Expiratory resistive loading in patients with severe chronic air-flow limitation. An evaluation of ventilatory mechanics and compensatory responses

In order to estimate the extent of dynamic compression in patients with COPD who were flow-limited at rest, we measured tidal expiratory flows before and after application of small expiratory resistive loads (ERL). We sought also to evaluate the compensatory strategies available to such patients during ERL by measuring steady-state ventilatory responses. Nine patients with severe COPD (FEV1 +/- SE, 27 +/- 3% predicted) completed the study. Mean tidal flow-volume plots representing all breaths analyzed during 4 min of ERL (resistance, 8 cm H2O/L/s) and unloaded control (4 min) were compared at isoabsolute volume in each individual subject. In 6 subjects, ERL resulted in appreciable reduction of expiratory flows throughout the tidal volume (VT) when compared with volume-matched flows during control. In the remaining subjects, expiratory flows during loading and control coincided during part of the VT. In the group as a whole at 50, 30, and 10% of VT during ERL, when mouth pressure was increased by 3, 2.5, and 2 cm H2O, respectively, flow rates were significantly lower than volume-matched flows during control (delta V, = 0.10, 0.09 and 0.06 L/s, respectively). Minute ventilation was reduced significantly by ERL, but only small insignificant changes in breathing pattern parameters occurred. End-expiratory volume increased by 0.1 L +/- 0.02 (p less than 0.005). We conclude that the majority of patients with chronic air-flow limitation do not sustain significant dynamic compression at rest, and loading response to ERL in patients with COPD are attenuated when compared with those in normal subjects.     

IL-17 Genetic Variations Increase the Risk of Cirrhotic/Hepatocellular Carcinoma in Patients with Hepatitis B Virus Infection.

Background: Genetic variation in immune regulatory genes might influence the HBV infection outcome. Objective: This study aimed to determinethe association of IL-17A rs2275913 (G197A), IL-17F rs763780 (A7488G), and IL-23R rs10889677 (C2370A) gene polymorphisms, as well as the emerged haplotypes in the individual infected by HBV and to investigate their association with the infection outcome. Materials and Methods: 300 chronic HBV infections with Cirrhotic/Hepatocellular carcinoma (C/HCC), chronic active (CA), and asymptomatic carrier (AC) and 38 individuals whose infection was spontaneously cleared (SC) were enrolled. Genomic DNA was extracted, and IL-17A/F and IL-23R genotyping were performed by using the PCR-RFLP method. Results: Out of 338 subjects, 238 and 100 were respectively male and /female with a mean age of 47.61±13.41. The frequency of GA genotype (p=0.01) and A alleles (p=0.001) of IL-17A rs2275913 (G197A), as well as the frequency of AA genotype (p=0.014) and A alleles (p=0.018) of IL-17F rs763780 (A7488G) gene locus, was found to be significantly higher in the C/HCC than CA and AC groups. Furthermore, the frequency of GA and AG haplotype in CA individuals was higher than those with C/HCC and AC (p=0.003). Also, the GG haplotype was higher in AC individuals than those with C/HCC (P=0.022), and the AA haplotype was higher in C/HCC individuals than the CA patients (P=0.001). Conclusion: Our findings suggest that A allele and GA genotype at IL-17A rs2275913 (G197A), as well as A allele and AA genotype at IL-17F rs763780 (A7488G) locus, might be associated with increased risk of C/HCC among patients with hepatitis B virus infection.     

Magnetic CoFe2O4 nanoparticles supported on graphene oxide (CoFe2O4/GO) with high catalytic activity for peroxymonosulfate activation and degradation of rhodamine B

Herein, we report the preparation of magnetic CoFe₂O₄ nanoparticles and CoFe₂O₄/graphene oxide (GO) hybrids and evaluate their catalytic activity as heterogeneous peroxymonosulfate (PMS) activators for the decomposition of rhodamine B. The surface morphologies and structures of both CoFe₂O₄ nanoparticles and CoFe₂O₄/GO hybrids were investigated by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), Fourier transform infrared spectroscopy (FTIR) and nitrogen adsorption–desorption isotherms. The magnetic properties of the samples were assessed using a SQUID magnetometer at 298 K. Catalytic oxidation experiments demonstrated that CoFe₂O₄/GO hybrids exhibited much better catalytic activity than CoFe₂O₄ nanoparticles or CoFe₂O₄/reduced graphene oxide (rGO) hybrids, suggesting that GO plays an important role in CoFe₂O₄/GO hybrids in the decomposition of rhodamine B. The influence of various reaction conditions such as temperature, concentration of PMS, pH and decomposition time of rhodamine B over the CoFe₂O₄/GO catalyst were investigated and optimized. The rhodamine B degradation process was found to fit a pseudo-first order kinetics model. The catalyst could be easily separated from the reaction mixture by applying an external magnet. In particular, the as-prepared CoFe₂O₄/GO hybrid exhibited good reusability and stability in successive degradation experiments in PMS solution.

Herein, we report the preparation of magnetic CoFe₂O₄ nanoparticles and CoFe₂O₄/graphene oxide (GO) hybrids and evaluate their catalytic activity as heterogeneous peroxymonosulfate (PMS) activators for the decomposition of rhodamine B.     

Synthesis,Characterization, and In vitro Studies of PLGA–PEG Nanoparticles for Oral Insulin Delivery

Therapeutic proteins and peptides are corresponding to a major area of research in biotechnology companies and current pharmaceutical. Because of their natural instability, the enormous majority of these drugs require parentéral administration. Oral insulin delivery would be a highly attractive alternative process of administration, though it continues to be a mysterious target due to the enzymatic digestion of insulin and low levels of absorption from the gastrointestinal region. Hydrogel polymers can be considered as potential carriers for oral insulin delivery. In particular, a pH responsive hydrogel composed of PLGA–PEG has shown the ability to protect insulin from enzymes in the gastric environment and release in small intestines. However, this material has not shown similar potential for oral protein delivery of further model drugs. To date, the unique interaction between PLGA–PEG and insulin, as a potential drug for oral delivery, is not completely understood. The focus of this research is synthetization and characterization of hydrogels PLGA–PEG insulin nanoparticles and also pH sensitivity of insulin nanoparticles was investigated.     

Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture

Ghrelin is a peptide hormone primarily produced in the previously unidentified X/A endocrine cells of the stomach. Extensive studies have focused on the effects of ghrelin on growth hormone release and appetite regulation. However, the mechanisms regulating ghrelin secretion are less understood. In the present study, we developed a primary culture of newborn rat stomach cells to investigate the mechanisms regulating ghrelin synthesis and secretion. We demonstrated that this cell preparation secretes ghrelin in a regulated manner through the increase of cAMP, intracellular calcium, and activation of protein kinase C. Norepinephrine (NE) (0.1-10 μm) stimulated ghrelin secretion through the β1-adrenergic receptor via increased cAMP and protein kinase A activity, whereas acetylcholine had no effect. Because circulating ghrelin levels were previously shown to be inversely correlated with insulin levels, we investigated the effect of insulin on ghrelin secretion. We first demonstrated that ghrelin cells express the insulin receptor α- and β-subunits. Next, we determined that insulin (1-10 nm) inhibited both basal and NE-stimulated ghrelin secretion, caused an increase in phosphorylated serine-threonine kinase (AKT) and a reduction in intracellular cAMP, but did not alter proghrelin mRNA levels. The inhibitory effect of insulin was blocked by inhibiting phospho-inositol-3 kinase and AKT but not MAPK. Higher dose insulin (100 nm) did not suppress ghrelin secretion, which prompted the investigation of cellular insulin resistance by pretreating the cells with 100 nm insulin for 24 h. This caused a reduction in insulin receptor expression and prevented the insulin-mediated AKT activation and the suppression of ghrelin secretion with no impact on NE-stimulated ghrelin secretion. Our findings highlight the role of the sympathetic nervous system, insulin, and insulin resistance in the regulation of ghrelin secretion.     

Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma

A subset of patients with advanced classical Hodgkin's lymphoma is refractory to standard therapies. Therefore, it is relevant to identify new biologically-based prognostic markers. Recently, tumor associated macrophages have been proposed as a factor that predicts survival, although contradictory results have also been reported. Here we analyzed four macrophage markers (CD68, CD163, LYZ, and STAT1) using immunohistochemistry and automated quantification, in two independent series of advanced classical Hodgkin's lymphoma (n=266 and 103 patients, respectively). Our results did not confirm that specific macrophage immunohistochemical markers could be used as surrogates for gene expression profiling studies. Survival analyses did not show correlation between CD163, LYZ or STAT1 and either failure-free or disease-specific survival. There was an association between CD68 and disease-specific survival, but it was not consistent in both series. In conclusion, individual tumor associated macrophage markers cannot be used to predict outcome before technical standardization and prospective validation in independent series of patients with comparable stages and treatments.     

LMO2 and BCL6 are associated with improved survival in primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is an aggressive sub‐variant of non‐Hodgkin lymphoma (NHL) with morphological similarities to diffuse large B‐cell lymphoma (DLBCL). While methotrexate (MTX)‐based therapies have improved patient survival, the disease remains incurable in most cases and its pathogenesis is poorly understood. We evaluated 69 cases of PCNSL for the expression of HGAL (also known as GCSAM), LMO2 and BCL6 – genes associated with DLBCL prognosis and pathobiology, and analysed their correlation to survival in 49 PCNSL patients receiving MTX‐based therapy. We demonstrate that PCNSL expresses LMO2, HGAL(also known as GCSAM) and BCL6 proteins in 52%, 65% and 56% of tumours, respectively. BCL6 protein expression was associated with longer progression‐free survival (P = 0·006) and overall survival (OS, P = 0·05), while expression of LMO2 protein was associated with longer OS (P = 0·027). Further research is needed to elucidate the function of BCL6 and LMO2 in PCNSL.     

Acute Lipotoxicity Regulates Severity of Biliary Acute Pancreatitis without Affecting Its Initiation

Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O–positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate–induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction.The mystique of acute pancreatitis (AP) lies in its diverse origins, unpredictable course, and outcomes, ranging from resolution with minimal care to being a debilitating, protracted, and potentially lethal condition despite intensive care and complex interventions to manage its complications. The course AP takes seems unrelated to the origin in most cases, with differences in the predominant origin of AP reported in studies from different countries.^1–5 However, studies have repeatedly reported a higher body mass index (BMI) or obesity to be associated with severe AP (SAP).^1–8 SAP may result from severe pancreatic necrosis, in which >30% of the pancreas is necrosed,^9,10 or from persistent or multisystem organ failure, such as respiratory and renal failure. Obese patients have been reported to be more prone to both these types of complications of AP.¹⁻⁸In contrast to the clinical scenario, conventional animal models of AP differ in the initiating factor used, and the severity associated with these has been attributed to the inciting stimulus^11–13 or species in which the model has been executed.^12–15 For example, rat intraductal bile salt–induced pancreatitis has been classified as severe in contrast to the caerulein model, which is mild.^12,13 Interestingly, caerulein-induced AP is milder in rats than in mice, which have more pancreatic necrosis, and thus mouse caerulein pancreatitis is classified as severe.^14,15 However, in both these cases, the pancreas returns to normal a few days after cessation of the insult, with no residual necrotic areas or organ failure. On the basis of such models, a potential target is regarded as therapeutically relevant if it plays a role in mechanistically dissimilar models of AP. An example of this is phosphatidylinositol 3-kinases and associated trypsin generation,^11,16,17 which we and others have previously found to be relevant to AP of different causes.^11,16,17This discord (ie, the lack of association of outcomes to cause as noted clinically) and how animal models are interpreted have resulted in serious discrepancies between what is predicted to be beneficial in animal models of AP and the success of such interventions in clinical trials. The failure of serine protease and trypsin inhibition to improve outcomes of AP in >70 clinical trials performed during the last 5 decades is a classic example.^18–27Recently, the mechanistic proof of obesity being a modifier of AP outcomes has emerged, with the same model being mild in lean mice and severe in obese mice, associated with an exaggerated inflammatory response and mortality.²⁸ Our recent studies have found that lipolysis of visceral fat in obese mice may contribute to this severity.²⁹ However, obesity is also associated with a baseline proinflammatory state,^30–32 and because fatty acids (FAs) are proinflammatory,^29,33,34 it has yet to be decided whether short-term generation of FAs by the lipolysis of visceral fat or the preexistent inflammatory state associated with obesity determines the severity of AP in these models.We therefore analyzed human postpancreatitis necrotic collections (PPNCs) for the nature of FAs in them. We also noted the most common cause of AP in our patients. Because biliary AP was the most common type of AP and unsaturated FAs (UFAs) were abundant in PPNCs, we studied whether their acute lipolytic generation in rats, which are otherwise normal, results in the severe outcomes noted in SAP and whether inhibition of such lipolysis, using 2 distinct lipase inhibitors separately, alters the initiation of AP or the parameters of its severity. Interestingly, we realize that the beneficial effect of lipase inhibition, which decreases the generation of UFAs, is independent of the initiation of biliary AP. These findings have relevance to how we design and interpret animal models of AP in the context of human disease.     

Functional outcomes for 2 years comparing hip resurfacing and total hip arthroplasty

This prospective observational study of 499 patients with hip resurfacing and 255 patients with total hip arthroplasty compared outcomes for 2 years. We used propensity scores to identify matched cohorts of 118 patients with hip resurfacing and 118 patients with total hip arthroplasty. We used these cohorts to compare improvements in the Western Ontario and McMaster University (WOMAC) osteoarthritis index and Medical Outcomes Short-Form 36 physical function component (SF-36 PF) scores at 3 months and at 1 and 2 years postsurgery. Both groups demonstrated significant improvements from baseline in WOMAC and SF-36 PF. Improvements in SF-36 PF were greater for patients with hip resurfacing than for patients with total hip arthroplasty 1 and 2 years postsurgery; improvements in WOMAC were similar for both groups. The clinical significance of this observation needs further investigation.