Spatial variability of precipitation regimes over Turkey

Turkish annual precipitation regimes are analysed to provide large-scale perspective and redefine precipitation regions. Monthly total precipitation data are employed for 107 stations (1963–2002). Precipitation regime shape (seasonality) and magnitude (size) are classified using a novel multivariate methodology. Six shape and five magnitude classes are identified, which exhibit clear spatial structure. A composite (shape and magnitude) regime classification reveals dominant controls on spatial variability of precipitation. Intra-annual timing and magnitude of precipitation is highly variable due to seasonal shifts in Polar and Subtropical zones and physiographic factors. Nonetheless, the classification methodology is shown to be a powerful tool that identifies physically-interpretable precipitation regions: (1) coastal regimes for Marmara, coastal Aegean, Mediterranean and Black Sea; (2) transitional regimes in continental Aegean and Southeast Anatolia; and (3) inland regimes across central and Eastern Anatolia. This research has practical implications for understanding water resources, which are under ever growing pressure in Turkey

Death is associated with complement C3 depletion in cerebrospinal fluid of patients with pneumococcal meningitis.

Pneumococcal meningitis can lead to death or serious neurological sequelae as a result of the host inflammatory response. We investigated the association between host response protein expression and outcome in patients with pneumococcal meningitis. Cerebrospinal fluid (CSF) was obtained from 80 patients with pneumococcal meningitis (40 nonsurvivors and 40 survivors) and 10 normal controls. Candidate proteins were analyzed for an association with survival. Complement C3 levels were 5-fold lower in nonsurvivors than in survivors (P < 0.05). This C3 reduction was not associated with lower levels in serum, indicating a compartmentalized CSF response. Transferrin levels were significantly higher in CSF (but not serum) from nonsurvivors than in CSF from survivors, suggestive of blood-brain barrier damage. Classical apoptosis proteins caspase 3 and apoptosis-inducing factor were not present in CSF. Expression of creatine kinase BB in clinically infected CSF suggested neuronal necrosis, but there was no clear association between level of expression and clinical outcome. Increased blood-brain barrier permeability and complement C3 depletion may have a role in determining outcome from bacterial meningitis. Therapeutic use of citicoline or caspase inhibitors is unlikely to have beneficial effects in patients with meningitis. IMPORTANCE: We previously identified proteins associated with clinical outcome in patients diagnosed with pneumococcal meningitis in a pilot proteomics study of cerebrospinal fluid (CSF). In this article, we have quantitatively assayed specific proteins identified from this previous proteomics analysis along with proteins associated with cell death by using Western blotting

Multiple communication mechanisms between sensor kinases are crucial for virulence in Pseudomonas aeruginosa

This is the author accepted manuscript. The final version is available as an open access article from the publisher via the DOI in this recordBacteria and many non-metazoan Eukaryotes respond to stresses and threats using two-component systems (TCSs) comprising sensor kinases (SKs) and response regulators (RRs). Multikinase networks, where multiple SKs work together, detect and integrate different signals to control important lifestyle decisions such as sporulation and virulence. Here, we study interactions between two SKs from Pseudomonas aeruginosa, GacS and RetS, which control the switch between acute and chronic virulence. We demonstrate three mechanisms by which RetS attenuates GacS signalling: RetS takes phosphoryl groups from GacS-P; RetS has transmitter phosphatase activity against the receiver domain of GacS-P; and RetS inhibits GacS autophosphorylation. These mechanisms play important roles in vivo and during infection, and exemplify an unprecedented degree of signal processing by SKs that may be exploited in other multikinase networks.This work was supported by the Medical Research Council (MRC) (grant number MR/ M020045/1), the Leverhulme Trust (grant number RPG-2014-228), the RoseTrees Trust (grant number M328) and a NERC PhD studentship (grant number 1076449)

Dairy heifers naturally exposed to Fasciola hepatica develop a type-2 immune response and concomitant suppression of leukocyte proliferation

Fasciola hepatica is a parasitic trematode of global importance in livestock. Control strategies reliant on anthelmintics are unsustainable due to the emergence of drug resistance. Vaccines are under development, but efficacy is variable. Evidence from experimental infection suggest vaccine efficacy may be affected by parasite-induced immunomodulation. Little is known about the immune response to F. hepatica following natural exposure. Hence we analysed the immune responses over time in calves naturally exposed to F. hepatica infection.Cohorts of replacement dairy heifer calves (n=42) with no prior exposure to F. hepatica, on three commercial dairy farms, were sampled over the course of a grazing season. Exposure was determined through F. hepatica-specific serum antibody ELISA and fluke egg counts. Concurrent changes in peripheral blood leukocyte sub-populations, lymphocyte proliferation and cytokine responses were measured. Relationships between fluke infection and immune responses were analysed using multivariable linear mixed effect models.All calves from one farm showed evidence of exposure, whilst cohorts from the remaining two farms remained negative over the grazing season. A type-2 immune response was associated with exposure, with increased interleukin (IL)-4 production, IL-5 transcription and eosinophilia. Suppression of parasite-specific PBMC proliferation was evident; while decreased mitogen stimulated IFN-γ production suggested immunomodulation, which was not restricted to parasite-specific responses. Our findings show that the global immune response is modulated towards a non-proliferative type-2 state following natural challenge with F. hepatica This has implications for vaccination programmes in terms of the timing of administration of vaccination programmes, and for host susceptibility to co-infecting pathogens

Efficacy of tadalafil in Egyptian and Turkish men with erectile dysfunction

A randomised, double-blind, parallel, placebo-controlled, 12-week study was carried out to evaluate the efficacy and safety of 20-mg tadalafil taken ‘as needed’ in a population of men with erectile dysfunction (ED) from Egypt and Turkey. One hundred and thirty-two patients were randomised in this study. Tadalafil was superior to placebo on all three co-primary efficacy end points. The mean change from baseline for the erectile function domain of the International Index of Erectile Function was 9.3 ± 0.8 for the tadalafil group and 2.3 ± 1.6 for the placebo group. Tadalafil-treated patients reported a significantly greater improvement in the mean percentage of successful penetrations (tadalafil: 34.5 ± 4.1; placebo: −4.6 ± 8.1) and successful intercourse attempts (tadalafil: 52.2 ± 3.8; placebo: 16.8 ± 7.8) than placebo-treated patients as measured by the Sexual Encounter Profile. Tadalafil was generally well tolerated with 82% of adverse events being mild in severity. Tadalafil 20-mg taken ‘as needed’ significantly improved the erectile function in Egyptian and Turkish men with ED

T Regulatory Cells Control Susceptibility to Invasive Pneumococcal Pneumonia in Mice

Streptococcus pneumoniae is an important human pathogen responsible for a spectrum of diseases including pneumonia. Immunological and pro-inflammatory processes induced in the lung during pneumococcal infection are well documented, but little is known about the role played by immunoregulatory cells and cytokines in the control of such responses. We demonstrate considerable differences in the immunomodulatory cytokine transforming growth factor (TGF)-β between the pneumococcal pneumonia resistant BALB/c and susceptible CBA/Ca mouse strains. Immunohistochemistry and flow cytometry reveal higher levels of TGF-β protein in BALB/c lungs during pneumococcal pneumonia that correlates with a rapid rise in lung Foxp3+Helios+ T regulatory cells. These cells have protective functions during pneumococcal pneumonia, because blocking their induction with an inhibitor of TGF-β impairs BALB/c resistance to infection and aids bacterial dissemination from lungs. Conversely, adoptive transfer of T regulatory cells to CBA/Ca mice, prior to infection, prolongs survival and decreases bacterial dissemination from lungs to blood. Importantly, strong T regulatory cell responses also correlate with disease-resistance in outbred MF1 mice, confirming the importance of immunoregulatory cells in controlling protective responses to the pneumococcus. This study provides exciting new evidence for the importance of immunomodulation during pulmonary pneumococcal infection and suggests that TGF-β signalling is a potential target for immunotherapy or drug design

Exposure to diesel exhaust particles increases susceptibility to invasive pneumococcal disease.

BACKGROUND: The World Health Organization estimates that air pollution is responsible for 7 million deaths per annum, with 7% of these attributable to pneumonia. Many of these fatalities have been linked to exposure to high levels of airborne particulates, such as diesel exhaust particles (DEPs). OBJECTIVES: We sought to determine whether exposure to DEPs could promote the progression of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae to invasive pneumococcal disease. METHODS: We used mouse models and in vitro assays to provide a mechanistic understanding of the link between DEP exposure and pneumococcal disease risk, and we confirmed our findings by using induced sputum macrophages isolated from healthy human volunteers. RESULTS: We demonstrate that inhaled exposure to DEPs disrupts asymptomatic nasopharyngeal carriage of S pneumoniae in mice, leading to dissemination to lungs and blood. Pneumococci are transported from the nasopharynx to the lungs following exposure to DEPs, leading to increased proinflammatory cytokine production, reduced phagocytic function of alveolar macrophages, and consequently, increased pneumococcal loads within the lungs and translocation into blood. These findings were confirmed by using DEP-exposed induced sputum macrophages isolated from healthy volunteers, demonstrating that impaired innate immune mechanisms following DEP exposure are also at play in humans. CONCLUSION: Lung inhaled DEPs increase susceptibility to pneumococcal disease by leading to loss of immunological control of pneumococcal colonisation, increased inflammation, tissue damage, and systemic bacterial dissemination

Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Pneumolysin Activates the NLRP3 Inflammasome and Promotes Proinflammatory Cytokines Independently of TLR4

Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1β, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1β plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1β secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system