascular disease. Physical activity has been inversely associated with CRP. However, the clinical trials examining the effect of exercise training have produced conflicting results. PURPOSE:: The purpose of this study was to examine the influence an exercise training program on CRP in postmenopausal women. METHODS:: Sedentary, overweight/obese, postmenopausal women with elevated systolic blood pressure (120.0 to 159.9 mm Hg)(N= 464) were randomized into 1 of 4 groups: a non-exercise control or 1 of 3 aerobic exercise groups; exercise energy expenditure of 4, 8, or 12 kcal/kg/week (KKW), for 6 months at a training intensity of 50% of peak VO2. RESULTS:: Complete data was available of 421 participants and mean baseline CRP was 5.7 (5.5) mg/L with no significant differences across groups. While VO2 increased in a dose response manner, there were no significant changes in CRP in any of the exercise intervention groups compared to the control group. Change in fitness was not associated with change in CRP, whereas change in weight was significantly associated with change in CRP. CONCLUSION:: Despite increasing fitness, six months of aerobic exercise training did not improve CRP. However, improvements in CRP were associated with reductions in weight.

INTRODUCTION/PURPOSE:: Inflammatory cytokines are associated with age- and inactivity-related disease. We examined the influence of moderate-high intensity resistance exercise training (RT) on inflammatory cytokines (IL-6,IL-1beta, and TNF-alpha) in circulation and LPS-stimulated whole blood in elderly women. METHOD:: Previously sedentary women (72+/-6.1 yr) were grouped according to their hormone replacement regimen: traditional estrogen/progesterone (HRT, N=12), selective estrogen receptor modulator (SER, N=7), no hormone replacement (NHR, N=9), or non-exercise control group taking no hormone replacement (CON; N=7). HRT, SER, and NHR trained (three sets, 10 exercises at 8RM) three days per week while CON maintained their "normal" activity for 10 weeks. Participants performed a bout of resistance exercise (RE; 8RM)(HRT,SER,NHR) or sat quietly (CON) before (BT) and after (AT) RT to assess the influence of training on the acute responses to RE. Blood samples were obtained pre-exercise (PR), post-exercise (PO), and two hours post-exercise (2H)(same time points for resting CON). RESULTS:: Hormone status had no influence on dependent variables so HRT, SER and NHR were collapsed into one exercise group (EX; N=28) and compared to CON. RT significantly reduced resting serum TNF-alpha by 37%. RT also reduced LPS-stimulated production of IL-6, IL-1beta and TNF-alpha at all time points (PR, PO, 2H; per monocyte). Acute RE transiently increased plasma TNF-alpha, but blunted the circadian increase in LPS-stimulated inflammatory cytokines observed in CON. The blunting effect in EX was significantly greater AT compared to BT. RE also resulted in an increase in plasma IL-6 which was significantly reduced AT (BT:PR=1.6+/-0.5, PO=2.8+/-0.5; AT:PR=1.8+/-0.3, PO=2.4+/-0.3). CONCLUSION:: We found that 10 weeks of moderate-high intensity RT: 1) reduced the systemic inflammatory milieu and 2) abrogated exercise-induced circulating IL-6 in previously sedentary elderly women.

The C-type lectin dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) mediates the innate immune recognition of microbial carbohydrates. We investigated the function of this molecule in the host response to pathogens in vivo, by generating mouse lines lacking the DC-SIGN homologues SIGNR1, SIGNR3, and SIGNR5. Resistance to Mycobacterium tuberculosis was impaired only in SIGNR3-deficient animals. SIGNR3 was expressed in lung phagocytes during infection, and interacted with M. tuberculosis bacilli and mycobacterial surface glycoconjugates to induce secretion of critical host defense inflammatory cytokines, including tumor necrosis factor (TNF). SIGNR3 signaling was dependent on an intracellular tyrosine-based motif and the tyrosine kinase Syk. Thus, the mouse DC-SIGN homologue SIGNR3 makes a unique contribution to protection of the host against a pulmonary bacterial pathogen.

Background:The key mediator of new vessel formation in cancer and other diseases is VEGF-A. VEGF-A exists as alternatively spliced isoforms - the pro-angiogenic VEGF(xxx) family generated by exon 8 proximal splicing, and a sister family, termed VEGF(xxx)b, exemplified by VEGF(165)b, generated by distal splicing of exon 8. However, it is unknown whether this anti-angiogenic property of VEGF(165)b is a general property of the VEGF(xxx)b family of isoforms.Methods:The mRNA and protein expression of VEGF(121)b was studied in human tissue. The effect of VEGF(121)b was analysed by saturation binding to VEGF receptors, endothelial migration, apoptosis, xenograft tumour growth, pre-retinal neovascularisation and imaging of biodistribution in tumour-bearing mice with radioactive VEGF(121)b.Results:The existence of VEGF(121)b was confirmed in normal human tissues. VEGF(121)b binds both VEGF receptors with similar affinity as other VEGF isoforms, but inhibits endothelial cell migration and is cytoprotective to endothelial cells through VEGFR-2 activation. Administration of VEGF(121)b normalised retinal vasculature by reducing both angiogenesis and ischaemia. VEGF(121)b reduced the growth of xenografted human colon tumours in association with reduced microvascular density, and an intravenous bolus of VEGF(121)b is taken up into colon tumour xenografts.Conclusion:Here we identify a second member of the family, VEGF(121)b, with similar properties to those of VEGF(165)b, and underline the importance of the six amino acids of exon 8b in the anti-angiogenic activity of the VEGF(xxx)b isoforms.British Journal of Cancer advance online publication, 25 August 2009; doi:10.1038/sj.bjc.6605249 www.bjcancer.com.

Background Obesity prevalence is unusually high among adults with intellectual disability (ID). There is limited and conflicting evidence on obesity prevalence among ambulatory children and adolescents with ID. The present study aimed to estimate obesity prevalence in this group and to compare with population prevalence. Methods Survey of nine schools (n = 206, 150 boys) for ambulatory children and adolescents with mild-moderate ID in Scotland in 2007. Obesity was defined as measured body mass index (BMI) at or above the 95th percentile relative to UK 1990 reference data, and using the international definition based on BMI. Obesity prevalence observed was compared against Scottish population data on obesity prevalence from the most recent nationally representative survey. Results Obesity prevalence (at or above 95th percentile for BMI) was 36%, and was significantly higher among those attending secondary schools compared with primary schools (P < 0.01). Prevalence of obesity was significantly higher than in the general paediatric population in both boys and girls (P < 0.01). Conclusions The present study suggests that that obesity may be very prevalent among ambulatory children and adolescents with ID, and that increased obesity risk may begin in childhood.

The objective of the current study was to determine the origin of the slow spike and wave discharges (SSWD) in the transgenic mouse with postnatal over-expression of the GABA(B) receptor subunit R1a (GABA(B)R1a(tg)), a mutant animal with a characteristic phenotype consisting of atypical absence seizures and cognitive dysfunction. Using simultaneous electrocorticographic (ECoG) recordings from cortical and depth electrodes in freely moving GABA(B)R1a(tg) mice, we showed that the SSWD in this model of atypical absence seizures arise exclusively from midline thalamus (MT), reticular nucleus of the thalamus (nRT), and the CA1 region of the hippocampus. Lesioning of the MT and nRT with ibotenic acid abolished SSWD. Microinjection of the GABA(B) receptor agonist,(-) baclofen, into MT and nRT exacerbated, and the GABA(B)R antagonist, CGP 35348 abolished, SSWD in the GABA(B)R1a(tg) mice. These data suggest that the nRT and MT are necessary for the generation of SSWD in the GABA(B)R1a(tg) model of atypical absence seizures, and indicate that GABA(B)R-mediated mechanisms within thalamus are necessary for the genesis of SSWD in atypical absence seizures. A putative cortico-thalamo-hippocampal circuit is proposed to explain the unique electrographic findings, ictal behavior, pharmacology, and impairment of cognition that characterize atypical absence seizures.

In publicly funded health systems with finite resources, management decisions are based on assessments of clinical effectiveness and cost-effectiveness. The UK National Institute for Health and Clinical Excellence commissioned a systematic review to inform their 2009 update to guidance on the use of antiviral drugs for the treatment of influenza. We searched databases for studies of the use of neuraminidase inhibitors for the treatment of seasonal influenza. We present the results for healthy adults (ie, adults without known comorbidities) and people at-risk of influenza-related complications. There was an overall reduction in the median time to symptom alleviation in healthy adults by 0.57 days (95% CI -1.07 to -0.08; p=0.02; 2701 individuals) with zanamivir, and 0.55 days (95% CI -0.96 to -0.14; p=0.008; 1410 individuals) with oseltamivir. In those at risk, the median time to symptom alleviation was reduced by 0.98 days (95% CI -1.84 to -0.11; p=0.03; 1252 individuals) with zanamivir, and 0.74 days (95% CI -1.51 to 0.02; p=0.06; 1472 individuals) with oseltamivir. Little information was available on the incidence of complications. In view of the advantages and disadvantages of different management strategies for controlling seasonal influenza in healthy adults recommending the use of antiviral drugs for the treatment of people presenting with symptoms is unlikely to be the most appropriate course of action.