An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions and poorly regenerate club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex-vivo analysis reveals a specific role for alloantigen-primed effector CD8+ T cells in preventing club cell proliferation and maintenance. Taken together, we demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a new model to identify the underlying mechanisms of OB

Status Epilepticus in Post-Transplantation Hyperammonemia Involves Careful Metabolic Management

Hyperammonemia is a condition that may result after solid organ transplantation, particularly lung transplantation. However, it is very uncommon for this presentation to occur more than 30 days post-transplantation. Hyperammonemia and the resulting encephalopathy typically manifest with altered sensorium, a clinical situation which is not often included in the differential diagnosis of presumed nonconvulsive status epilepticus (NCSE). Seizures are common among this subset of patients with hyperammonemia and may be refractory to traditional treatments. Evidence of elevated intracranial pressure by invasive monitoring and neuroimaging findings of diffuse cerebral edema are commonly reported. Here we examine the therapeutic importance of identifying the specific cause of hyperammonemic encephalopathy, a condition which may result in status epilepticus and ultimately cerebral edema or even brain death

Identifying the Timing of Swallowing Sounds Using Videoendoscopy Findings in Healthy Adults

Cervical auscultation is a useful tool for detecting dysphagia; however, the sites where swallowing sounds are produced are unknown. In this study, we investigated the relationship between swallowing sounds and videoendoscopy (VE) images in healthy adults to identify the timing of swallowing sounds. Fifteen healthy young adults participated in the study. Each participant was seated in an upright position while a stethoscope probe with an inserted microphone was placed at the center of his or her lower neck to detect swallowing sounds during the VE. The detected sounds were recorded simultaneously with the VE images while the subjects swallowed 4g of liquid or jelly. Swallowing duration, swallowing sound duration, and VE findings at the beginning and end of swallowing sounds were analyzed. One hundred and thirty-four sound samples produced by a single swallowed bolus were obtained and analyzed. The mean swallowing duration for each material ranged from 1.25 to 2.39s. Swallowing duration was significantly longer for jelly compared with liquids (p<0.01). Swallowing sound duration was approximately 0.5s in all samples, and there were no significant differences between materials. Most swallowing sounds started during velopharyngeal closure (109/134, 81.3%), and most swallowing sounds ended during velopharyngeal closure (98/134, 73.1%). For all materials, swallowing sounds did not start when the materials flowed into the pyriform sinuses, and very few sounds corresponded with epiglottic movements. These results show that many movements associated with physiologic events―including hyoid bone and laryngeal excursion, and opening of the upper esophageal sphincter―may be involved in the production of swallowing sounds

Determination of Benzene and Phenol in Body Fluids by Headspace Solid-Phase Microextraction (SPME. and Capillary Gas Chromatography

Benzene and its metabolite phenol are extractable from human whole blood and urine using headspace solid-phase microextraction (SPME. with a Carboxen/polydimethylsiloxane fiber. Both compounds were assayed using ethylbenzene and 2,4-dimethylphenol as internal standards (IS. and capillary gas chromatography (GC. with flame ionization detection. The headspace SPME-GC gave sharp peaks for benzene, phenol, and IS-1, 2; with the whole blood and urine samples showing low background noise. The extraction efficiencies of benzene and phenol were 51.8–99.4% and 10.6–14.3%, respectively, for both whole blood and urine. Regression equations also showed excellent linearity in the range of 5–400ng/0.5ml for benzene and 10–500ng/0.5ml for phenol extracted from whole blood and urine. The detection limits (signal-to-noise ratio=3. for the benzene and phenol were 5–10ng/0.5ml for whole blood and 2–5ng/0.5ml for urine. The coefficients of within-day variation in terms of extraction efficiency for both compounds in whole blood and urine samples were not greater than 13.8%. These data indicate that benzene and phenol can be successfully separated and determined from human samples using the established headspace SPME method

Development of Novel CXC Chemokine Receptor 7 (CXCR7) Ligands: Selectivity Switch from CXCR4 Antagonists with a Cyclic Pentapeptide Scaffold

The CXC chemokine receptor 7 (CXCR7)/ACKR3 is a chemokine receptor that recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and interferon-inducible T-cell α chemoattractant (I-TAC)/CXCL11. Here, we report the development of novel CXCR7-selective ligands with a cyclic pentapeptide scaffold through an SAR study of CXC chemokine receptor 4 (CXCR4) selective antagonist FC131 [<i>cyclo</i>(-d-Tyr-l-Arg-l-Arg-l-Nal-Gly-), Nal = 3-(2-naphthyl)­alanine]. Substitution of Gly with l-Pro switched the receptor preference of the peptides from CXCR4 to CXCR7. The SAR study led to the identification of a potent CXCR7 ligand, FC313 [<i>cyclo</i>(-d-Tyr-l-Arg-l-MeArg-l-Nal-l-Pro-)], which recruits β-arrestin to CXCR7. Investigations via receptor mutagenesis and molecular modeling experiments suggest a possible binding mode of the cyclic pentapeptide CXCR7 agonist

PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity

The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy