Genetic Variation of the Human Urinary Tract Innate Immune Response and Asymptomatic Bacteriuria in Women

BACKGROUND:Although several studies suggest that genetic factors are associated with human UTI susceptibility, the role of DNA variation in regulating early in vivo urine inflammatory responses has not been fully examined. We examined whether candidate gene polymorphisms were associated with altered urine inflammatory profiles in asymptomatic women with or without bacteriuria. METHODOLOGY:We conducted a cross-sectional analysis of asymptomatic bacteriuria (ASB) in 1,261 asymptomatic women ages 18-49 years originally enrolled as participants in a population-based case-control study of recurrent UTI and pyelonephritis. We genotyped polymorphisms in CXCR1, CXCR2, TLR1, TLR2, TLR4, TLR5, and TIRAP in women with and without ASB. We collected urine samples and measured levels of uropathogenic bacteria, neutrophils, and chemokines. PRINCIPAL FINDINGS:Polymorphism TLR2_G2258A, a variant associated with decreased lipopeptide-induced signaling, was associated with increased ASB risk (odds ratio 3.44, 95%CI; 1.65-7.17). Three CXCR1 polymorphisms were associated with ASB caused by gram-positive organisms. ASB was associated with urinary CXCL-8 levels, but not CXCL-5, CXCL-6, or sICAM-1 (P< or =0.0001). Urinary levels of CXCL-8 and CXCL-6, but not ICAM-1, were associated with higher neutrophil levels (P< or =0.0001). In addition, polymorphism CXCR1_G827C was associated with increased CXCL-8 levels in women with ASB (P = 0.004). CONCLUSIONS:TLR2 and CXCR1 polymorphisms were associated with ASB and a CXCR1 variant was associated with urine CXCL-8 levels. These results suggest that genetic factors are associated with early in vivo human bladder immune responses prior to the development of symptomatic UTIs

Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women

BACKGROUND:Although behavioral risk factors are strongly associated with urinary tract infection (UTI) risk, the role of genetics in acquiring this disease is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS:To test the hypothesis that polymorphisms in Toll-like receptor (TLR) pathway genes are associated with susceptibility to UTIs, we conducted a population-based case-control study of women ages 18-49 years. We examined DNA variants in 9 TLR pathway genes in 431 recurrent cystitis (rUTI) cases, 400 pyelonephritis cases, and 430 controls with no history of UTIs. In the Caucasian subgroup of 987 women, polymorphism TLR4_A896G was associated with protection from rUTI, but not pyelonephritis, with an odds ratio (OR) of 0.54 and a 95% confidence interval (CI) of 0.31 to 0.96. Polymorphism TLR5_C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of rUTI (OR(95%CI): 1.81 (1.00-3.08)), but not pyelonephritis. Polymorphism TLR1_G1805T was associated with protection from pyelonephritis (OR(95%CI): 0.53 (0.29-0.96)). CONCLUSIONS:These results provide the first evidence of associations of TLR5 and TLR1 variants with altered risks of acquiring rUTI and pyelonephritis, respectively. Although these data suggest that TLR polymorphisms are associated with adult susceptibility to UTIs, the statistical significance was modest and will require further study including validation with independent cohorts

Analysis of the adoption of security headers in HTTP.

With the increase in the number of threats within Web-based systems, a more integrated approach is required to ensure the enforcement of security policies from the server to the client. These policies aim to stop man-in-the-middle attacks, code injection, and so on. This paper analyses some of the newest security options used within HTTP responses, and scans the Alexa Top 1 Million sites for their implementation within HTTP responses. These options scanned for include: Content Security Policy (CSP); Public Key Pinning Extension for HTTP (HPKP); HTTP Strict Transport Security (HSTS) and HTTP Header Field X-Frame-Options (XFO), in order to understand the impact that these options have on the most popular Web sites.The results show that, while the implementation of the parameters are increasing, they are still not implemented on many of the top sites. Along with this the paper shows the profile of adoption of Let’s Encrypt digital certificates across the one million sites, along with a way of assessing the quality of the security headers

Treatment of Cryptococcal Meningitis with Combination Amphotericin B and Flucytosine for Four as Compared with Six Weeks

Abstract One hundred ninety-four patients with cryptococcal meningitis were enrolled in a multicenter, prospective, randomized clinical trial to compare the efficacy and toxicity of four as compared with six weeks of combination amphotericin B and flucytosine therapy. Among 91 patients who met preestablished criteria for randomization, cure or improvement was noted in 75 percent of those treated for four weeks and in 85 percent of those treated for six weeks. The estimated relapse rate for the four-week regimen was higher — 27 as compared with 16 percent — whereas the incidence of toxic effects for the two regimens was similar — 44 as compared with 43 percent. Among 23 transplant recipients, 4 of 5 treated for four weeks relapsed, leading to the decision to treat the rest of the group for six weeks. Only 3 of the 18 treated for six weeks relapsed. In a third group of 80 patients, the protocol was not followed during the initial four weeks, and these patients were not randomized. Thirty-eight died or relapsed. Multifactorial analysis of pretreatment factors for all 194 patients identified three significant predictors (P These and other findings in this study are consistent with the view that the four-week regimen should be reserved for patients who have meningitis without neurologic complications, underlying disease, or immunosuppressive therapy; a pretreatment cerebrospinal fluid white-cell count above 20 per cubic millimeter and a serum cryptococcal antigen titer below 1:32; and at four weeks of therapy, a negative cerebrospinal fluid India ink preparation and serum and cerebrospinal fluid cryptococcal-antigen titers below 1:8. Patients who do not meet these criteria should receive at least six weeks of therapy. (N Engl J Med 1987; 317:334–41.

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead