Adaptive and innate immune mechanisms in cardiac fibrosis complicating pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a syndrome diagnosed by increased mean pulmonary artery (PA) pressure and resistance and normal pulmonary capillary wedge pressure. PAH is characterized pathologically by distal pulmonary artery remodeling, increased pulmonary vascular resistance, and plexiform lesions (PLs). Right ventricular fibrosis and hypertrophy, leading to right ventricular failure, are the main determinants of mortality in PAH. Recent work suggests that right ventricular fibrosis results from resident cardiac fibroblast activation and conversion to myofibroblasts, leading to replacement of contractile cardiomyocytes with nondistensible tissue incapable of conductivity or contractility. However, the origins, triggers, and consequences of myofibroblast expansion and its pathophysiological relationship with PAH are unclear. Recent advances indicate that signals generated by adaptive and innate immune cells may play a role in right ventricular fibrosis and remodeling. This review summarizes recent insights into the mechanisms by which adaptive and innate immune signals participate in the transition of cardiac fibroblasts to activated myofibroblasts and highlights the existing gaps of knowledge as relates to the development of right ventricular fibrosis.

Association between tumor architecture derived from generalized Q-space MRI and survival in glioblastoma.

While it is recognized that the overall resistance of glioblastoma to treatment may be related to intra-tumor patterns of structural heterogeneity, imaging methods to assess such patterns remain rudimentary. METHODS: We utilized a generalized Q-space imaging (GQI) algorithm to analyze magnetic resonance imaging (MRI) derived from a rodent model of glioblastoma and 2 clinical datasets to correlate GQI, histology, and survival. RESULTS: In a rodent glioblastoma model, GQI demonstrated a poorly coherent core region, consisting of diffusion tracts <5 mm, surrounded by a shell of highly coherent diffusion tracts, 6-25 mm. Histologically, the core region possessed a high degree of necrosis, whereas the shell consisted of organized sheets of anaplastic cells with elevated mitotic index. These attributes define tumor architecture as the macroscopic organization of variably aligned tumor cells. Applied to MRI data from The Cancer Imaging Atlas (TCGA), the core-shell diffusion tract-length ratio (c/s ratio) correlated linearly with necrosis, which, in turn, was inversely associated with survival (p = 0.00002). We confirmed in an independent cohort of patients (n = 62) that the c/s ratio correlated inversely with survival (p = 0.0004). CONCLUSIONS: The analysis of MR images by GQI affords insight into tumor architectural patterns in glioblastoma that correlate with biological heterogeneity and clinical outcome.

Improved molecular fingerprint analysis employing multi-branched gold nanoparticles in conjunction with surface-enhanced Raman scattering.

Vibrational spectroscopy is a powerful analytical tool that assesses molecular properties based on spectroscopic signatures. In this study, the effect of gold nanoparticle morphology (spherical vs multi-branched) was assessed for the characterization of a Raman signal (ie, molecular fingerprint) that may be helpful for numerous medical applications. Multi-branched gold nanoparticles (MBAuNPs) were fabricated using a green chemistry method which employed the reduction of gold ion solute by 2-[4-(2-hydroxyethyl)-1-piperazyl] ethane sulfonic acid. Two types of reporter dyes, indocyanine (IR820 and IR792) and carbocyanine (DTTC [3,3'-diethylthiatricarbocyanine iodide] and DTDC [3,3'-diethylthiadicarbocyanine iodide]), were functionalized to the surface of the MBAuNPs and stabilized with denatured bovine serum albumin, thus forming the surface-enhanced Raman spectroscopy tag. Fluorescein isothiocyanate-conjugated anti-epidermal growth factor receptor to the surface-enhanced Raman spectroscopy tags and the properties of the resulting conjugates were assessed through determination of the Raman signal. Using the MBAuNP Raman probes synthesized in this manner, we demonstrated that MBAuNP provided significantly more surface-enhanced Raman scattering signal when compared with the associated spherical gold nanoparticle of similar size and concentration. MBAuNP enhancements were retained in the surface-enhanced Raman spectroscopy tags complexed to anti-epidermal growth factor receptor, providing evidence that this could be a useful biological probe for enhanced Raman molecular fingerprinting. Furthermore, while utilizing IR820 as a novel reporter dye linked with MBAuNP, superior Raman signal fingerprint results were obtained. Such results provide significant promise for the use of MBAuNP in the detection of numerous diseases for which biologically specific surface markers exist.

Generalized Q-space MRI reveals macroscopic patterns of tumor architecture in vivo.

Current approaches for studying tumor activity in patients involve molecular characterization in excised tissue or biopsied samples. Recognizing that tumors are composed of heterogeneous arrays of cells and their environment, there is a compelling rationale to explore the macroscopic organization of tumor tissue. We present a novel methodology for probing the micro-structural constituents of tumors in vivo utilizing generalized Q-space MRI. This approach employs varying magnetic field gradients and diffusion sensitivities to yield voxel-scale probability distribution functions of proton diffusivity, and then maps multi-voxel cellular alignment with tractography. Using this methodology, we describe the presence of macroscopic organizational features in patients with head and neck cancers, specifically depicting regional differences between the geometrically coherent periphery and incoherent core region. Such methods may comprise a method for assessing attributes of tumor biology in vivo and for predicting the response of such tumors to various drugs and interventions.

Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation.

OBJECTIVE: There is a strong association between reflux and end-stage lung disease, especially idiopathic pulmonary fibrosis. The presence of reflux after lung transplantation might predispose to the development of bronchiolitis obliterans. We evaluated the risk and physiologic effect of laparoscopic fundoplication in patients on the lung transplant waiting list. METHODS: One hundred forty-nine patients on the lung transplant waiting list between March 2001 and January 2005 were evaluated. Nineteen were found to have a history of reflux, continued symptoms, and severe reflux by means of pH and manometric studies and underwent laparoscopic fundoplication. The postoperative course of these 19 patients, including lung function, was retrospectively reviewed. Postoperatively, the lung function of the 14 patients with idiopathic pulmonary fibrosis who underwent the laparoscopic Nissen procedure was compared with that of 31 patients with idiopathic pulmonary fibrosis on the transplant waiting list who did not undergo fundoplication. RESULTS: There were no perioperative complications and no decrease in lung function over the 15-month average follow-up. Exercise capacity remained stable, as determined on the basis of 6-minute walk distance. Patients with idiopathic pulmonary fibrosis treated with fundoplication had stable oxygen requirements, whereas control patients with idiopathic pulmonary fibrosis on the waiting list had a statistically significant deterioration in oxygen requirement. CONCLUSIONS: Laparoscopic fundoplication can be performed safely in patients with end-stage lung disease awaiting lung transplantation. Overall, these patients maintained stable lung function during the follow-up period. When compared with a control group of patients with idiopathic pulmonary fibrosis not undergoing fundoplication, there was stabilization of oxygen requirement. A larger prospective trial evaluating the effect of laparoscopic fundoplication on underlying lung function in this patient population is warranted.

Antireflux operation for gastroesophageal reflux after Roux-en-y gastric bypass for obesity.

Gastroesophageal reflux disease (GERD) affects many morbidly obese patients. The Roux-en-y gastric bypass operation often achieves the simultaneous aims of weight reduction as well as reflux correction. However, some patients continue to suffer from severe gastroesophageal symptoms after successful postoperative weight reduction. There are no reports describing surgical treatments for these patients. Here we report our management of intractable postoperative reflux with a Belsey Mark IV fundoplication performed one year after a successful Roux-en-y gastric bypass operation. The patient tolerated the operation without problems and experienced successful resolution of her reflux symptoms.