The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy

Background It is becoming increasingly clear that, during successful highly active antiretroviral therapy (HAART), a proportion of treated patients develop opportunistic infections (OIs), referred to in this setting as immune restoration disease (IRD). We examined the risk of developing IRD in HAART-treated HIV-infected patients. Methods A retrospective study of a cohort including all 389 patients treated with HAART between I January 1998 and 31 May 2004 in our HIV unit was performed to evaluate the occurrence of and risk factors for IRD during HAART. Baseline and follow-up values of CD4 T-cell counts and plasma viral loads (pVLs) were compared to assess the success of HAART. Results During successful HAART (significant increase in CD4 T-cell counts and decrease in pVL), at least one IRD episode occurred in 65 patients (16.7%). The median time to IRD was 4.6 months (range 212 months). IRDs included dermatomal herpes zoster (26 patients), pulmonary tuberculosis (four patients), tuberculous exudative pericarditis (two patients), tuberculous lymphadenitis (two patients), cerebral toxoplasmosis (one patient), progressive multifocal leucoencephalopathy (PML) (one patient), inflamed molluscum (one patient), inflamed Candida albicans angular cheilitis (three patients), genital herpes simplex (two patients), tinea corporis (two patients), cytomegalovirus (CMV) retinitis (two patients), CMV vitritis (one patient) and hepatitis B (three patients) or C (fifteen patients). A baseline CD4 T-cell count below 100 cells/mu L was shown to be the single predictor [odds ratio (OR) 2.5, 95% confidence interval (CI) 0.9-6.4] of IRD, while a CD4 T-cell count increase to gt 400 cells/mu L, but not undetectable pVL, was a negative predictor of IRD (OR 0.3, 95% CI 0.1-0.8). Conclusions To avoid IRD in advanced patients, HAART should be initiated before the CD4 T-cell count falls below 100 cells/mu L

Anterior Cruciate Ligament Injury: Compensation during Gait using Hamstring Muscle Activity

Previous research has shown that an increase in hamstring activation may compensate for anterior tibial transalation (ATT) in patients with anterior cruciate ligament deficient knee (ACLd); however, the effects of this compensation still remain unclear. The goals of this study were to quantify the activation of the hamstring muscles needed to compensate the ATT in ACLd knee during the complete gait cycle and to evaluate the effect of this compensation on quadriceps activation and joint contact forces. A two dimensional model of the knee was used, which included the tibiofemoral and patellofemoral joints, knee ligaments, the medial capsule and two muscles units. Simulations were conducted to determine the ATT in healthy and ACLd knee and the hamstring activation needed to correct the abnormal ATT to normal levels (100% compensation) and to 50% compensation. Then, the quadriceps activation and the joint contact forces were calculated. Results showed that 100% compensation would require hamstring and quadriceps activations larger than their maximum isometric force, and would generate an increment in the peak contact force at the tibiofemoral (115%) and patellofemoral (48%) joint with respect to the healthy knee. On the other hand, 50% compensation would require less force generated by the muscles (less than 0.85 of maximum isometric force) and smaller contact forces (peak tibiofemoral contact force increased 23% and peak patellofemoral contact force decreased 7.5% with respect to the healthy knee). Total compensation of ATT by means of increased hamstring activity is possible; however, partial compensation represents a less deleterious strategy

Biomechanical testing of fixed and adjustable femoral cortical suspension devices for ACL reconstruction under high loads and extended cyclic loading

Purpose: To compare loop elongation after 5000 cycles, loop-elongation at failure, and load at failure of the fixed-loop G-Lok device and three adjustable-loop devices (UltraButton, RigidLoop Adjustable and ProCinch RT), during testing over extended cycles under high loading. Methods: Five devices of each type were tested on a custom-built rig fixed to an Instron machine. The testing protocol had four stages: preloading, cyclic preconditioning, incremental cyclic loading and pull-to-failure. Outcome measures were loop elongation after 5000 cycles, loop-elongation at failure, and load at failure. Results: The loop elongation after 5000 cycles for G-Lok was 1.46 ± 0.25 mm, which was comparable to that of RigidLoop (1.51 ± 0.16 mm, p = 1.000) and ProCinch (1.60 ± 0.09 mm, p = 1.000). In comparison, the loop elongation for UltraButton was 2.66 ± 0.28 mm, which was significantly larger than all other devices (p = 0.048). The failure load for all devices ranged between 1455 and 2178 N. G-Lok was significantly stronger than all adjustable-loop devices (p = 0.048). The elongation at failure was largest for UltraButton (4.20 ± 0.33 mm), which was significantly greater than G-Lok (3.17 ± 0.33 mm, p = 0.048), RigidLoop (2.88 ± 0.20 mm, p = 0.048) and ProCinch (2.78 ± 0.08 mm, p = 0.048). There was no significant difference in elongation at failure for the rest of the devices. Conclusions: Our study has shown that the G-Lok fixed-loop device and the three adjustable-loop devices (UltraButton, RigidLoop Adjustable and ProCinch RT) all elongated less than 3 mm during testing over an extended number of cycles at high loads, nonetheless, the fixed loop device performed best in terms of least elongation and highest load at failure.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted versio

Functional Characterization of a Newly Identified Group B Streptococcus Pullulanase Eliciting Antibodies Able to Prevent Alpha-Glucans Degradation

Streptococcal pullulanases have been recently proposed as key components of the metabolic machinery involved in bacterial adaptation to host niches. By sequence analysis of the Group B Streptococcus (GBS) genome we found a novel putative surface exposed protein with pullulanase activity. We named such a protein SAP. The sap gene is highly conserved among GBS strains and homologous genes, such as PulA and SpuA, have been described in other pathogenic streptococci. The SAP protein contains two N-terminal carbohydrate-binding motifs, followed by a catalytic domain and a C-terminal LPXTG cell wall-anchoring domain. In vitro analysis revealed that the recombinant form of SAP is able to degrade α-glucan polysaccharides, such as pullulan, glycogen and starch. Moreover, NMR analysis showed that SAP acts as a type I pullulanase. Studies performed on whole bacteria indicated that the presence of α-glucan polysaccharides in culture medium up-regulated the expression of SAP on bacterial surface as confirmed by FACS analysis and confocal imaging. Deletion of the sap gene resulted in a reduced capacity of bacteria to grow in medium containing pullulan or glycogen, but not glucose or maltose, confirming the pivotal role of SAP in GBS metabolism of α-glucans. As reported for other streptococcal pullulanases, we found specific anti-SAP antibodies in human sera from healthy volunteers. Investigation of the functional role of anti-SAP antibodies revealed that incubation of GBS in the presence of sera from animals immunized with SAP reduced the capacity of the bacterium to degrade pullulan. Of interest, anti-SAP sera, although to a lower extent, also inhibited Group A Streptococcus pullulanase activity. These data open new perspectives on the possibility to use SAP as a potential vaccine component inducing functional cross-reacting antibodies interfering with streptococcal infections

Immune reconstitution inflammatory syndrome from Penicillium marneffei in an HIV-infected child: a case report and review of literature

<p>Abstract</p> <p>Backgrounds</p> <p>Disseminated <it>Penicillium marneffei </it>infection is one of the most common HIV-related opportunistic infections in Southeast Asia. Immune reconstitution inflammatory syndrome (IRIS) is a complication related to antiretroviral therapy (ART)-induced immune restoration. The aim of this report is to present a case of HIV-infected child who developed an unmasking type of IRIS caused by disseminated <it>P. marneffei </it>infection after ART initiation.</p> <p>Case presentation</p> <p>A 14-year-old Thai HIV-infected girl presented with high-grade fever, multiple painful ulcerated oral lesions, generalized non-pruritic erythrematous skin papules and nodules with central umbilication, and multiple swollen, warm, and tender joints 8 weeks after ART initiation. At that time, her CD4⁺cell count was 7.2% or 39 cells/mm³. On admission, her repeated CD4⁺cell count was 11% or 51 cells/mm³and her plasma HIV-RNA level was < 50 copies/mL. Her skin biopsy showed necrotizing histiocytic granuloma formation with neutrophilic infiltration in the upper and reticular dermis. Tissue sections stained with hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Grocott methenamine silver (GMS) stain revealed numerous intracellular and extracellular, round to oval, elongated, thin-walled yeast cells with central septation. The hemoculture, bone marrow culture, and skin culture revealed no growth of fungus or bacteria. Our patient responded well to intravenous amphotericin B followed by oral itraconazole. She fully recovered after 4-month antifungal treatment without evidence of recurrence of disease.</p> <p>Conclusions</p> <p>IRIS from <it>P. marneffei </it>in HIV-infected people is rare. Appropriate recognition and properly treatment is important for a good prognosis.</p

Tissue factor/FVIIa activates Bcl-2 and prevents doxorubicin-induced apoptosis in neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Tissue factor (TF) is a transmembrane protein that acts as a receptor for activated coagulation factor VII (FVIIa), initiating the coagulation cascade. Recent studies demonstrate that expression of tumor-derived TF also mediates intracellular signaling relevant to tumor growth and apoptosis. Our present study investigates the possible mechanism by which the interaction between TF and FVIIa regulates chemotherapy resistance in neuroblastoma cell lines.</p> <p>Methods</p> <p>Gene and siRNA transfection was used to enforce TF expression in a TF-negative neuroblastoma cell line and to silence endogenous TF expression in a TF-overexpressing neuroblastoma line, respectively. The expression of TF, Bcl-2, STAT5, and Akt as well as the phosphorylation of STAT5 and Akt in gene transfected cells or cells treated with JAK inhibitor and LY294002 were determined by Western blot assay. Tumor cell growth was determined by a clonogenic assay. Cytotoxic and apoptotic effect of doxorubicin on neuroblastoma cell lines was analyzed by WST assay and annexin-V staining (by flow cytometry) respectively.</p> <p>Results</p> <p>Enforced expression of TF in a TF-negative neuroblastoma cell line in the presence of FVIIa induced upregulation of Bcl-2, leading to resistance to doxorubicin. Conversely, inhibition of endogenous TF expression in a TF-overexpressing neuroblastoma cell line using siRNA resulted in down-regulation of Bcl-2 and sensitization to doxorubicin-induced apoptosis. Additionally, neuroblastoma cells expressing high levels of either endogenous or transfected TF treated with FVIIa readily phosphorylated STAT5 and Akt. Using selective pharmacologic inhibitors, we demonstrated that JAK inhibitor I, but not the PI3K inhibitor LY294002, blocked the TF/FVIIa-induced upregulation of Bcl-2.</p> <p>Conclusion</p> <p>This study shows that in neuroblastoma cell lines overexpressed TF ligated with FVIIa produced upregulation of Bcl-2 expression through the JAK/STAT5 signaling pathway, resulting in resistance to apoptosis. We surmise that this TF-FVIIa pathway may contribute, at least in part, to chemotherapy resistance in neuroblastoma.</p

Clinical Impact of Ceftriaxone Resistance in Escherichia coli Bloodstream Infections: A Multicenter Prospective Cohort Study

BACKGROUND: Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common. METHODS: This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding. RESULTS: Notable differences between patients infected with CRO-R and CRO-S E coli BSI included the proportion with Pitt bacteremia score ≥4 (23% vs 15%, P = .079) and the median time to active antibiotic therapy (12 hours [interquartile range {IQR}, 1-35 hours] vs 1 hour [IQR, 0-6 hours]; P \u3c .001). Unadjusted DOOR analyses indicated a 58% probability (95% confidence interval [CI], 52%-63%) for a worse clinical outcome in CRO-R versus CRO-S BSI. In the IPW-adjusted cohort, no difference was observed (54% [95% CI, 47%-61%]). Secondary outcomes included unadjusted and adjusted differences in the proportion of 30-day mortality between CRO-R and CRO-S BSIs (-5.3% [95% CI, -10.3% to -.4%] and -1.8 [95% CI, -6.7% to 3.2%], respectively), postculture median length of stay (8 days [IQR, 5-13 days] vs 6 days [IQR, 4-9 days]; P \u3c .001), and incident admission to a long-term care facility (22% vs 12%, P = .045). CONCLUSIONS: Patients with CRO-R E coli BSI generally have poorer outcomes compared to patients infected with CRO-S E coli BSI, even after adjusting for important confounders

Investigation of the biomechanical effect of variable stiffness shoe on external knee adduction moment in various dynamic exercises

10.1186/1757-1146-6-39Journal of Foot and Ankle Research61

Risk and prognostic significance of tuberculosis in patients from The TREAT Asia HIV Observational Database

10.1186/1471-2334-9-46BMC Infectious Diseases94