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Background Long-term Proton Pump Inhibitor use is associated with low response rates and the risk of adverse events. Objective The objective of this study was to assess the effectiveness of Osteopathic Treatment in patients with Gastroesophageal Reflux Disease (GERD). Methods This study was a randomized controlled trial with a series of osteopathic interventions and an untreated control group. Patients in the osteopathic group (OG) received 4 osteopathic treatments within a time of eight weeks. The control group (CG) did not receive any osteopathic treatment. Primary outcome parameters were gastrointestinal symptoms, assessed by means of the Reflux Disease Questionnaire (RDQ). Secondary outcome parameters were Quality of life with regards to GERD symptoms, assessed by means of the Quality of Life in Reflux and Dyspepsia (QUOLRAD) questionnaire, medication use and osteopathic dysfunctions. Results Seventy patients were randomized. RDQ mean scores decreased statistically significantly in the OG but did not change in the CG; however, these data cannot be interpreted due to a large number of incorrectly completed questionnaires. The between group difference of the changes for the QOLRAD score was statistically significant 0.69 [95%CI = 0.35 to 1.0]. At week 20, changes in the QOLRAD of the OG were sustainable. Medication use decreased substantially in the OG whilst it remained the same in the CG. Conclusion A series of osteopathic treatments might potentially be beneficial for patients suffering from GERD. Future studies should include longer follow-up times and establish the clinical significance of results by introducing a global rating of change measurement.

Background Melanoma causes the majority of skin cancer deaths. Australia (AUS) has the world's highest incidence rate, whereas the United Kingdom's (UK) incidence rate is one third of that, but rising rapidly. Osteopaths, many of whom routinely look at least at a part of the patient's skin as part of their osteopathic examination, are potentially in an ideal position for melanoma recognition. Objective To investigate the current attitudes, practice, confidence and knowledge of osteopaths practising in the UK and Australia with regard to melanoma recognition. Materials and methods A link to an electronic questionnaire was sent out by e-mail to 2368 osteopaths registered with the General Osteopathic Council (UK) and to 942 osteopaths registered with the Osteopathy Board of Australia. Descriptive and inferential statistics were applied to the quantitative data. The qualitative data were evaluated with a thematic analysis approach. Results Following exclusions, 378 responses from UK osteopaths and 137 responses from AUS osteopaths were analysed. Melanoma recognition was seen as a valuable part of osteopathic practice by 85% of all osteopaths, but the topic of melanoma constituted only a minor aspect in everyday interactions with patients and colleagues, and confidence-levels with regard to early recognition were in the medium-to-low range only. Participants did not perform better than by chance when discriminating melanoma from benign lesions in picture tests, but scored high in melanoma background knowledge. The vast majority of osteopaths relied on rule-based approaches, for example the ABC(D)(E) acronym, rather than the more promising "ugly duckling sign" (a lesion that appears different from a patient's other moles). Conclusions UK and AUS osteopaths have a positive attitude towards melanoma recognition, however they demonstrate limited levels of confidence and knowledge. Future research should evaluate the reliability of melanoma recognition rates by osteopaths using the "ugly duckling sign" versus osteopaths using rule-based approaches.

Carbon nanotubes (CNTs) have promised a range of applications in biomedicine. Although influenced by the dispersants used, CNTs are recognized by the innate immune system, predominantly by the classical pathway of the complement system. Here, we confirm that complement activation by the CNT used here continues up to C3 and C5, indicating that the entire complement system is activated including the formation of membrane-attack complexes. Using recombinant forms of the globular regions of human C1q (gC1q) as inhibitors of CNT-mediated classical pathway activation, we show that C1q, the first recognition subcomponent of the classical pathway, binds CNTs via the gC1q domain. Complement opsonisation of CNTs significantly enhances their uptake by U937 cells, with concomitant downregulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines in both U937 cells and human monocytes. We propose that CNT-mediated complement activation may cause recruitment of cellular infiltration, followed by phagocytosis without inducing a pro-inflammatory immune response. Carbon nanotubes (CNTs) are recognized by the innate immune system, especially by the classical pathway of the complement system. Complement activation is usually associated with a pro-inflammatory response. Here, we show that complement deposition on CMC- and RNA-CNTs can enhance their uptake by phagocytes, which in turn, leads to dampening of pro-inflammatory cytokine production. It appears that CNT-mediated complement activation may cause recruitment of cellular infiltration, followed by enhanced phagocytosis and suppression of cytokine storm.

Although cyberbullying is characterized by worrying prevalence rates and associated with a broad range of detrimental consequences, there is a lack of scientifically based and evaluated preventive strategies. Therefore, the present study introduces a theory-based cyberbullying prevention program (Media Heroes; German original: Medienhelden) and evaluates its effectiveness. In a pretest–posttest design (9-month interval), schools were asked to randomly assign their participating classes to either control or intervention group. Longitudinal data were available from 593 middle school students (M Age = 13.3 years, 53 % girls) out of 35 classes, who provided information on cyberbullying behavior as well as socio-demographic and psychosocial variables. While the present results revealed worrying prevalence rates of cyberbullying in middle school, multilevel analyses clearly demonstrate the program’s effectiveness in reducing cyberbullying behavior within intervention classes in contrast to classes of the control group. Hence, this study presents a promising program which evidentially prevents cyberbullying in schools.

Summary Objective Craniosacral therapy (CST) is an alternative treatment approach, aiming to release restrictions around the spinal cord and brain and subsequently restore body function. A previously conducted systematic review did not obtain valid scientific evidence that CST was beneficial to patients. The aim of this review was to identify and critically evaluate the available literature regarding CST and to determine the clinical benefit of CST in the treatment of patients with a variety of clinical conditions. Methods Computerised literature searches were performed in Embase/Medline, Medline ® In-Process, The Cochrane library, CINAHL, and AMED from database start to April 2011. Studies were identified according to pre-defined eligibility criteria. This included studies describing observational or randomised controlled trials (RCTs) in which CST as the only treatment method was used, and studies published in the English language. The methodological quality of the trials was assessed using the Downs and Black checklist. Results Only seven studies met the inclusion criteria, of which three studies were RCTs and four were of observational study design. Positive clinical outcomes were reported for pain reduction and improvement in general well-being of patients. Methodological Downs and Black quality scores ranged from 2 to 22 points out of a theoretical maximum of 27 points, with RCTs showing the highest overall scores. Conclusion This review revealed the paucity of CST research in patients with different clinical pathologies. CST assessment is feasible in RCTs and has the potential of providing valuable outcomes to further support clinical decision making. However, due to the current moderate methodological quality of the included studies, further research is needed.

Non-small cell lung cancer (NSCLC) is associated with high morbidity and mortality. Surgery is generally accepted as the first-line treatment in patients with advanced/metastatic NSCLC, followed by radiotherapy and chemotherapy as second-line treatments. Docetaxel or erlotinib are generally recommended as the first-line chemotherapy option. The objective of this review was to identify previously published economic evaluations in NSCLC for second- and later-line treatments in order to (i) determine common modelling approaches and (ii) establish the relative cost effectiveness of these treatments. An overview of model critique was also produced to identify common criticisms from health technology assessment (HTA) bodies on the models submitted. MEDLINE, Embase, EconLit, MEDLINE in Process® and NHS Economic Evaluation Database (NHSEED) were searched (database start–October 2011), along with proceedings from eight major conferences (2007–2011). National Institute for Health and Clinical Excellence (NICE), Scottish Medicines Consortium (SMC), Pharmaceutical Benefits Advisory Committee (PBAC) and Canadian Agency for Drugs and Technologies in Health (CADTH) websites and the International Network of Agencies for Health Technology Assessment (INAHTA) database were also searched for appraisals in second- or later-line NSCLC. All published studies and HTA appraisals that reported economic evaluations of interventions used in current clinical practice as second- or later-line treatment in patients with advanced/metastatic NSCLC were included. Only studies in English were considered for inclusion. Studies which met the eligibility criteria after the screening of full-text articles were extracted by a reviewer and checked by a second party. Where multiple publications were identified describing a single study, the extracted data were compiled into one entry. A total of 29 studies were included which clearly evaluated second-line or later-line regimens. Most studies were either cost-effectiveness or cost-utility evaluations. Three-state transition Markov models were frequently used in cost-effectiveness and cost-utility evaluations. The model inputs were well reported and commonly consisted of data from pivotal trials. Sensitivity analyses were conducted in the majority of studies and covered variables such as cost, effectiveness, hospitalization and treatment duration. Therapies (docetaxel, pemetrexed and erlotinib) are for the most part cost-effective/cost-saving second-line therapies compared with best supportive care (BSC). Six erlotinib HTAs, across NICE, SMC, and PBAC, and four pemetrexed HTAs, one by NICE and three by SMC, were identified. The CADTH website did not provide sufficient detail on the appraisals and was excluded. Certain aspects of the models and model assumptions, e.g. efficacy inputs, were criticized or determined unjustifiable by the NICE, SMC and PBAC appraisal committees. Erlotinib and pemetrexed were considered to be cost effective versus docetaxel by NICE and SMC in the final submissions. PBAC considered erlotinib to be cost effective versus BSC following a price reduction in 2008. Three-state Markov models are often used to conduct economic analysis in NSCLC and are regarded as appropriate to HTA agencies. Docetaxel, erlotinib and BSC are suitable comparators that should be considered for use in the model in the UK and Australia. Further, manufacturers should carefully select underlying assumptions used in the model, for both costs and clinical inputs, where the latter is derived from direct head-to-head trial data.

Although many studies have reported on internalising and externalising problems related to cyberbullying roles, there is a lack of longitudinal research in this area. This study reports (1) cross-sectional data from 412 German middle-school students to examine differences between cyberbullies, cybervictims and cyberbully–victims compared to non-involved students in regard to internalising (depressiveness and loneliness) and externalising (instrumental and reactive aggression) problems; and (2) longitudinal data from 223 students about links of cyberbullying and cybervictimisation with internalising and externalising problems across two measurement occasions, analysed using path analysis (separately by gender). Self-report measures were used. The results revealed no significant differences between groups in internalising problems, but all three cyberbullying groups differed significantly from the non-involved group in externalising problems. Female victims showed increases in externalising problems while m...

Transient ischemic attack (TIA) is a serious condition which should be considered on the same spectrum as other conditions involving brain ischemia. Efficient management of these patients is therefore critical. The aim of this research was to gain insights into 'real-world' global trends of the current management approaches for patients with suspected and diagnosed TIA, and highlight the unmet need and areas of improvement to ensure effective management of this patient group.Tele-interviews were conducted with 120 physicians and five operational managers across France, Germany, Italy, Spain, UK, and the US including stakeholders from primary care group practice, those with hospital responsibilities (ER physician and Neurologists), or from home health agencies. Information from the interviewees regarding the management of patients with TIA (including entrance into the clinical pathway, diagnosis, and treatment) were obtained and analyzed qualitatively.The majority of patients with suspected TIA were reported to enter the clinical pathway via the GP or ER, irrespective of country. Once initially seen, the neurologist then plays a central role in the diagnosis, treatment and follow-up of the patients. Although a number of tests are routinely employed, interviewees reported that streamlining and simplification of diagnosis, faster initiation of treatment, improved efficacy and fewer side-effects with treatment were needed for patients with suspected TIA. The study is designed to provide a directional indication of the current situation rather than strong, quantitative conclusions, given limitations of the small sample size and subjective nature of the data.The importance of correct management of patients with TIA is becoming increasingly recognized by physicians. Improved education for patients regarding symptom recognition and severity is required along with a standardized diagnostic process. These would enable correct and fast diagnosis and initiation of treatment thereby reducing the risk of further events.

This review describes current knowledge on the severity and long-term sequelae of meningococcal disease (MD) specifically. The literature databases Medline and Embase were used by combining search terms for MD and Neisseria meningitidis with terms for severity, mortality and sequelae. Case fatality for sufferers of MD remains high, typically 5-10%, despite the best medical care. Long-term sequelae in survivors may include physical, neurological, cognitive, behavioral and psychological consequences, such as hearing loss, amputations, skin scarring and neurodevelopmental deficits. A significantly lower quality of life is seen in survivors of MD compared with unaffected controls, with detrimental effects of childhood MD continuing into adulthood. MD carries a substantial risk of long-term sequelae and mortality. This should be recognized by physicians treating patients with this disease and lends support for the implementation of preventative measures such as vaccination.

Cranial osteopathic manipulative medicine (OMM) involves the manipulation of the primary respiratory mechanism to improve structure and function in children and adults.To identify and critically evaluate the literature regarding the clinical efficacy of cranial OMM.The clinical keywords "cranial manipulation" OR "osteopathy in the cranial field" OR "cranial osteopathy" OR "craniosacral technique" were searched in the following electronic databases: EMBASE, MEDLINE In-ProcessOther Non-Indexed Citations, The Cochrane Central Register of Controlled Trials, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and AMED (Alternative Medicine). Searches were conducted in April 2011 with no date restriction for when the studies were completed.Randomized controlled trials and observational studies that measured the effectiveness of cranial OMM on humans were included in the study. Exclusion criteria included non-English language articles, studies not relevant to cranial OMM, animal studies, and studies in which there was no clear indication of the use of cranial OMM. Studies that described the use of cranial OMM with other treatment modalities and that did not perform subgroup analysis were also excluded. The present study did not have criteria regarding type of disease.Outcome measures on pain, sleep, quality of life, motor function, and autonomic nervous system function were extracted. The methodological quality of the trials was assessed using the Downs and Black checklist.Of the 8 studies that met the inclusion criteria, 7 were randomized controlled trials and 1 was an observational study. A range of cranial OMM techniques used for the management of a variety of conditions were identified in the included studies. Positive clinical outcomes were reported for pain reduction, change in autonomic nervous system function, and improvement of sleeping patterns. Methodological Downs and Black quality scores ranged from 14 to 23 points out of a maximum of 27 points (overall median score, 16).The currently available evidence on the clinical efficacy of cranial OMM is heterogeneous and insufficient to draw definitive conclusions. Because of the moderate methodological quality of the studies and scarcity of available data, further research into this area is needed.

Surfactant proteins A (SP-A) and D (SP-D), both members of the collectin family, play a well established role in apoptotic cell recognition and clearance. Recent in vitro data show that SP-A and SP-D interact with apoptotic neutrophils in a distinct manner. SP-A and SP-D bind in a Ca(2+)-dependent manner to viable and early apoptotic neutrophils whereas the much greater interaction with late apoptotic neutrophils is Ca(2+)-independent. Cell surface molecules on the apoptotic target cells responsible for these interactions had not been identified and this study was done to find candidate target molecules. Myeloperoxidase (MPO), a specific intracellular defense molecule of neutrophils that becomes exposed on the outside of the cell upon apoptosis, was identified by affinity purification, mass-spectrometry and western blotting as a novel binding molecule for SP-A and SP-D. To confirm its role in recognition, it was shown that purified immobilised MPO binds SP-A and SP-D, and that MPO is surface-exposed on late apoptotic neutrophils. SP-A and SP-D inhibit binding of an anti-MPO monoclonal Ab to late apoptotic cells. Fluorescence microscopy confirmed that anti-MPO mAb and SP-A/SP-D colocalise on late apoptotic neutrophils. Desmoplakin was identified as a further potential ligand for SP-A, and neutrophil defensin as a target for both proteins.

The role of surfactant protein A (SP-A) in the recognition and clearance of apoptotic cells is well established, but to date, it is still not clear which surface molecules of apoptotic cells are involved in the process. Here we present evidence that phosphatidylserine (PS) is a relevant binding molecule for human SP-A. The binding is Ca(2+)-dependent and is not inhibited by mannose, suggesting that the sugar-binding site of the carbohydrate recognition domain (CRD) of SP-A is not involved. Flow cytometry studies on apoptotic Jurkat cells revealed apparent inhibition of annexin V binding by increasing concentrations of SP-A in late apoptotic but not early apoptotic cells, and this was consistent for Jurkat cells and neutrophils. Supporting these data, confocal microscopy results show a co-localisation of annexin V and SP-A in late apoptotic but not early apoptotic cells. However, we cannot conclude that this inhibition is exclusively due to the binding of SP-A to PS on the cell surface, as annexin V is not wholly specific for PS and SP-A also interacts with other phospholipids that might become exposed on the apoptotic cell surface.

The role of the lung surfactant proteins SP-A and SP-D in immune defence is well established. They bind to foreign organisms that invade the lungs and target them for phagocytic clearance by resident alveolar macrophages. SP-A and SP-D also bind to various apoptotic cells and facilitate their phagocytic uptake. To date, the molecular mechanisms by which the lung surfactant proteins interact with apoptotic cells and phagocytes are poorly understood. The aims of this study were to investigate further the interactions between SP-A and SP-D and apoptotic cells using human neutrophils and Jurkat cells as model systems. Specifically the binding behaviour of SP-A and SP-D with viable, early apoptotic and late apoptotic cells was investigated and compared. SP-A and SP-D show very distinct binding to the various cell types. SP-A bound to viable and early apoptotic cells in a predominantly Ca(2+)-dependent manner but the interaction with late apoptotic cells was Ca(2+)-independent, suggesting involvement of other than the lectin- or Ca(2+)-binding sites. This was consistent for neutrophils and Jurkat cells. SP-D in contrast, did not interact with viable and early apoptotic Jurkat cells but strongly and in a Ca(2+)-independent manner with late apoptotic Jurkat cells. SP-D-binding to viable and early apoptotic neutrophils was inhibited by maltose and ethylene-diamin-tetra-acetate (EDTA), suggesting lectin-binding site involvement whereas the binding to late apoptotic neutrophils was predominantly Ca(2+)-independent. These results represent a detailed study of the binding behaviour of SP-A and SP-D with different cell types and stages of viability. The mechanisms of these interactions appear to involve preferential recognition of different ligands on the apoptotic cell surface, which may include nucleic acid, phospholipid, protein and glycan structures.

Sera from healthy infants (under 1 year old), toddlers (3–4 years) and adults (18–65 years) were assayed for their ability to bind to inner core (ic) lipopolysaccharide (LPS) epitopes of Neisseria meningitidis. Antibodies (Abs) reacting to inner core structures, including different substitutions of the first heptose (HepI) and second heptose (HepII) residues of the LPS backbone, truncated and fully extended LPS glycoforms, were detected and for each structure, these inner core antibodies showed an age-related pattern of acquisition. A novel column-based methodology was used to affinity purify IgG antibodies in which purified inner core LPS (derived from a mutant MC58) was covalently linked to Sepharose 4B. Comparison of reactivity before and after affinity purification of the pooled sera showed that the purified Abs bound to the surface of N. meningitidis organisms displaying truncated and extended LPS with a homologous inner core region, promoted the deposition of C3b, were opsonophagocytic in vitro and decreased bacteraemia when used to passively protect infants rats. In addition, the purified Abs were bactericidal in vitro against the mutant strain displaying truncated LPS with a homologous inner core region. These results demonstrate that naturally occurring serum human antibodies to N. meningitidis LPS can access inner core epitopes of encapsulated organisms with a fully extended LPS.

Surfactant Protein A (SP-A) and D (SP-D) are calcium-dependent collagen-containing lectins, also called collectins, which play a significant role in surfactant homeostasis and pulmonary immunity. The role of SP-A and SP-D in immune defence is well- established. They are known to bind to a range of microbial pathogens that invade the lungs and target them for phagocytic clearance by resident alveolar macrophages. They are also involved in the clearance of apoptotic and necrotic cells and subsequent resolution of pulmonary inflammation. To date, the molecular mechanisms by which SP-A and SP-D interact with various immune cells are poorly understood. In spite of overall structural similarity, SP-A and SP-D show a number of functional differences in their interaction with surface molecules of microorganisms and host cells. The aim of this review is to provide an overview of the current knowledge of ligands and receptors that are known to interact with SP-A and SP-D.

Dendritic-cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN; CD209) has an important role in mediating adherence of Mycobacteria species, including M. tuberculosis and M. bovis BCG to human dendritic cells and macrophages, in which these bacteria can survive intracellularly. DC-SIGN is a C-type lectin, and interactions with mycobacterial cells are believed to occur via mannosylated structures on the mycobacterial surface. Recent studies suggest more varied modes of binding to multiple mycobacterial ligands. Here we identify, by affinity chromatography and mass-spectrometry, four novel ligands of M. bovis BCG that bind to DC-SIGN. The novel ligands are chaperone protein DnaK, 60 kDa chaperonin-1 (Cpn60.1), glyceraldehyde-3 phosphate dehydrogenase (GAPDH) and lipoprotein lprG. Other published work strongly suggests that these are on the cell surface. Of these ligands, lprG appears to bind DC-SIGN via typical proteinglycan interactions, but DnaK and Cpn60.1 binding do not show evidence of carbohydrate-dependent interactions. LprG was also identified as a ligand for DC-SIGNR (L-SIGN; CD299) and the M. tuberculosis orthologue of lprG has been found previously to interact with human toll-like receptor 2. Collectively, these findings offer new targets for combating mycobacterial adhesion and within-host survival, and reinforce the role of DCSIGN as an important host ligand in mycobacterial infection. Instituto de Biotecnología Fil: Carroll, Maria V. University of Oxford. Department of Pharmacology; Gran Bretaña Fil: Sim, Robert B. University of Oxford. Department of Pharmacology; Gran Bretaña Fil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina Fil: Jäkel, Anne. University of Oxford. Department of Pharmacology; Gran Bretaña Fil: Antrobus, Robin. Addenbrooke’s Hospital. Cambridge Institute of Medical Research; Gran Bretaña Fil: Mitchell, Daniel A. University of Warwick. CSRI-UHCW Walsgrave Campus; Gran Bretaña