Facile and Novel Synthetic Approach, Molecular Docking, Molecular Dynamics, and Drug-Likeness Evaluation of 9-Substituted Acridine Derivatives as Dual Anticancer and Antimicrobial Agents.

In the present study, numerous acridine derivatives A1-A20 were synthesized via aromatic nucleophilic substitution (SNAr) reaction of 9-chloroacridine with carbonyl hydrazides, amines, or phenolic derivatives depending upon facile, novel, and eco-friendly approaches (Microwave and ultrasonication assisted synthesis). The structures of the new compounds were elucidated using spectroscopic methods. The title products were assessed for their antimicrobial, antioxidant, and antiproliferative activities using numerous assays. Promisingly, the investigated compounds mainstream revealed promising antibacterial and anticancer activities. Thereafter, the investigated compounds' expected mode of action was debated by using an array of in silico studies. Compounds A2 and A3 were the most promising antimicrobial agents, while compounds A2, A5, and A7 revealed the most cytotoxic activities. Accordingly, RMSD, RMSF, Rg, and SASA analyses of compounds A2 and A3 were performed, and MMPBSA was calculated. Lastly, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses of the novel acridine derivatives were investigated. The tested compounds' existing screening results afford an inspiring basis leading to developing new compelling antimicrobial and anticancer agents based on the acridine scaffold.

Female Genital Cutting and Deinfibulation: Applying the Theory of Planned Behavior to Research and Practice.

At least 200 million girls and women across the world have experienced female genital cutting (FGC). International migration has grown substantially in recent decades, leading to a need for health care providers in regions of the world that do not practice FGC to become knowledgeable and skilled in their care of women who have undergone the procedure. There are four commonly recognized types of FGC (Types I, II, III, and IV). To adhere to recommendations advanced by the World Health Organization (WHO) and numerous professional organizations, providers should discuss and offer deinfibulation to female patients who have undergone infibulation (Type III FGC), particularly before intercourse and childbirth. Infibulation involves narrowing the vaginal orifice through cutting and appositioning the labia minora and/or labia majora, and creating a covering seal over the vagina with appositioned tissue. The WHO has published a handbook for health care providers that includes guidance in counseling patients about deinfibulation and performing the procedure. Providers may benefit from additional guidance in how to discuss FGC and deinfibulation in a manner that is sensitive to each patient's culture, community, and values. Little research is available to describe decision-making about deinfibulation among women. This article introduces a theoretically informed conceptual model to guide future research and clinical conversations about FGC and deinfibulation with women who have undergone FGC, as well as their partners and families. This conceptual model, based on the Theory of Planned Behavior, may facilitate conversations that lead to shared decision-making between providers and patients.

Understanding Women's Responses to Sexual Pain After Female Genital Cutting: An Integrative Psychological Pain Response Model.

The World Health Organization estimates that over 200 million women and girls have experienced female genital cutting (FGC). Many women and girls who have undergone FGC have migrated to areas of the world where providers are unfamiliar with the health needs associated with FGC. Both providers in Western healthcare systems and female immigrant and refugee patients report communication difficulties leading to distrust of providers by women who have experienced FGC. Sexual pain is one common problem requiring discussion with healthcare providers and possible intervention. Yet, existing clinical and research literature provides little guidance for assessment and intervention when sexual pain is a result of FGC. Several conceptual frameworks have been developed to conceptualize and guide treatments for other types of pain, such as back pain and headaches. In this article, we integrate four prominent models-the fear avoidance model, eustress endurance model, distress endurance model, and pain resilience model-to conceptualize sexual pain in women who have experienced FGC. The resulting integrative psychological pain response model will aid in providing culturally responsive clinical management of sexual pain to women who have experienced FGC. This integrative model also provides a theoretical foundation for future research in this population.

Clitoral Reconstruction After Female Genital Mutilation/Cutting: A Review of Surgical Techniques and Ethical Debate.

INTRODUCTION: Clitoral reconstruction (CR) is a controversial surgical procedure performed for women who have undergone medically unnecessary, often ritualistic genital cutting involving the clitoris. Such cutting is known by several terms; we will use female genital mutilation/cutting (FGM/C). Treatments offered to women affected by complications of FGM/C include defibulation (releasing the scar of infibulation to allow penetrative intercourse, urinary flow, physiological delivery, and menstruation) and CR to decrease pain, improve sexual response, and create a pre-FGM/C genital appearance. AIM: In this study, our aim is to summarize the medical literature regarding CR techniques and outcomes, and stimulate ethical discussion surrounding potential adverse impacts on women who undergo the procedure. METHODS: A broad literature review was carried out to search any previous peer-reviewed publications regarding the techniques and ethical considerations for CR. MAIN OUTCOME MEASURE: The main outcome measure includes benefits, risks, and ethical analysis of CR. RESULTS: While we discuss the limited evidence regarding the risks and efficacy of CR, we did not find any peer-reviewed reports focused on ethical implications to date. CLINICAL IMPLICATIONS: CR can be indicated as a treatment for pain and potential improvement of associated sexual dysfunction when these have not responded to more conservative measures. Women must be appropriately informed about the risks of CR and the lack of strong evidence regarding potential benefits. They must be educated about their genital anatomy and disabused of any myths surrounding female sexual function as well as assessed and treated in accordance with the current scientific evidence and best clinical practices. STRENGTH & LIMITATIONS: This is the first formal ethical discussion surrounding CR. This is not a systematic review, and the ethical discussion of CR has only just begun. CONCLUSION: We present a preliminary ethical analysis of the procedure and its potential impact on women with FGM/C. Sharif Mohamed F, Wild V, Earp BD, et al. Clitoral Reconstruction After Female Genital Mutilation/Cutting: A Review of Surgical Techniques and Ethical Debate. J Sex Med 2020;17:531-542.

Metabolic signature of obesity-associated insulin resistance and type 2 diabetes.

BACKGROUND: Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. METHODS: In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. RESULTS: Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. CONCLUSION: This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis.

BACKGROUND: Parkinson's disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M-F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies. METHODS: We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M-F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M-F ratios. RESULTS: On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M-F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M-F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M-F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M- F ratios increased with age (0.26 per 10 years, p trend=0.005). CONCLUSIONS: Age-increasing M-F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.

Septicaemia models using Streptococcus pneumoniae and Listeria monocytogenes: understanding the role of complement properdin.

Streptococcus pneumoniae and Listeria monocytogenes, pathogens which can cause severe infectious disease in human, were used to infect properdin-deficient and wildtype mice. The aim was to deduce a role for properdin, positive regulator of the alternative pathway of complement activation, by comparing and contrasting the immune response of the two genotypes in vivo. We show that properdin-deficient and wildtype mice mounted antipneumococcal serotype-specific IgM antibodies, which were protective. Properdin-deficient mice, however, had increased survival in the model of streptococcal pneumonia and sepsis. Low activity of the classical pathway of complement and modulation of FcγR2b expression appear to be pathogenically involved. In listeriosis, however, properdin-deficient mice had reduced survival and a dendritic cell population that was impaired in maturation and activity. In vitro analyses of splenocytes and bone marrow-derived myeloid cells support the view that the opposing outcomes of properdin-deficient and wildtype mice in these two infection models is likely to be due to a skewing of macrophage activity to an M2 phenotype in the properdin-deficient mice. The phenotypes observed thus appear to reflect the extent to which M2- or M1-polarised macrophages are involved in the immune responses to S. pneumoniae and L. monocytogenes. We conclude that properdin controls the strength of immune responses by affecting humoral as well as cellular phenotypes during acute bacterial infection and ensuing inflammation.

Efficiency of assertiveness training on the stress, anxiety, and depression levels of college students (Randomized control trial).

BACKGROUND: The significance of assertiveness in promoting mental health is well acknowledged. To investigate the impact of assertiveness training on lowering anxiety, stress, and depression among college students at a private university in Cairo. MATERIALS AND METHODS: In this study, three questionnaires were used: demographic, Depression Anxiety Stress Scales (DASS-21), and Rathus Assertiveness Schedule. Students were randomly allocated to either a group that underwent assertiveness training (experimental group) or a control group. A randomized controlled trial (RCT) was utilized with a pre- and post-assessment. The training program is an adapted version of DBT skills training. The training program includes mindfulness, assertiveness, and problem-solving skills through eight 90-min group sessions. RESULTS: There were (n = 50) students in the experimental group compared with (n = 50) the control group. Assertiveness group, in comparison with control group, resulted in significantly greater reductions in stress as shown in DASS scores (the effect size, d = 0.52, P < .000), anxiety (the effect size, d = 0.30, P < .000), depression (the effect size, d = 0.21, P < .000), and total scores of DASS (the effect size, d = 0.45, P < .000). Assertiveness group, in comparison with control group, resulted in significantly greater increase in assertiveness as shown in RAS scores (the effect size, d = 0.38, P < .000). CONCLUSION: It is possible that increasing an individual's level of assertiveness might be a helpful strategy for reducing feelings of anxiety, stress, and depression.

MAVMET trial: maraviroc and/or metformin for metabolic dysfunction associated fatty liver disease in adults with suppressed HIV.

OBJECTIVE: Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. DESIGN: Open-label, 48-week randomized trial with a 2 x 2 factorial design. SETTING: Multicenter HIV clinics. PARTICIPANTS: Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). INTERVENTION: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. PRIMARY OUTCOME: Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF). RESULTS: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97-5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P  = 0.45]), MET (-0.62 [-1.81 to 0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. CONCLUSION: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone.

Sustained corneal nerve loss predicts the development of diabetic neuropathy in type 2 diabetes.

Introduction: This study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D). Methods: Participants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4-7 years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD, <24 fibers/mm2), corneal nerve branch density (CNBD, <21 branches/mm2), and corneal nerve fiber length (CNFL, <16 mm/mm2) persisting for ≥50% of the study duration. Results: A total of 107 participants with a mean duration of T2D of 13.3 ± 7.3 years, aged 54.8 ± 8.5 years, underwent baseline and follow-up assessments over a median duration of 4 years, ranging from 1 to 7 years. The DPN prevalence at baseline was 18/107 (16.8%), and of the 89 participants without DPN at baseline, 13 (14.6%) developed DPN during follow-up. Approximately half of the cohort had sustained corneal nerve damage, and corneal nerve measures were significantly lower in this group than those without sustained damage (p < 0.0001). Sustained corneal nerve damage was associated with the development of DPN (p < 0.0001), a progressive loss of vibration perception (p ≤ 0.05), an increased incidence of burning pain, numbness, or a combination of both (p = 0.01-0.001), and a borderline association with progressive sudomotor dysfunction (p = 0.07). Sustained abnormal CNFL effectively distinguished between participants who developed DPN and those who did not (AUC: 76.3, 95% CI: 65.9-86.8%, p < 0.0001), while baseline and other sustained measures did not predict DPN onset. Conclusion: Sustained abnormal CCM is associated with more severe corneal nerve damage, DPN development, and the progression of neuropathic symptoms and deficits. Regular CCM monitoring may enable the identification of those at greater risk of developing and worsening DPN who may benefit from more aggressive risk factor reduction.

Knowledge, Attitude and Practice of Community Pharmacists in Relation to Dispensing Antibiotics Without Prescription in Sudan: A Cross-sectional Study.

Background: Dispensing antibiotics without prescription (DAwP) is a widespread practice, especially in developing countries, contributing to antibiotic resistance. Community pharmacists play a significant role in promoting rational use of antibiotics by refraining from DAwP, and providing drug information to patients. This study aimed to evaluate community pharmacists' knowledge, attitude and practice, and to assess the factors behind DAwP. Methods: A cross-sectional study was conducted in 2020 among random sample of community pharmacists in Sudan. Online semi-structured questionnaire was used for data collection. The association between dependent and independent variables was assessed using Chi-square test; a P-value less than 0.05 was considered significant. Results: Of the 1217 pharmacists who participated, the majority were female (n = 645, 53%). Most pharmacists have a B. Pharm degree (n = 1026, 84%) and less than 5 years' experience (n = 718, 59%). Notably, the majority of community pharmacists have good knowledge (n = 735, 61.7%), which is significantly associated with years of experience (P < 0.00). More than half (n = 623, 52.2%) of the pharmacists have above average score of practice. Nearly all the pharmacists who participated have a positive attitude in relation to DAwP (n = 1204, 98.9%). More than half of the pharmacists were DAwP for tonsillitis (n = 817, 67%), wound infection (n = 766, 62.9%), and urinary tract infection (n = 664, 54%). The leading factor behind DAwP was the low socioeconomic status of the patients (n = 624, 51%). Additionally, 47% of the pharmacists (n = 572) thought that they were knowledgeable enough to DAwP. Conclusion: Despite their positive attitude and average level of knowledge regarding DAwP, Sudanese community pharmacists frequently are DAwP for tonsillitis. Low patients' socioeconomic status was the leading factor behind DAwP. Accordingly, extensive work from health authorities to improve the accessibility and affordability of the health system as well as the development of an antibiotic stewardship program are required to diminish DAwP.

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes.

AIMS/INTRODUCTION: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. MATERIALS AND METHODS: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up. RESULTS: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain. CONCLUSIONS: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss.

Molecular detection of human papillomavirus-16 among Sudanese patients diagnosed with squamous cell carcinoma and salivary gland carcinoma.

OBJECTIVE: Human papillomavirus (HPV) gained momentum as a potential etiological factor for many types of cancers. Therefore, the aim of this study was to assess the prevalence of HPV-16 infection among Sudanese patients diagnosed with Squamous Cell Carcinoma (SCC) and Salivary Gland Carcinoma. A descriptive, hospital-based study was conducted. 150 formalin-fixed paraffin-embedded blocks were collected. RESULTS: The study population included a total of 150 patients aged between 18 to 87 years with a mean age of 48.8 ± 11.9 years. Based on gender, females constituted 46.7% while males constituted 53.3%. The 150 patients were classified into 40 (26.0%) esophageal, 30 (20.0%) nasopharyngeal, 18 (12.0%) conjunctival, 18 (12.0%) tongue 12 (8.0%) laryngeal, 8 (5.3%) lip, 6 (4.0%) oropharyngeal, 6 (4.0%) mucoepidermoid, and 6 (4.0%) adenoid cystic, and 6 (4.0%) myoepithelial carcinomas. Odds ratio for male and female diagnosed with carcinoma was 1.025 [0.439-2.394, 95% CI]. Molecular detection of HPV-16 revealed a prevalence of 26 (17.3%) patients were positive for HPV-16. According to cancer diagnosis, esophageal SCC patients showed a high proportion of HPV-16; 14/40 (35.0%). A statistically significant difference was seen for the distribution of HPV-16 positive patients based on cancer diagnosis, P value 0.001.

Antiproliferative activity of a series of 5­(1H­1,2,3­triazolyl) methyl­ and 5­acetamidomethyl­oxazolidinone derivatives.

In the face of increasing resistance to the existing antibiotics, oxazolidinones (exemplified by linezolid) have been developed as promising antibacterial agents, but may have other useful actions. In the present study, a series of 5­(1H­1,2,3­triazoly) l­methyl­, 5­acetamidomethyl­morpholino and N­substituted­piperazino oxazolidinone derivatives were investigated to determine whether they are active against eukaryotic cells. An MTT assay, validated by cell counting, was used to assess the effect of nine oxazolidinone derivatives (concentrations 100 nM­10 µM) on the proliferation of MCF7 human breast cancer cells. The three most active compounds were then tested on MDA231 breast cancer cells. Cytotoxicity of the selected derivatives was determined by assessing the extent of apoptosis by flow cytometry. The antimetastatic potential of these compounds was assessed on MDA231 cells using wound healing and agarose invasion assays. The 5­triazolylmethyl piperazino­oxazolidinone derivatives containing 4­N­(2­chlorocinnamoyl), 4­N­(4­nitrobenzoyl) and 4­N­methylsulfonyl moieties exhibited the most potent cytostatic activity against cancer, inhibiting proliferation by up to 70%, in the same order as their reported antibacterial activity against Staphylococcus aureus, but at higher concentrations. Unexpectedly, several derivatives stimulated proliferation at 100 nM, well below their antibacterial minimum inhibitory concentrations. Certain compounds also retarded the motility and invasion of MDA231 cells. Three of the tested derivatives had no effect on the eukaryotic cell lines, demonstrating their preferential activity against bacteria. Two compounds actually stimulated eukaryotic cell proliferation. The remaining three exhibited potent cytostatic activity against and cancer cells, displaying differences in response at low and high concentrations, which may suggest multiple targets on eukaryotic cells. These latter compounds may be useful as anticancer agents.

Personalised dosing: Printing a dose of one's own medicine.

Ink-jet printing is a versatile, precise and relatively inexpensive method of depositing small volumes of solutions with remarkable accuracy and repeatability. Although developed primarily as a technology for image reproduction, its areas of application have expanded significantly in recent years. It is particularly suited to the manufacture of low dose medicines or to short production runs and so offers a potential manufacturing solution for the paradigm of personalised medicines. This review discusses the technical and clinical aspects of ink-jet printing that must be considered in order for the technology to become widely adopted in the pharmaceutical arena and considers applications in the literature.

On the Functional Overlap between Complement and Anti-Microbial Peptides.

Intriguingly, activated complement and anti-microbial peptides share certain functionalities; lytic, phagocytic, and chemo-attractant activities and each may, in addition, exert cell instructive roles. Each has been shown to have distinct LPS detoxifying activity and may play a role in the development of endotoxin tolerance. In search of the origin of complement, a functional homolog of complement C3 involved in opsonization has been identified in horseshoe crabs. Horseshoe crabs possess anti-microbial peptides able to bind to acyl chains or phosphate groups/saccharides of endotoxin, LPS. Complement activity as a whole is detectable in marine invertebrates. These are also a source of anti-microbial peptides with potential pharmaceutical applicability. Investigating the locality for the production of complement pathway proteins and their role in modulating cellular immune responses are emerging fields. The significance of local synthesis of complement components is becoming clearer from in vivo studies of parenchymatous disease involving specifically generated, complement-deficient mouse lines. Complement C3 is a central component of complement activation. Its provision by cells of the myeloid lineage varies. Their effector functions in turn are increased in the presence of anti-microbial peptides. This may point to a potentiating range of activities, which should serve the maintenance of health but may also cause disease. Because of the therapeutic implications, this review will consider closely studies dealing with complement activation and anti-microbial peptide activity in acute inflammation (e.g., dialysis-related peritonitis, appendicitis, and ischemia).

A crucial role of Flagellin in the induction of airway mucus production by Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. Flagellin is a P. aeruginosa virulence factor involved in host response to this pathogen. We examined the role of flagellin in P. aeruginosa-induced mucus secretion. Using a mouse model of pulmonary infection we showed that PAK, a wild type strain of P. aeruginosa, induced airway mucus secretion and mucin muc5ac expression at higher levels than its flagellin-deficient mutant (ΔFliC). PAK induced expression of MUC5AC and MUC2 in both human airway epithelial NCI-H292 cell line and in primary epithelial cells. In contrast, ΔFliC infection had lower to no effect on MUC5AC and MUC2 expressions. A purified P. aeruginosa flagellin induced MUC5AC expression in parallel to IL-8 secretion in NCI-H292 cells. Accordingly, ΔFliC mutant stimulated IL-8 secretion at significantly lower levels compared to PAK. Incubation of NCI-H292 cells with exogenous IL-8 induced MUC5AC expression and pre-incubation of these cells with an anti-IL-8 antibody abrogated flagellin-mediated MUC5AC expression. Silencing of TLR5 and Naip, siRNA inhibited both flagellin-induced MUC5AC expression and IL-8 secretion. Finally, inhibition of ERK abolished the expression of both PAK- and flagellin-induced MUC5AC. We conclude that: (i) flagellin is crucial in P. aeruginosa-induced mucus hyper-secretion through TLR5 and Naip pathways; (ii) this process is mediated by ERK and amplified by IL-8. Our findings help understand the mechanisms involved in mucus secretion during pulmonary infectious disease induced by P. aeruginosa, such as in cystic fibrosis.

A molecular epidemiological and genetic diversity study of tuberculosis in Ibadan, Nnewi and Abuja, Nigeria.

BACKGROUND: Nigeria has the tenth highest burden of tuberculosis (TB) among the 22 TB high-burden countries in the world. This study describes the biodiversity and epidemiology of drug-susceptible and drug-resistant TB in Ibadan, Nnewi and Abuja, using 409 DNAs extracted from culture positive TB isolates. METHODOLOGY/PRINCIPAL FINDINGS: DNAs extracted from clinical isolates of Mycobacterium tuberculosis complex were studied by spoligotyping and 24 VNTR typing. The Cameroon clade (CAM) was predominant followed by the M. africanum (West African 1) and T (mainly T2) clades. By using a smooth definition of clusters, 32 likely epi-linked clusters related to the Cameroon genotype family and 15 likely epi-linked clusters related to other "modern" genotypes were detected. Eight clusters concerned M. africanum West African 1. The recent transmission rate of TB was 38%. This large study shows that the recent transmission of TB in Nigeria is high, without major regional differences, with MDR-TB clusters. Improvement in the TB control programme is imperative to address the TB control problem in Nigeria.