Monoclonal Light Chain–Mesangial Cell Interactions: Early Signaling Events and Subsequent Pathologic Effects

Glomerulopathic monoclonal light chains (G-LC) interact with mesangial cells (MC), resulting in alterations of mesangial homeostasis. Early signaling events control mitogenic activities and cytokine production, which in turn participate in the subsequent pathologic events. Mesangial homeostasis is affected in two very different ways, depending on whether the G-LC is from a patient with light chain deposition disease (LCDD) or light chain–related amyloidosis (AL-Am). In contrast, tubulopathic (T)-LC chains from patients with myeloma cast nephropathy do not significantly interact with MC and result in no alterations in mesangial homeostasis. Therefore, understanding early events in the monoclonal LC–MC interactions is fundamental. MC in culture were exposed to LC obtained and purified from the urine of patients with plasma cell dyscrasias and biopsy-proven renal disease, including LCDD, AL-Am, and myeloma cast nephropathy. Incubation of MC with G-LC, but not T-LC, resulted in cytoskeletal and cell shape changes, activation of platelet-derived growth factor-β (PDGF-β) and its corresponding receptor, cytoplasmic to nuclear migration of c-fos and NF-κβ signals, and production of monocyte chemoattractant protein-1 (MCP-1), as well as increased expression of Ki-67, a proliferation marker. Although NF-κβ activation was directly related to MCP-1 production, c-fos activation regulated proliferative signals and cytoskeletal changes in MC. Amyloidogenic LC were avidly internalized by the MC, whereas LCDD-LC effector targets were located at the MC surface. These cellular events are likely initiated as a result of interactions of the G-LC with yet-uncharacterized MC surface receptors. Dissecting the events taking place when G-LC interact with MC may define potential important targets for selective therapeutic manipulation to ameliorate or prevent the glomerular injury that ensues

Completeness and Incompleteness of Synchronous Kleene Algebra

Synchronous Kleene algebra (SKA), an extension of Kleene algebra (KA), was proposed by Prisacariu as a tool for reasoning about programs that may execute synchronously, i.e., in lock-step. We provide a countermodel witnessing that the axioms of SKA are incomplete w.r.t. its language semantics, by exploiting a lack of interaction between the synchronous product operator and the Kleene star. We then propose an alternative set of axioms for SKA, based on Salomaa's axiomatisation of regular languages, and show that these provide a sound and complete characterisation w.r.t. the original language semantics.Comment: Accepted at MPC 201

Failure of erythromycin to eliminate airway colonization with ureaplasma urealyticum in very low birth weight infants

BACKGROUND: Airway colonization of mechanically ventilated very low birth weight infants (birth weight < 1500 grams) by Ureaplasma urealyticum (Uu) is associated with an increased risk of bronchopulmonary dysplasia (BPD). While Uu is sensitive to erythromycin in vitro, the efficacy of intravenous (IV) erythromycin to eliminate Uu from the airways has not been studied. METHODS: 17 very low birth weight infants with Uu positive tracheal aspirate (TA) cultures were randomized to either 5 (8 infants) or 10 days (9 infants) of IV erythromycin lactobionate (40 mg/kg/day in 3 divided doses). Tracheal aspirate cultures for Uu were performed on days 0, 5, 10 and 15. RESULTS: Intravenous erythromycin failed to eliminate airway colonization in a large proportion of infants regardless of whether they received 5 or 10 days of treatment. Ureaplasma urealyticum was isolated from 4/15 (27%) of TAs obtained at 5 days, 5/12 TAs (42%) obtained at 10 days and 6/11(55%) TAs obtained at 15 days (combined group data). CONCLUSIONS: Erythromycin administered IV does not eliminate Uu from the airways in a large proportion of infants. Failure of erythromycin to eliminate Uu from the airways may contribute to the lack of efficacy of this drug in reducing the incidence of BPD in very low birth weight infants

The Angiotensin Converting Enzyme Insertion/Deletion polymorphism is not associated with an increased risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants

BACKGROUND: The ACE gene contains a polymorphism consisting of either the presence (insertion, I) or absence (deletion, D) of a 287 bp alu repeat in intron 16. The D allele is associated with increased ACE activity in both tissue and plasma. The DD genotype is associated with risk of developing ARDS and mortality. The frequency of the D allele is higher in patients with pulmonary fibrosis, sarcoidosis and berylliosis. The role of this polymorphism has not been studied in the development of BPD in the premature newborn. METHODS: ACE I/D genotype was determined in 245 (194 African-American, 47 Caucasian and 4 Hispanic) mechanically ventilated infants weighing less than 1250 grams at birth and compared to outcome (death and/or development of BPD). RESULTS: The incidence of the D allele in the study population was 0.58. Eighty-eight (35.9%) infants were homozygous DD, 107 (43.7%) were heterozygous ID and 50 (20.4%) were homozygous II. There were no significant differences between genotype groups with respect to ethnic origin, birth weight, gestation, or gender. There was no effect of the ACE I/D polymorphism on mortality or development of BPD (O(2 )on 28 days or 36 weeks PCA). Secondary outcomes (intraventricular hemorrhage and periventricular leukomalacia) similarly were not influenced by the ACE ID polymorphism. CONCLUSIONS: The ACE I/D polymorphism does not significantly influence the development of BPD in ventilated infants less than 1250 grams

Elevated platelet-derived growth factor-BB concentrations in premature neonates who develop chronic lung disease

BACKGROUND: Chronic lung disease (CLD) in the preterm newborn is associated with inflammation and fibrosis. Platelet-derived growth factor-BB (PDGF-BB), a potent chemotactic growth factor, may mediate the fibrotic component of CLD. The objectives of this study were to determine if tracheal aspirate (TA) concentrations of PDGF-BB increase the first 2 weeks of life in premature neonates undergoing mechanical ventilation for respiratory distress syndrome (RDS), its relationship to the development of CLD, pulmonary hemorrhage (PH) and its relationship to airway colonization with Ureaplasma urealyticum (Uu). METHODS: Infants with a birth weight less than 1500 grams who required mechanical ventilation for RDS were enrolled into this study with parental consent. Tracheal aspirates were collected daily during clinically indicated suctioning. Uu cultures were performed on TA collected in the first week of life. TA supernatants were assayed for PDGF-BB and secretory component of IgA concentrations using ELISA techniques. RESULTS: Fifty premature neonates were enrolled into the study. Twenty-eight infants were oxygen dependent at 28 days of life and 16 infants were oxygen dependent at 36 weeks postconceptual age. PDGF-BB concentrations peaked between 4 and 6 days of life. Maximum PDGF-BB concentrations were significantly higher in infants who developed CLD or died from respiratory failure. PH was associated with increased risk of CLD and was associated with higher PDGF-BB concentrations. There was no correlation between maximum PDGF-BB concentrations and Uu isolation from the airway. CONCLUSIONS: PDGF-BB concentrations increase in TAs of infants who undergo mechanical ventilation for RDS during the first 2 weeks of life and maximal concentrations are greater in those infants who subsequently develop CLD. Elevation in lung PDGF-BB may play a role in the development of CLD

beta-Hydroxy-beta-methylbutyrate free acid reduces markers of exercise-induced muscle damage and improves recovery in resistance-trained men

The purpose of the present study was to determine the effects of short-term supplementation with the free acid form of beta-hydroxy-beta-methylbutyrate (HMB-FA) on indices of muscle damage, protein breakdown, recovery and hormone status following a high-volume resistance training session in trained athletes. A total of twenty resistance-trained males were recruited to participate in a high-volume resistance training session centred on full squats, bench presses and dead lifts. Subjects were randomly assigned to receive either 3 g/d of HMB-FA or a placebo. Immediately before the exercise session and 48 h post-exercise, serum creatine kinase (CK), urinary 3-methylhistadine (3-MH), testosterone, cortisol and perceived recovery status (PRS) scale measurements were taken. The results showed that CK increased to a greater extent in the placebo (329%) than in the HMB-FA group (104%) (P=0.004, d=1.6). There was also a significant change for PRS, which decreased to a greater extent in the placebo (9.1 (SEM 0.4) to 4.6 (SEM 0.5)) than in the HMB-FA group (9.1 (SEM 0.3) to 6.3 (SEM 0.3)) (P=0.005, d = -0.48). Muscle protein breakdown, measured by 3-MH analysis, numerically decreased with HMB-FA supplementation and approached significance (P=0.08, d = 0.12). There were no acute changes in plasma total or free testosterone, cortisol or C-reactive protein. In conclusion, these results suggest that an HMB-FA supplement given to trained athletes before exercise can blunt increases in muscle damage and prevent declines in perceived readiness to train following a high-volume, muscle-damaging resistance-training session

Deep-Inelastic Final States in a Space-Time Description of Shower Development and Hadronization

We extend a quantum kinetic approach to the description of hadronic showers in space, time and momentum space to deep-inelastic $ep$ collisions, with particular reference to experiments at HERA. We follow the history of hard scattering events back to the initial hadronic state and forward to the formation of colour-singlet pre-hadronic clusters and their decays into hadrons. The time evolution of the space-like initial-state shower and the time-like secondary partons are treated similarly, and cluster formation is treated using a spatial criterion motivated by confinement and a non-perturbative model for hadronization. We calculate the time evolution of particle distributions in rapidity, transverse and longitudinal space. We also compare the transverse hadronic energy flow and the distribution of observed hadronic masses with experimental data from HERA, and find encouraging results. The techniques developed in this paper may be applied in the future to more complicated processes such as eA, pp, pA and AA collisions.Comment: 44 pages plus 14 postscript figure

Interleukin-4 and 13 concentrations in infants at risk to develop Bronchopulmonary Dysplasia

BACKGROUND: An exaggerated inflammatory response occurs in the first few days of life in infants who subsequently develop bronchopulmonary dysplasia (BPD). The increase of inflammatory cytokines in many disease processes is generally balanced by a rise in anti-inflammatory cytokines. Interleukin-4 (IL-4) and interleukin-13 (IL-13) have been shown to inhibit production of several inflammatory cytokines important in the development of BPD. METHODS: We sought to determine if a correlation exists between the presence or absence of IL-4 and IL-13 in tracheal aspirates (TA) during the first 3 weeks of life and the development of BPD in premature infants. Serial TAs were prospectively obtained from 36 very low birth weight infants and IL-4 and IL-13 concentrations were determined by ELISA. RESULTS: Infants who developed BPD (n = 19) were less mature (25.3 ± 0.02 wks vs. 27.8 ± 0.05 wks; p < 0.001), and had lower birth weights (739 ± 27 g vs.1052 ± 41 g; p < 0.001). IL-4 and IL-13 were detectable in only 27 of 132 and 9 of 132 samples assayed respectively. Furthermore, the levels detected for IL-4 and IL-13 were very low and did not correlate with the development of BPD. CONCLUSIONS: TA concentrations of IL-4 and IL-13 do not increase significantly during acute lung injury in premature infants

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Towards a “Sample-In, Answer-Out” Point-of-Care Platform for Nucleic Acid Extraction and Amplification: Using an HPV E6/E7 mRNA Model System

The paper presents the development of a “proof-of-principle” hands-free and self-contained diagnostic platform for detection of human papillomavirus (HPV) E6/E7 mRNA in clinical specimens. The automated platform performs chip-based sample preconcentration, nucleic acid extraction, amplification, and real-time fluorescent detection with minimal user interfacing. It consists of two modular prototypes, one for sample preparation and one for amplification and detection; however, a common interface is available to facilitate later integration into one single module. Nucleic acid extracts (n = 28) from cervical cytology specimens extracted on the sample preparation chip were tested using the PreTect HPV-Proofer and achieved an overall detection rate for HPV across all dilutions of 50%–85.7%. A subset of 6 clinical samples extracted on the sample preparation chip module was chosen for complete validation on the NASBA chip module. For 4 of the samples, a 100% amplification for HPV 16 or 33 was obtained at the 1 : 10 dilution for microfluidic channels that filled correctly. The modules of a “sample-in, answer-out” diagnostic platform have been demonstrated from clinical sample input through sample preparation, amplification and final detection