Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an <i>in vitro</i> model of CNS tuberculosis

Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB

Determinants of low family planning use and high unmet need in Butajira District, South Central Ethiopia

<p>Abstract</p> <p>Background</p> <p>The rapid population growth does not match with available resource in Ethiopia. Though household level family planning delivery has been put in place, the impact of such programs in densely populated rural areas was not studied. The study aims at measuring contraception and unmet need and identifying its determinants among married women.</p> <p>Methods</p> <p>A total of 5746 married women are interviewed from October to December 2009 in the Butajira Demographic Surveillance Area. Contraceptive prevalence rate and unmet need with their 95% confidence interval is measured among married women in the Butajira district. The association of background characteristics and family planning use is ascertained using crude and adjusted Odds ratio in logistic regression model.</p> <p>Results</p> <p>Current contraceptive prevalence rate among married women is 25.4% (95% CI: 24.2, 26.5). Unmet need of contraception is 52.4% of which 74.8% was attributed to spacing and the rest for limiting. Reasons for the high unmet need include commodities' insecurity, religion, and complaints related to providers, methods, diet and work load. Contraception is 2.3 (95% CI: 1.7, 3.2) times higher in urbanites compared to rural highlanders. Married women who attained primary and secondary plus level of education have about 1.3 (95% CI: 1.1, 1.6) and 2 (95% CI: 1.4, 2.9) times more risk to contraception; those with no child death are 1.3 (95% CI: 1.1, 1.5) times more likely to use contraceptives compared to counterparts. Besides, the odds of contraception is 1.3 (95% CI: 1.1, 1.6) and 1.5 (1.1, 2.0) times more likely among women whose partners completed primary and secondary plus level of education. Women discussing about contraception with partners were 2.2 (95% CI: 1.8, 2.7) times more likely to use family planning. Nevertheless, contraception was about 2.6 (95% CI: 2.1, 3.2) more likely among married women whose partners supported the use of family planning.</p> <p>Conclusions</p> <p>The local government should focus on increasing educational level. It must also ensure family planning methods security, increase competence of providers, and create awareness on various methods and their side effects to empower women to make an appropriate choice. Emphasis should be given to rural communities.</p

Sequence-Signature Optimization Enables Improved Identification of Human HV6-1-Derived Class Antibodies That Neutralize Diverse Influenza A Viruses

Sequence signatures of multidonor broadly neutralizing influenza antibodies can be used to quantify the prevalence of B cells with virus-neutralizing potential to accelerate development of broadly protective vaccine strategies. Antibodies of the same class share similar recognition modes and developmental pathways, and several antibody classes have been identified that neutralize diverse group 1- and group 2-influenza A viruses and have been observed in multiple human donors. One such multidonor antibody class, the HV6-1-derived class, targets the stem region of hemagglutinin with extraordinary neutralization breadth. Here, we use an iterative process to combine informatics, biochemical, and structural analyses to delineate an improved sequence signature for HV6-1-class antibodies. Based on sequence and structure analyses of known HV6-1 class antibodies, we derived a more inclusive signature (version 1), which we used to search for matching B-cell transcripts from published next-generation sequencing datasets of influenza vaccination studies. We expressed selected antibodies, evaluated their function, and identified amino acid-level requirements from which to refine the sequence signature (version 2). The cryo-electron microscopy structure for one of the signature-identified antibodies in complex with hemagglutinin confirmed motif recognition to be similar to known HV6-1-class members, MEDI8852 and 56.a.09, despite differences in recognition-loop length. Threading indicated the refined signature to have increased accuracy, and signature-identified heavy chains, when paired with the light chain of MEDI8852, showed neutralization comparable to the most potent members of the class. Incorporating sequences of additional class members thus enables an improved sequence signature for HV6-1-class antibodies, which can identify class members with increased accuracy

Maternal Serum Macrophage Inhibitory Cytokine-1 as a Biomarker for Ectopic Pregnancy in Women with a Pregnancy of Unknown Location

Ectopic pregnancy (EP) occurs in 1-2% of pregnancies, but is over-represented as a leading cause of maternal death in early pregnancy. It remains a challenge to diagnose early and accurately. Women often present in early pregnancy with a 'pregnancy of unknown location' (PUL) and the diagnosis and exclusion of EP is difficult due to a lack of reliable biomarkers. A serum biomarker able to clearly distinguish between EP and other pregnancy outcomes would greatly assist clinicians in diagnosing and safely managing PULs. This study evaluates the ability of maternal serum macrophage inhibitory cytokine-1 (MIC-1) levels to differentiate between EP and other pregnancy outcomes in women with a PUL.Sera were collected from 120 women with a PUL at first clinical presentation and assayed for MIC-1 by ELISA. Results were classified according to ultimate pregnancy outcome and the discriminatory ability of MIC-1 to diagnose EP was assessed.Serum MIC-1 levels were lower in women with histologically confirmed (definite) EP (dEP) (median 552 ng/mL; interquartile range (IQR) 414-693 ng/mL) compared to women with definite viable intra-uterine pregnancies (dVIUPs) (722 ng/mL; IQR 412-1122 ng/mL), and higher when compared to women with definite non-viable intra-uterine pregnancies (dNVIUPs) (465 ng/mL; IQR 341-675 ng/mL). MIC-1 levels were significantly higher in women with dEP compared to women whose PULs resolved without medical intervention (srPUL) (401 ng/mL; IQR 315-475 ng/mL) (p<0.003). There were no women with an ectopic pregnancy where serum MIC-1>1000 ng/mL.Serum MIC-1 levels in PUL were not able to categorically diagnose EP, however, MIC-1 could distinguish women with an EP that required medical intervention and those women whose PULs spontaneously resolved. A single serum MIC-1 measurement also excluded EP at levels above 1000 ng/mL. MIC-1 may play a role in the development of a combined assay of biomarkers for the diagnosis of EP

Lack of awareness of erectile dysfunction in many men with risk factors for erectile dysfunction

<p>Abstract</p> <p>Background</p> <p>Men with erectile dysfunction often have concurrent medical conditions. Conversely, men with these conditions may also have underlying erectile dysfunction. The prevalence of unrecognized erectile dysfunction in men with comorbidities commonly associated with erectile dysfunction was determined in men invited to participate in a double-blind, randomized, placebo-controlled trial of sildenafil citrate.</p> <p>Methods</p> <p>Men ≥30 years old presenting with ≥1 erectile dysfunction risk factor (controlled hypertension, hypercholesterolemia, smoking, metabolic syndrome, stable coronary artery disease, diabetes, depression, lower urinary tract symptoms, obesity [body mass index ≥30 kg/m²] or waist circumference ≥40 inches), and not previously diagnosed with erectile dysfunction were evaluated. The screening question, "Do you have erectile dysfunction?," with responses of "no," "yes," and "unsure," and the Erectile Function domain of the International Index of Erectile Function (IIEF-EF) were administered.</p> <p>Results</p> <p>Of 1084 men screened, 1053 answered the screening question and also had IIEF-EF scores. IIEF-EF scores indicating erectile dysfunction occurred in 71% (744/1053), of whom 54% (399/744) had moderate or severe erectile dysfunction. Of 139 answering "yes," 526 answering "unsure," and 388 answering "no," 96%, 90%, and 36%, respectively, had some degree of erectile dysfunction. The mean±SD (range) number of risk factors was 2.9 ± 1.7 (3-8) in the "yes" group, 3.2 ± 1.7 (3-9) in the "unsure" group, and 2.6 ± 1.5 (2-8) in the "no" group.</p> <p>Conclusion</p> <p>Although awareness of having erectile dysfunction was low, most men with risk factors had IIEF-EF scores indicating erectile dysfunction. Erectile dysfunction should be suspected and assessed in men with risk factors, regardless of their apparent level of awareness of erectile dysfunction.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier NCT00343200.</p

Author Correction: Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses.

In the version of this article initially published, the labels (50 Å) above the scale bars in Fig. 1b were incorrect. The correct size is 50 nm. The error has been corrected in the HTML and PDF versions of the article

Predictors and outcome of surgical repair of obstetric fistula at a regional referral hospital, Mbarara, western Uganda

<p>Abstract</p> <p>Background</p> <p>Obstetric fistula although virtually eliminated in high income countries, still remains a prevalent and debilitating condition in many parts of the developing world. It occurs in areas where access to care at childbirth is limited, or of poor quality and where few hospitals offer the necessary corrective surgery.</p> <p>Methods</p> <p>This was a prospective observational study where all women who attended Mbarara Regional Referral Hospital in western Uganda with obstetric fistula during the study period were assessed pre-operatively for social demographics, fistula characteristics, classification and outcomes after surgery. Assessment for fistula closure and stress incontinence after surgery was done using a dye test before discharge</p> <p>Results</p> <p>Of the 77 women who were recruited in this study, 60 (77.9%) had successful closure of their fistulae. Unsuccessful fistula closure was significantly associated with large fistula size (Odds Ratio 6 95% Confidential interval 1.46-24.63), circumferential fistulae (Odds ratio 9.33 95% Confidential interval 2.23-39.12) and moderate to severe vaginal scarring (Odds ratio 12.24 95% Confidential interval 1.52-98.30). Vaginal scarring was the only factor independently associated with unsuccessful fistula repair (Odds ratio 10 95% confidential interval 1.12-100.57). Residual stress incontinence after successful fistula closure was associated with type IIb fistulae (Odds ratio 5.56 95% Confidential interval 1.34-23.02), circumferential fistulae (Odds ratio 10.5 95% Confidential interval 1.39-79.13) and previous unsuccessful fistula repair (Odds ratio 4.8 95% Confidential interval 1.27-18.11). Independent predictors for residual stress incontinence after successful fistula closure were urethral involvement (Odds Ratio 4.024 95% Confidential interval 2.77-5.83) and previous unsuccessful fistula repair (Odds ratio 38.69 95% Confidential interval 2.13-703.88).</p> <p>Conclusions</p> <p>This study demonstrated that large fistula size, circumferential fistulae and marked vaginal scarring are predictors for unsuccessful fistula repair while predictors for residual stress incontinence after successful fistula closure were urethral involvement, circumferential fistulae and previous unsuccessful fistula repair.</p

Economic Status, Education and Empowerment: Implications for Maternal Health Service Utilization in Developing Countries

, and maternal health service utilization in developing countries. are significantly associated with utilization of maternal health services. The odds of having a skilled attendant at delivery for women in the poorest wealth quintile are 94% lower than that for women in the highest wealth quintile and almost 5 times higher for women with complete primary education relative to those less educated. The likelihood of using modern contraception and attending four or more antenatal care visits are 2.01 and 2.89 times, respectively, higher for women with complete primary education than for those less educated. Women with the highest empowerment score are between 1.31 and 1.82 times more likely than those with a null empowerment score to use modern contraception, attend four or more antenatal care visits and have a skilled attendant at birth.Efforts to expand maternal health service utilization can be accelerated by parallel investments in programs aimed at poverty eradication (MDG 1), universal primary education (MDG 2), and women's empowerment (MDG 3)

Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate

The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate