High recurrence rate supports need for secondary prophylaxis in non-HIV patients with disseminated mycobacterium avium complex infection: a multi-center observational study

© 2016 Sridhar et al.Background: Long-term outcomes in non-HIV immunocompromised patients with disseminated Mycobacterium avium complex (dMAC) infections are unknown and the need for post-treatment secondary prophylaxis against MAC is uncertain in this setting. The objective of this study was to determine the need of continuing secondary anti-MAC prophylaxis in non-HIV patients after completing treatment of the primary dMAC episode. Methods: We conducted a ten-year multi-center analysis of non-HIV immunosuppressed patients with dMAC infections in Hong Kong. Results: We observed sixteen patients with dMAC during the study period of which five (31 %) were non-HIV immunosuppressed patients. In the non-HIV immunosuppressed group, three patients completed a treatment course without secondary prophylaxis, one patient received azithromycin-based secondary prophylaxis and one patient was still receiving therapy for the first dMAC episode. All the three patients who completed treatment without being given secondary prophylaxis developed recurrent dMAC infection requiring retreatment. Conclusions: In view of the high rate of dMAC infection recurrence in non-HIV immunocompromised patients following treatment completion, our data support long-term anti-MAC suppression therapy after treatment of the first dMAC infection episode in immunocompromised non-HIV patients, as is recommended for patients with advanced HIV. Tests of cell mediated immune function need to be evaluated to guide prophylaxis discontinuation in non-HIV patients.published_or_final_versio

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

Modeling the effect of age in T1-2 breast cancer using the SEER database

BACKGROUND: Modeling the relationship between age and mortality for breast cancer patients may have important prognostic and therapeutic implications. METHODS: Data from 9 registries of the Surveillance, Epidemiology, and End Results Program (SEER) of the United States were used. This study employed proportional hazards to model mortality in women with T1-2 breast cancers. The residuals of the model were used to examine the effect of age on mortality. This procedure was applied to node-negative (N0) and node-positive (N+) patients. All causes mortality and breast cancer specific mortality were evaluated. RESULTS: The relationship between age and mortality is biphasic. For both N0 and N+ patients among the T1-2 group, the analysis suggested two age components. One component is linear and corresponds to a natural increase of mortality with each year of age. The other component is quasi-quadratic and is centered around age 50. This component contributes to an increased risk of mortality as age increases beyond 50. It suggests a hormonally related process: the farther from menopause in either direction, the more prognosis is adversely influenced by the quasi-quadratic component. There is a complex relationship between hormone receptor status and other prognostic factors, like age. CONCLUSION: The present analysis confirms the findings of many epidemiological and clinical trials that the relationship between age and mortality is biphasic. Compared with older patients, young women experience an abnormally high risk of death. Among elderly patients, the risk of death from breast cancer does not decrease with increasing age. These facts are important in the discussion of options for adjuvant treatment with breast cancer patients

Effect of clinical and virological parameters on the level of neutralizing antibody against pandemic influenza A virus H1N1 2009

Background. Little is known about the antibody response in natural infection by the novel 2009 influenza A (H1N1) virus and its relationship with clinical and virological parameters. The relative lack of background neutralizing antibody against this novel virus provides a unique opportunity for understanding this issue. Methods. Case patients presenting with influenza-like illness who were positive for the pandemic H1 gene by reverse transcription polymerase chain reaction were identified. The serum antibody response was assayed by neutralizing antibody titer (NAT) against the virus in 881 convalescent donors. We retrospectively analyzed clinical parameters and viral load. Results. Ninety percent of the 881 convalescent donors had seroprotective titer of 1:40 or greater. The geometric mean titer of donors with convalescent NAT measured between day 21 and 42 was 1:101.1. Multivariate analysis by ordinal regression showed that pneumonia (odds ratio, 3.39; 95% confidence interval, 1.49-9-7.61; P=.004) and sputum production (odds ratio, 1.75; 95% CI, 1.01-3.01; P=.046) were the 2 independent factors associated with a higher level of convalescent NAT. Being afebrile on influenza presentation was associated with subsequent poor NAT (<1:40) response (P = .04). A positive correlation between the nasopharyngeal viral load on presentation and the convalescent NAT was demonstrated (Spearman correlation r, 0.238; P = .026). Conclusions. About 10% of these convalescent patients do not have a seroprotective NAT and may benefit from vaccination to prevent reinfection. The convalescent NAT correlated well with the initial viral load and was independently associated with severity of the viral illness, including pneumonia. The findings provide both the clinical and virological markers for identifying potential convalescent plasma donors with high serum NAT, which can be used to produce hyperimmune intravenous immunoglobulin in a randomized treatment trial for patients with severe pandemic H1N1 infection. © 2010 by the Infectious Diseases Society of America. All rights reserved.published_or_final_versio

Insights into Interactions of Mycobacteria with the Host Innate Immune System from a Novel Array of Synthetic Mycobacterial Glycans.

An array of homogeneous glycans representing all the major carbohydrate structures present in the cell wall of the human pathogen Mycobacterium tuberculosis and other mycobacteria has been probed with a panel of glycan-binding receptors expressed on cells of the mammalian innate immune system. The results provide an overview of interactions between mycobacterial glycans and receptors that mediate uptake and survival in macrophages, dendritic cells, and sinusoidal endothelial cells. A subset of the wide variety of glycan structures present on mycobacterial surfaces interact with cells of the innate immune system through the receptors tested. Endocytic receptors, including the mannose receptor, DC-SIGN, langerin, and DC-SIGNR (L-SIGN), interact predominantly with mannose-containing caps found on the mycobacterial polysaccharide lipoarabinomannan. Some of these receptors also interact with phosphatidyl-myo-inositol mannosides and mannose-containing phenolic glycolipids. Many glycans are ligands for overlapping sets of receptors, suggesting multiple, redundant routes by which mycobacteria can enter cells. Receptors with signaling capability interact with two distinct sets of mycobacterial glycans: targets for dectin-2 overlap with ligands for the mannose-binding endocytic receptors, while mincle binds exclusively to trehalose-containing structures such as trehalose dimycolate. None of the receptors surveyed bind furanose residues, which often form part of the epitopes recognized by antibodies to mycobacteria. Thus, the innate and adaptive immune systems can target different sets of mycobacterial glycans. This array, the first of its kind, represents an important new tool for probing, at a molecular level, biological roles of a broad range of mycobacterial glycans, a task that has not previously been possible

Comments on Holographic Entanglement Entropy and RG Flows

Using holographic entanglement entropy for strip geometry, we construct a candidate for a c-function in arbitrary dimensions. For holographic theories dual to Einstein gravity, this c-function is shown to decrease monotonically along RG flows. A sufficient condition required for this monotonic flow is that the stress tensor of the matter fields driving the holographic RG flow must satisfy the null energy condition over the holographic surface used to calculate the entanglement entropy. In the case where the bulk theory is described by Gauss-Bonnet gravity, the latter condition alone is not sufficient to establish the monotonic flow of the c-function. We also observe that for certain holographic RG flows, the entanglement entropy undergoes a 'phase transition' as the size of the system grows and as a result, evolution of the c-function may exhibit a discontinuous drop.Comment: References adde

Nearly Monodispersion CoSm Alloy Nanoparticles Formed by an In-situ Rapid Cooling and Passivating Microfluidic Process

An in siturapid cooling and passivating microfluidic processhas been developed for the synthesis of nearly monodispersed cobalt samarium nanoparticles (NPs) with tunable crystal structures and surface properties. This process involves promoting the nucleation and growth of NPs at an elevated temperature and rapidly quenching the NP colloids in a solution containing a passivating reagent at a reduced temperature. We have shown that Cobalt samarium NPs having amorphous crystal structures and a thin passivating layer can be synthesized with uniform nonspherical shapes and size of about 4.8 nm. The amorphous CoSm NPs in our study have blocking temperature near 40 K and average coercivity of 225 Oe at 10 K. The NPs also exhibit high anisotropic magnetic properties with a wasp-waist hysteresis loop and a bias shift of coercivity due to the shape anisotropy and the exchange coupling between the core and the thin oxidized surface layer

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms