The Role of Chemokines in Acute Liver Injury

Chemokines are small molecular weight proteins primarily known to drive migration of immune cell populations. In both acute and chronic liver injury, hepatic chemokine expression is induced resulting in inflammatory cell infiltration, angiogenesis, and cell activation and survival. During acute injury, massive parenchymal cell death due to apoptosis and/or necrosis leads to chemokine production by hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells. The specific chemokine profile expressed during injury is dependent on both the type and course of injury. Hepatotoxicity by acetaminophen for example leads to cellular necrosis and activation of Toll-like receptors while the inciting insult in ischemia reperfusion injury produces reactive oxygen species and subsequent production of pro-inflammatory chemokines. Chemokine expression by these cells generates a chemoattractant gradient promoting infiltration by monocytes/macrophages, NK cells, NKT cells, neutrophils, B cells, and T cells whose activity are highly regulated by the specific chemokine profiles within the liver. Additionally, resident hepatic cells express chemokine receptors both in the normal and injured liver. While the role of these receptors in normal liver has not been well described, during injury, receptor up-regulation, and chemokine engagement leads to cellular survival, proliferation, apoptosis, fibrogenesis, and expression of additional chemokines and growth factors. Hepatic-derived chemokines can therefore function in both paracrine and autocrine fashions further expanding their role in liver disease. More recently it has been appreciated that chemokines can have diverging effects depending on their temporal expression pattern and the type of injury. A better understanding of chemokine/chemokine receptor axes will therefore pave the way for development of novel targeted therapies for the treatment of liver disease

Strategi Najib Razak Dalam Upaya Pemenangan Pemilihan Raya Malaysia 2013

This research is aimed to see how Najib Razak uses his foreign policy attacking Sabah as his winning strategy on Malaysia Election Pemilihan Raya in 2013. Najib Razak and his party, UMNO (United Malay National Organization) is not in good condition where it has lost many votes in 2008 election. Toward this situation, Najib Razak also faced Sulus Attack that is commited by MNLF.This research uses pluralism perspective and idiosincratic theory where stuffs related to personal life of the actor will influence the policy taken. The research methods is descriptive with library reasearch technique which used collect and elaborate the data and information from text book, journals, thesis and internet website.The result of this research shows that Najib Razak strategy has shown the result. 1Malaysia strategy that had benn used on fixing Najibs image has increase the people supports and votes. Najib Razak has also gotten the advantages from Sulu that contraining MNLF and Sabah conflict. Najib Razak use Serangan Fajar attack in order to defend sovereigntyand figthing terrorism. Nationalism that occured from Malaysians made them voted Najib Razak on Malaysia 2013 Election by getting 133 chairs from 222 chairs that was competed.Keyword : Najib Razak, Sabah Conflict, 1Malaysia, MNL

Microbiology of airway disease in a cohort of patients with Cystic Fibrosis

BACKGROUND: Recent reports document an increasing incidence of new Gram-negative pathogens such as Stenotrophomonas maltophilia and Alcaligenes xylosoxidans isolated from patients with Cystic Fibrosis, along with an increase in common Gram-negative pathogens such as Pseudomonas aeruginosa and Burkholderia cepacia complex. Furthermore, the increase in multidrug-resistance of such organisms makes the therapeutic management of these patients more problematic. Therefore, careful isolation and identification, and accurate studies of susceptibility to antibiotics are critical for predicting the spread of strains, improving therapeutic measures and facilitating our understanding of the epidemiology of emerging pathogens. The first aim of this study was to determine the incidence and the prevalence of colonization by Gram-negative organisms isolated from respiratory samples of Cystic Fibrosis patients in the Regional Referral Cystic Fibrosis Centre of Naples; the second was to evaluate the spectrum of multidrug-resistance of these organisms. METHODS: Patients (n = 300) attending the Regional Cystic Fibrosis Unit were enrolled in this study over 3 years. Sputum was processed for microscopic tests and culture. An automated system, Phoenix (Becton Dickinson, Sparks, Maryland, USA), was used for phenotypic identification of all strains; the API 20 NE identification system (bioMérieux, Marcy l'Etoile, France) was used when the identification with the Phoenix system was inaccurate. A PCR-RFLP method was used to characterize the organisms in the Burkholderia cepacia complex. A chemosusceptibility test on microbroth dilutions (Phoenix) was used. Primary outcomes such as FEV1 were correlate with different pathogens. RESULTS: During the period of study, 40% of patients was infected by Pseudomonas aeruginosa, 7% by Burkholderia cepacia complex, 11% by Stenotrophomonas maltophilia and 7% by Alcaligenes xylosoxidans. Of the strains isolated, 460 were multidrug-resistant. Multiresistant were Pseudomonas aeruginosa and Burkholderia cepacia complex. CONCLUSION: The results confirm previously reported data; in particular, they show an increase the isolation of non-fermentative Gram-negative bacteria in Cystic Fibrosis patients. They also demonstrate increased resistance to antibiotics. Beta-lactams are rarely effective, with exception of ceftazidime, which is the most efficacious agent against multiresistant strains. Aminoglycosides and quinolones are poorly efficacious

Networking the way towards antimicrobial combination therapies

Publicado em "8th International Conference on Practical Applications of Computational Biology & Bioinformatics (PACBB 2014)"The exploration of new antimicrobial combinations is a pressing concern for Clinical Microbiology due to the growing number of resistant strains emerging in healthcare settings and in the general community. Researchers are screening agents with alternative modes of action and interest is rising for the potential of antimicrobial peptides (AMPs). This work presents the first ever network reconstruction of AMP combinations reported in the literature fighting Pseudomonas aeruginosa infections. The network, containing 193 combinations of AMPs with 39 AMPs and 154 traditional antibiotics, is expected to help in the design of new studies, notably by unveiling different mechanisms of action and helping in the prediction of new combinations and synergisms. The challenges faced in the attempted text-mining approaches and other considerations regarding the manual curation of the data are pointed out, reflecting about the future automation of this type of reconstruction as means to widen the scope of analysis

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis

OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ± 0.23 L/h/kg and 0.30 ± 0.17 L/kg, respectively. Half-life was 1.11 ± 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule

Optimal Management of Severe/Refractory Asthma

Asthma is a chronic inflammatory disease of the airways, affecting approximately 300 million people worldwide. Asthma results in airway hyperresponsiveness, leading to paroxysmal symptoms of wheeze, cough, shortness of breath, and chest tightness. When these symptoms remain uncontrolled, despite treatment with high doses of inhaled and ingested corticosteroids, asthmatic patients are predisposed to greater morbidity and require more health care support. Treating patients with severe asthma can be difficult and often poses a challenge to physicians when providing ongoing management. This clinical review aims to discuss the definition, prevalence and evaluation of severe asthmatics, and provides a review of the existing pharmacologic and non-pharmacologic treatment options

Multicenter observational study on factors and outcomes associated with various methicillin-resistant Staphylococcus aureus types in children with cystic fibrosis

Rationale: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type. Objectives: We hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health care-associated" (SCCmec II) versus "community-associated" (SCCmec IV)MRSAstrains. Methods: To determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from patients not more than 18 years old at seven CF centers were typed and the association of potential risk factors and subsequent clinical course was assessed, using data provided by the CF Patient Registry. Measurements and Main Results: Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%) had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IVPVL(1) strains.SCCmec IV, comparedwith SCCmec II, increased during the study period, 1996-2010 (P = 0.03). SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95% confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics were prescribed more frequently in those with SCCmec II strains and increased hospitalizations occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(1) strains (adjusted difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior. Conclusions: Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA detection regardless of SCCmec type

Achromobacter xylosoxidans respiratory tract infection in cystic fibrosis patients

The aims of this study were to evaluate the frequency of Achromobacter xylosoxidans infection in a cohort of cystic fibrosis patients, to investigate antimicrobial sensitivity, to establish possible clonal likeness among strains, and to address the clinical impact of this infection or colonization on the general outcome of these patients. The study was undertaken between January 2004 and December 2008 on 300 patients receiving care at the Regional Cystic Fibrosis Center of the Naples University “Federico II”. Sputum samples were checked for bacterial identification. For DNA fingerprinting, pulsed-field gel electrophoresis (PFGE) was carried out. Fifty-three patients (17.6%) had at least one positive culture for A. xylosoxidans; of these, 6/53 (11.3%) patients were defined as chronically infected and all were co-colonized by Pseudomonas aeruginosa. Of the patients, 18.8% persistently carried multidrug-resistant isolates. Macrorestriction analysis showed the presence of seven major clusters. DNA fingerprinting also showed a genetic relationship among strains isolated from the same patients at different times. The results of DNA fingerprinting indicate evidence of bacterial clonal likeness among the enrolled infected patients. We found no significant differences in the forced expiratory volume in 1 s (FEV1) and body mass index (BMI) when comparing the case group of A. xylosoxidans chronically infected patients with the control group of P. aeruginosa chronically infected patients

US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with preexisting inflammatory lung disease such as cystic fibrosis(CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition