Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy.

ObjectivesTo examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy.DesignOpen-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study.MethodsHIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms.ResultsAll eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P = 0.008) and improvements in stool consistency (P = 0.008). Gut permeability was normal before and after the intervention, but D-xylose absorption increased in seven of eight participants. Mucosal CD4 lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P = 0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P = 0.039), and then fell below baseline in four of five who continued receiving SBI (P = 0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4 lymphocyte densities (r = -0.74, P = 0.046).ConclusionSBI significantly increases intestinal mucosal CD4 lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy

Naturally Rehearsing Passwords

We introduce quantitative usability and security models to guide the design of password management schemes --- systematic strategies to help users create and remember multiple passwords. In the same way that security proofs in cryptography are based on complexity-theoretic assumptions (e.g., hardness of factoring and discrete logarithm), we quantify usability by introducing usability assumptions. In particular, password management relies on assumptions about human memory, e.g., that a user who follows a particular rehearsal schedule will successfully maintain the corresponding memory. These assumptions are informed by research in cognitive science and validated through empirical studies. Given rehearsal requirements and a user's visitation schedule for each account, we use the total number of extra rehearsals that the user would have to do to remember all of his passwords as a measure of the usability of the password scheme. Our usability model leads us to a key observation: password reuse benefits users not only by reducing the number of passwords that the user has to memorize, but more importantly by increasing the natural rehearsal rate for each password. We also present a security model which accounts for the complexity of password management with multiple accounts and associated threats, including online, offline, and plaintext password leak attacks. Observing that current password management schemes are either insecure or unusable, we present Shared Cues--- a new scheme in which the underlying secret is strategically shared across accounts to ensure that most rehearsal requirements are satisfied naturally while simultaneously providing strong security. The construction uses the Chinese Remainder Theorem to achieve these competing goals

De dynamiek van vennen in schijnspiegelsystemen

Op verscheidene plaatsen in Nederland wordt getracht verdroging van vennen tegen te gaan door verwijdering van veel verdampende bomen. Het effect van deze maatregel op de levensgemeenschap in het ven is echter sterk afhankelijk van de ligging van slecht doorlatende lagen en de grootte van het schijnspiegelsysteem, die op hun beurt de reactie van het venpeil op neerslag beïnvloeden. Meer inzicht in de hydrologie van vennen is verkregen via het tijdreeksmodel PIRFICT, met als onderzoekslocatie Beegderheid

Low Sensitivity of T-Cell Based Detection of Tuberculosis among HIV Co-Infected Tanzanian In-Patients

Objective: To evaluate the performance of QuantiFERON-TB GOLD (QFTG) in a resource-poor setting among patients with and without HIV infection.Design: Cross-sectional study.Setting: Two hospitals in Northern Tanzania.Subjects: Eighty three adult male and female inpatients.Intervention: All patients were screened for HIV infection and underwent tuberculin skin test (TST) and QFTG.Results: Eighty-three subjects were enrolled, and 29 (35%) of 83 were HIV-infected. QFTG yielded indeterminate results in 12 (22%; 95%CI 12%-34%) of 54 HIV-uninfected and 13 (45%; 95%CI 26%-64%) of 29 HIV-infected subjects (p=0.0323). Among those with smear-positive pulmonary tuberculosis, TST was positive in 40 (100%; 95%CI 91%-100%) of 40 HIV-uninfected subjects compared with seven (54%; 95%CI 25%- 81%) of 13 HIV-infected subjects (p<0.0001), and QFTG was positive in 28(70%; 95%CI 53%-83%) of 40 HIV-uninfected subjects compared with three (23%; 95%CI 5%-54%) of 13 HIV-infected subjects (p=0.0029). Among medical inpatients at risk for latent tuberculosis infection, TST was positive in seven (50%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p=0.0701) and QFTG was positive among two (14%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p=0.7437).Conclusions: The presence of HIV co-infection was associated with a significant reduction in sensitivity of both the TST (p<0.0001) and QFTG (p=0.0029) for the diagnosis of active M.tuberculosis infection. The high proportion of indeterminate QFTG and lack of sensitivity, particularly among HIV-infected patients, may limit its applicability in settings like Tanzania. Larger studies in resource-poor settings are required.

Threshold cryptography based on asmuth-bloom secret sharing

In this paper, we investigate how threshold cryptography can be conducted with the Asmuth-Bloom secret sharing scheme and present two novel function sharing schemes, one for the RSA signature and the other for the ElGamal decryption functions, based on the Asmuth-Bloom scheme. To the best of our knowledge, these are the first threshold cryptosystems realized using the Asmuth-Bloom secret sharing. The proposed schemes compare favorably to the earlier function sharing schemes in performance as well as in certain theoretical aspects. © Springer-Verlag Berlin Heidelberg 2006

Exposure-response analysis of alemtuzumab in pediatric allogeneic HSCT for nonmalignant diseases: the ARTIC study

Alemtuzumab (anti-CD52 antibody) is frequently prescribed to children with nonmalignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGVHD). The aim of this multicenter study was the characterization of alemtuzumab population pharmacokinetics to perform a novel model–based exposure-response analysis in 53 children with nonmalignant immunological or hematological disease and a median age of 4.4 years (interquartile range [IQR], 0.8-8.7). The median cumulative alemtuzumab dose was 0.6 mg/kg (IQR, 0.6-1) administered over 2 to 7 days. A 2-compartment population pharmacokinetics model with parallel linear and nonlinear elimination including allometrically scaled bodyweight (median, 17.50 kg; IQR, 8.76-33.00) and lymphocyte count at baseline (mean, 2.24 × 109/L; standard deviation ± 1.87) as significant pharmacokinetic predictors was developed using nonlinear mixed effects modeling. Based on the model–estimated median concentration at day of HSCT (0.77 μg/mL; IQR, 0.33-1.82), patients were grouped into a low- (≤0.77 μg/mL) or high- (>0.77 μg/mL) exposure groups. High alemtuzumab exposure at day of HSCT correlated with delayed CD4+ and CD8+ T-cell reconstitution (P value < .0001) and increased risk of GF (P value = .043). In contrast, alemtuzumab exposure did not significantly influence the incidence of aGVHD grade ≥2, mortality, chimerism at 1 year, viral reactivations, and autoimmunity at a median follow-up of 3.3 years (IQR, 2.5-8.0). In conclusion, this novel population pharmacokinetics model is suitable for individualized intravenous precision dosing to predict alemtuzumab exposure in pediatric allogeneic HSCT for nonmalignant diseases, aiming at the achievement of early T-cell reconstitution and prevention of GF in future prospective studies

Practical threshold signatures with linear secret sharing schemes

Function sharing deals with the problem of distribution of the computation of a function (such as decryption or signature) among several parties. The necessary values for the computation are distributed to the participating parties using a secret sharing scheme (SSS). Several function sharing schemes have been proposed in the literature, with most of them using Shamir secret sharing as the underlying SSS. In this paper, we investigate how threshold cryptography can be conducted with any linear secret sharing scheme and present a function sharing scheme for the RSA cryptosystem. The challenge is that constructing the secret in a linear SSS requires the solution of a linear system, which normally involves computing inverses, while computing an inverse modulo φ(N) cannot be tolerated in a threshold RSA system in any way. The threshold RSA scheme we propose is a generalization of Shoup's Shamir-based scheme. It is similarly robust and provably secure under the static adversary model. At the end of the paper, we show how this scheme can be extended to other public key cryptosystems and give an example on the Paillier cryptosystem. © 2009 Springer Berlin Heidelberg

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.</p

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.</p

Anti-T-lymphocyte globulin exposure is associated with acute graft- versus-host disease and relapse in pediatric acute lymphoblastic leukemia patients undergoing hematopoietic stem cell transplantation: amultinational prospective study

Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentration-time data. The level of ATLG exposure (day active ATLG day 16 8.2%; PPersonalised Therapeutic