Hypoesthesia after anterior cruciate ligament reconstruction: The relationship between proprioception and vibration perception deficits in individuals greater than one year post-surgery

Background

While surgical reconstruction restores mechanical stability following anterior cruciate ligament (ACL) rupture, many experience early-onset osteoarthritis despite surgery. Neurophysiological changes are hypothesized to contribute to knee osteoarthritis progression. Proprioceptive deficits have been reported following ACL injury/reconstruction; however, vibration perception threshold (VPT) has been less studied. This study explored relationships between pain, VPT, proprioception, function, and strength following ACL-reconstruction.

Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes

Recognition of Gram-positive bacteria by Toll-like receptor 2 (TLR2) induces activation of proinflammatory pathways. In mice, sensitization with the Gram-positive Propionibacterium acnes followed by a challenge with the TLR4 ligand, lipopolysaccharide (LPS), results in fulminant hepatic failure. Here, we investigated the role of TLR2 in liver sensitization to LPS-induced injury. Stimulation of Chinese hamster ovary cells and peritoneal macrophages with heat-killed P. acnes required expression of TLR2 but not of TLR4, suggesting that P. acnes was a TLR2 ligand. Cell activation by P. acnes was myeloid differentiation primary-response protein 88 (MyD88)-dependent, and it was augmented by coexpression of CD14 in mouse peritoneal macrophages. In vitro, P. acnes behaved as a TLR2 ligand and induced TLR4 hetero- and TLR2 homotolerance in peritoneal macrophages. In vivo priming of wild-type mice with P. acnes, but not with the selective TLR2 ligands peptidoglycan and lipotheicoic acid, resulted in hepatocyte necrosis, hyperelevated serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, interferon-gamma (IFN-gamma), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1alpha, IL-6, IL-1beta, IL-18, IFN-gamma) in the liver after a LPS challenge. Furthermore, P. acnes priming sensitized TLR2-deficient (TLR2-/-) but not MyD88-/- mice to LPS-induced injury, evidenced by hepatocyte necrosis, increased levels of serum TNF-alpha, IFN-gamma, IL-6, and liver proinflammatory cytokine mRNA expression. IFN-gamma, a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2-/- and TLR9-/- but not MyD88-/- mice. These results suggest that although P. acnes triggers TLR2-mediated cell activation, TLR2-independent but MyD88-dependent mechanisms mediate in vivo sensitization by P. acnes for LPS-induced liver injury.     

Acute ethanol consumption synergizes with trauma to increase monocyte tumor necrosis factor α production late postinjury

The hypothesis that acute ethanol uptake plus trauma can synergize to increase immunosuppression was tested. We found that, unlike non-alcohol-exposed patients, patients with acute alcohol use prior to trauma have a transient decrease in monocyte tumor necrosis factor (TNF) production during the very early postinjury (0–3 days) period. However, TNF production by these alcoholexposed patients' monocytes (MØ) became hyperelevated late postinjury (>9 days). Consequently, these massively elevated MØ TNF levels can contribute to posttrauma immunosuppression after acute alcohol use. We also demonstrate that normal monocyte activation with the superantigen,Staphylococcus enterotoxin B (SEB), results in a preferential induction of cellassociated MØ TNF production, described as characteristic of immunosuppressed trauma patients. Acutein vitro ethanol treatment down-regulated the elevated TNF production by trauma patients' MØ after either SEB, muramyl-dipeptide (MDP), interferon- plus MDP, or lipopolysaccharide (LPS) stimulation. Both SEB- and LPS-induced TNF mRNA induction was inhibited by acute alcohol treatment in normal MØ, indicating that ethanol can regulate cytokine gene expression. An additional immunosuppressive effect of acute ethanol's stimulation was suggested by its induction of elevated transforming growth factor production in trauma patients' activated MØ.     

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.     

Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer.

PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.     

GyrB Polymorphisms Accurately Assign Invasive Viridans Group Streptococcal Species

Viridans group streptococci (VGS) are a heterogeneous group of medically important bacteria that cannot be accurately assigned to a particular species using conventional phenotypic methods. Although multilocus sequence analysis (MLSA) is considered the gold standard for VGS species-level identification, MLSA is not yet feasible in the clinical setting. Conversely, molecular methods, such as sodA and 16S rRNA gene sequencing, are clinically practical but not sufficiently accurate for VGS species-level identification. Here, we present data regarding the use of an ∼400-nucleotide internal fragment of the gene encoding DNA gyrase subunit B (GyrB) for VGS species-level identification. MLSA, internal gyrB, sodA, full-length, and 5′ 16S gene sequences were used to characterize 102 unique VGS blood isolates collected from 2011 to 2012. When using the MLSA species assignment as a reference, full-length and 5′ partial 16S gene and sodA sequence analyses failed to correctly assign all strains to a species. Precise species determination was particularly problematic for Streptococcus mitis and Streptococcus oralis isolates. However, the internal gyrB fragment allowed for accurate species designations for all 102 strains. We validated these findings using 54 VGS strains for which MLSA, 16S gene, sodA, and gyrB data are available at the NCBI, showing that gyrB is superior to 16S gene and sodA sequence analyses for VGS species identification. We also observed that specific polymorphisms in the 133-amino acid sequence of the internal GyrB fragment can be used to identify invasive VGS species. Thus, the GyrB amino acid sequence may offer a more practical and accurate method for classifying invasive VGS strains to the species level.     

Alcohol-Induced Regulation of Nuclear Regulatory Factor-Kβ in Human Monocytes

Acute ethanol exposure has the capacity to modulate immune functions, particularly, to down regulate monocyte production of inflammatory cytokines. However, the intracellular mechanisms for these effects of ethanol are yet to be understood. Considering that nuclear regulatory factor-kβ (NF-KB)/Rel is a common regulatory element of the promoter region of the inflammatory cytokine genes, herein, we tested the hypothesis that acute ethanol affects NF-kB activation in human monocytes. Adherence-isolated monocytes showed constitutive DNA binding activity of NF-kB. A clinically relevant dose (25 mM) of acute ethanol treatment in vitro increased NF-kB binding activity in monocytes with a preferential induction of the inhibitory, p50/p50, NF-kB/Rel homodimer, and resulted in no induction of the p65/p50 heterodimer. In contrast, lipopolysaccharide stimulation primarily induced the p65/p50 heterodimer that has been shown to result in gene activation. Thus, such unique activation of the inhibitory p50/p50 homodimer by acute ethanol treatment may result in inhibition rather than activation of NF-kB-regulated inflammatory cytokine genes. Consequently, these results suggest that physiologically relevant concentrations of ethanol may affect production of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6 by disrupting NF-kB signaling in monocytes.     

Evaluation of an Enzyme Immunoassay for Detection of Histoplasma capsulatum Antigen from Urine Specimens

Detection of Histoplasma capsulatum urinary antigen (UAg) is important for the initial diagnosis of infection and for monitoring of patient responses to antifungal therapy. This study evaluated an analyte-specific reagent (ASR) enzyme immunoassay (EIA) for the detection of H. capsulatum UAg from Immuno Mycologics, Inc. (IMMY) (Norman, OK) in comparison with routine testing with the MiraVista (MVista) H. capsulatum quantitative EIA (MiraVista Diagnostics, Indianapolis, IN). Using prospectively collected urine specimens (n = 1,003), we observed an overall percent agreement between the two assays of 97.6% (979/1,003 samples). Compared with the MVista EIA, the sensitivity and specificity of the IMMY ASR EIA were 64.5% (40/62 samples) and 99.8% (939/941 samples), respectively, using a cutoff value of 0.5 ng/ml. Based on available clinical histories for 23/24 discordant samples, 5 IMMY assay-negative/MVista assay-positive samples were considered falsely positive. Furthermore, 10/23 discordant samples were positive by the MVista EIA but were below the limit of quantitation (<0.4 ng/ml). The clinical significance of these low positive results in the MVista EIA is unclear. In addition to the prospective study, we tested 11 urine specimens collected from patients with culture-confirmed Histoplasma infections, and 100% (11/11 samples) were positive by the IMMY ASR EIA. In conclusion, the IMMY ASR EIA may offer an alternative approach for the detection of Histoplasma UAg. Additional prospective studies are needed to better characterize the performance of the IMMY ASR EIA in conjunction with clinical and laboratory findings.