The effectiveness of an unsupervised home-based pulmonary rehabilitation with self-management program in patients with chronic obstructive pulmonary disease.

AIMS: To assess the effectiveness of an unsupervised home-based pulmonary rehabilitation with self-management program in patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: A few recent studies have shown that unsupervised home-based pulmonary rehabilitation can improve the clinical outcome of patients with COPD. More studies are needed to prove its benefits. DESIGN: This study used a quasi-experimental design. METHODS: Seventy-two admitted COPD patients were assigned to experimental group or control group through purposeful sampling. Data were collected from March 2016 to November 2017 in the Thoracic Intensive Care Unit of a Medical Center in Taiwan. The Medical Research Council dyspnea scale, the COPD Self-Efficacy Scale and the Clinical COPD Questionnaire were measured before education and at the first, second and third months after discharge. RESULTS: The Medical Research Council dyspnea scale and COPD Self-Efficacy Scale results in the experimental group were significantly improved compared with the control group in the third month after discharge. The Clinical COPD Questionnaire score continued to improve in both groups in the third month after discharge, and there was no difference between the two groups. CONCLUSION: A short-term unsupervised home-based pulmonary rehabilitation with self- management program had significant benefits for patients with COPD. The long-term effects need to be confirmed.

The Use of Probiotic Therapy in Metabolic and Neurological Diseases.

The human gut is home to trillions of microbes that interact with host cells to influence and contribute to body functions. The number of scientific studies focusing on the gut microbiome has exponentially increased in recent years. Studies investigating factors that may potentially affect the gut microbiome and may be used for therapeutic purposes in diseases where dysbioses in the gut microbiome have been shown are of particular interest. This review compiles current evidence available in the scientific literature on the use of probiotics to treat metabolic diseases and autism spectrum disorders (ASDs) to analyze the efficacy of probiotics in these diseases. To do this, we must first define the healthy gut microbiome before looking at the interplay between the gut microbiome and diseases, and how probiotics affect this interaction. In metabolic diseases, such as obesity and diabetes, probiotic supplementation positively impacts pathological parameters. Conversely, the gut-brain axis significantly impacts neurodevelopmental disorders such as ASDs. However, manipulating the gut microbiome and disease symptoms using probiotics has less pronounced effects on neurodevelopmental diseases. This may be due to a more complex interplay between genetics and the environment in these diseases. In conclusion, the use of microbe-based probiotic therapy may potentially have beneficial effects in ameliorating the pathology of various diseases. Validation of available data for the development of personalized treatment regimens for affected patients is still required.

A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer.

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601.

Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8.

Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.

Diffusiophoresis of a Charged Porous Particle in a Charged Cavity.

The quasi-steady diffusiophoresis of a charged porous sphere situated at the center of a charged spherical cavity filled with a liquid solution of a symmetric electrolyte is analyzed. The porous particle can represent a solvent-permeable and ion-penetrable polyelectrolyte molecule or floc of nanoparticles in which fixed charges and frictional segments are uniformly distributed, whereas the spherical cavity can denote a charged pore involved in microfluidic or drug-delivery systems. The linearized electrokinetic differential equations governing the ionic concentration, electric potential, and fluid velocity distributions in the system are solved by using a perturbation method with the fixed charge density of the particle and the ζ-potential of the cavity wall as the small perturbation parameters. An expression for the diffusiophoretic (electrophoretic and chemiphoretic) mobility of the confined particle with arbitrary values of a/ b, κ a, and λ a is obtained in closed form, where a and b are the radii of the particle and cavity, respectively; κ and λ are the reciprocals of the Debye screening length and the length characterizing the extent of flow penetration into the porous particle, respectively. The presence of the charged cavity wall significantly affects the diffusiophoretic motion of the particle in typical cases. The diffusio-osmotic (electro-osmotic and chemiosmotic) flow occurring at the cavity wall can substantially alter the particle velocity and even reverse the direction of diffusiophoresis. In general, the particle velocity decreases with an increase in a/ b, increases with an increase in κ a, and decreases with an increase in λ a, but exceptions exist.

A review of clinical trials of biologic agents and small molecules for psoriasis in Asian subjects.

INTRODUCTION: Biologics are increasingly used in the treatment of moderate to severe psoriasis. However, most of the pivotal studies were performed mainly in western countries. The purpose of this review article was to compare the differences of clinical trial results between Asian and Western subjects of psoriasis regarding baseline demographics, efficacy, dermatology life quality index, safety and antidrug antibodies. EVIDENCE ACQUISITION: In this review article, we searched the PubMed/Medline, ClinicalTrials.gov, and posters from main dermatologic meetings. EVIDENCE SYNTHESIS: Only randomized controlled trial results or trial results for registration purposes of etanercept, adalimumab, infliximab, ustekinumab, secukinumab, brodalumab, ixekizumab, guselkumab, tofacitinib, and apremilast are included. CONCLUSIONS: Asian subjects were generally 15-20 Kgs lighter, with fewer psoriatic arthritis, shorter disease duration since diagnosis, and higher baseline severity compared to western subjects. Better efficacy had been found in some studies such as secukinumab, brodalumab, ixekizumab, and tofacitinib in Japanese groups. The safety in Asian trials was generally compatible with the pivotal studies, except for the occurrence of active tuberculosis in the infliximab trial in China. Additional indications of pustular and erythrodermic psoriasis are approved in Japan for some of the agents based on phase II/III studies.

Phenotypical characteristics of peripheral blood monocytes in normal pregnancy and gestosis.

Monocyte migration from the peripheral blood to the uterine decidual tissue is essential for the regulation of placental development. We evaluated the phenotypical changes in the peripheral blood monocytes in pregnant women. The peripheral blood counts of monocytes expressing CD11b, CD47, and integrin ß7 were elevated in women with normal gestation in comparison with nonpregnant women; the intensity of CD62P, CD11b, CD11c, CD29, CD31, and CD54 expression was higher in pregnancy. The counts of monocytes expressing adhesion molecules were similar in normal pregnancy and gestosis. Gestosis was characterized by higher counts of monocytes expressing IFN-γ receptor (CD119) and more intense expression of this receptor. Changes in the monocyte phenotype can promote their adhesion to the uterine vascular endothelium and further migration of these cells to the decidual tissue.

Hydrogen sulfide lowers proliferation and induces protective autophagy in colon epithelial cells.

Hydrogen sulfide (H(2)S) is a gaseous bacterial metabolite that reaches high levels in the large intestine. In the present study, the effect of H(2)S on the proliferation of normal and cancerous colon epithelial cells was investigated. An immortalized colon epithelial cell line (YAMC) and a panel of colon cancer cell lines (HT-29, SW1116, HCT116) were exposed to H(2)S at concentrations similar to those found in the human colon. H(2)S inhibited normal and cancerous colon epithelial cell proliferation as measured by MTT assay. The anti-mitogenic effect of H(2)S was accompanied by G(1)-phase cell cycle arrest and the induction of the cyclin-dependent kinase inhibitor p21(Cip). Moreover, exposure to H(2)S led to features characteristic of autophagy, including increased formation of LC3B(+) autophagic vacuoles and acidic vesicular organelles as determined by immunofluorescence and acridine orange staining, respectively. Abolition of autophagy by RNA interference targeting Vps34 or Atg7 enhanced the anti-proliferative effect of H(2)S. Further mechanistic investigation revealed that H(2)S stimulated the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase. Inhibition of AMPK significantly reversed H(2)S-induced autophagy and inhibition of cell proliferation. Collectively, we demonstrate that H(2)S inhibits colon epithelial cell proliferation and induces protective autophagy via the AMPK pathway.

Proteomic analysis of clear cell renal cell carcinoma. Identification of potential tumor markers.

OBJECTIVE: To identify new tumor specific proteins of renal cell carcinoma (RCC) using proteomic analysis. METHODS: Nine renal cell carcinomas were resected and these surgical operations were carried out from June 2007 to September 2008 in the Urology Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. The cancer tissues and para-cancer normal tissues were preserved in liquid nitrogen. We analyzed the RCC tissues and para-cancer normal tissues by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The 16 differentially expressed protein spots (p<0.05 by Student t-test) were identified by matrix assisted laser desorption ionization/time of flight mass spectrometry and tandem mass spectrometry. RESULTS: Six proteins were down regulated and 10 proteins were up regulated in clear cell RCC compared with corresponding normal kidney tissue. The down regulated proteins were calbindin, ester hydrolase C11orf54, alcohol dehydrogenase, ammecr1-like protein, adenosine diphosphate (ADP)/adenosine-5'-triphosphate (ATP) translocase 3 and leucine-tyrosine-arginine (LYR) motif-containing protein 5. The up regulated proteins were hypoxia inducible domain family member 1A, glutathione S-transferase P, thioredoxin-dependent peroxide reductase, peroxiredoxin-6, CD2-associated protein, annexin A5, gamma-enolase, retinal dehydrogenase 1, vimentin, and protein-glutamine gamma-glutamyltransferase 2. CONCLUSION: The data provide potential tumor markers for diagnosis of RCC.

Docosahexaenoic acid regulates serum amyloid A protein to promote lipolysis through down regulation of perilipin.

Docosahexaenoic acid (DHA) increases lipolysis and decreases lipogenesis through several pathways. DHA also enhances the expression of serum amyloid A protein (SAA), a possible lipid metabolism related gene. The question of whether DHA regulates the expression of SAA to affect lipid metabolism and increase lipolysis needs to be demonstrated in human adipocytes. We designed experiments to determine the role of SAA in regulating lipid metabolism in HepG2 cells using microarray technology. In human hepatocytes, recombinant human SAA1 (hSAA1) inhibited the expression of genes related to lipogenesis and promoted the expression of those involved in lipolysis. When human breast adipocytes were treated with hSAA1 or DHA in vitro, the expression of peroxisome proliferator-activated receptor gamma and other lipogenic genes was decreased, whereas the expression of several lipolytic genes was increased. Glycerol release was increased by both SAA and DHA treatments, suggesting that they increased lipolytic activity in human adipocytes. The expression of perilipin, a lipid droplet-protective protein, was decreased, and hormone-sensitive lipase was increased by both of hSAA1 and DHA treatment. We speculate that the mechanism of lipolysis by DHA or SAA is at least partially the result of increased expression of hormone-sensitive lipase and decreased expression of perilipin. Whereas DHA treatment increased expression of hSAA1 in human adipocytes, the DHA-mediated reduction in expression of lipogenesis genes and enhancement of lipolysis may be through the activity of hSAA1. These results may be useful in developing new approaches to reduce body fat deposition.

Docosahexaenoic acid enhances hepatic serum amyloid A expression via protein kinase A-dependent mechanism.

Serum amyloid A (SAA) reduces fat deposition in adipocytes and hepatoma cells. Human SAA1 mRNA is increased by docosahexaenoic acid (DHA) treatment in human cells. These studies asked whether DHA decreases fat deposition through SAA1 and explored the mechanisms involved. We demonstrated that DHA increased human SAA1 and C/EBPbeta mRNA expression in human hepatoma cells, SK-HEP-1. Utilizing a promoter deletion assay, we found that a CCAAT/enhancer-binding protein beta (C/EBPbeta)-binding site in the SAA1 promoter region between -242 and -102 bp was critical for DHA-mediated SAA1 expression. Mutation of the putative C/EBPbeta-binding site suppressed the DHA-induced SAA1 promoter activity. The addition of the protein kinase A inhibitor H89 negated the DHA-induced increase in C/EBPbeta protein expression. The up-regulation of SAA1 mRNA and protein by DHA was also inhibited by H89. We also demonstrated that DHA increased protein kinase A (PKA) activities. These data suggest that C/EBPbeta is involved in the DHA-regulated increase in SAA1 expression via PKA-dependent mechanisms. Furthermore, the suppressive effect of DHA on triacylglycerol accumulation was abolished by H89 in SK-HEP-1 cells and adipocytes, indicating that DHA also reduces lipid accumulation via PKA. The observation of increased SAA1 expression coupled with reduced fat accumulation mediated by DHA via PKA suggests that SAA1 is involved in DHA-induced triacylglycerol breakdown. These findings provide new insights into the complicated regulatory network in DHA-mediated lipid metabolism and are useful in developing new approaches to reduce body fat deposition and fatty liver.

Spray-as-you-go airway topical anesthesia in patients with a difficult airway: a randomized, double-blind comparison of 2% and 4% lidocaine.

BACKGROUND: We designed this randomized, double-blind clinical study to compare the safety and efficacy of 2% and 4% lidocaine during airway topical anesthesia with a spray-as-you-go technique via the fiberoptic bronchoscope. METHODS: Fifty-two adult patients with a difficult airway were randomly assigned to 1 of 2 study groups to receive 2% (Group 1) or 4% lidocaine (Group 2) by a spray-as-you-go technique with the fiberoptic bronchoscope, in a double-blind manner. After airway topical anesthesia, awake fiberoptic orotracheal intubation (FOI) was performed. Level of sedation, time for each lidocaine spray in different targeted areas, total times for airway sprays, total dosages of lidocaine used for airway sprays, intubation times, and number of intubation attempts were noted. An independent investigator scored patients' comfort during airway topical anesthesia, patients' reaction, coughing severity, and intubating condition during awake FOI, and observed changes of arterial blood pressure and heart rate during each stage in the airway manipulation process. Serial blood samples were obtained for analysis of plasma lidocaine concentrations. RESULTS: Except for the total dosages and plasma concentrations of lidocaine, there were no significant differences in any of the observed variables between groups. All patients exhibited excellent or acceptable intubating conditions. The total dosages of lidocaine were significantly smaller in Group 1 (3.4 +/- 0.6 mg/kg) than in Group 2 (7.1 +/- 2.1 mg/kg). The plasma lidocaine concentrations in all observed points after the supraglottic sprays were larger in Group 2 than in Group 1. CONCLUSIONS: Both 2% and 4% lidocaine administered topically by a spray-as-you-go technique can provide clinically acceptable intubating conditions for awake FOI in sedated patients with a difficult airway. As compared with 4% lidocaine, however, 2% lidocaine requires a smaller dosage and results in lower plasma concentrations.

Cricoid pressure impedes insertion of, and ventilation through, the ProSeal laryngeal mask airway in anesthetized, paralyzed patients.

BACKGROUND: We designed this prospective self-controlled study to assess whether cricoid pressure hampers placement of and ventilation through the ProSeal laryngeal mask airway (ProSeal LMA) in anesthetized, paralyzed adult patients. METHODS: After induction of anesthesia, the ProSeal LMA was inserted using the introducer tool with cricoid pressure advanced as far as possible, and the cuff pressure was set at 60 cm H2O. Ventilation adequacy and anatomic position were scored using measures previously described for ProSeal LMA assessment. Airway seal pressure was recorded. Cricoid pressure was then released, the ProSeal LMA further advanced and reseated, and the assessment repeated. RESULTS: Lung ventilation scores, anatomic position scores, and airway seal pressure were significantly better after release of cricoid pressure and reseating of the ProSeal LMA than in the first position, where the ProSeal LMA was seated with cricoid pressure (P < 0.05). Expiratory tidal volume during intermittent positive pressure ventilation was similar with and without cricoid pressure, but peak inspiratory pressure decreased from 28 cm H(2)O with cricoid pressure to 14 cm H(2)O without cricoid pressure (P < 0.05). CONCLUSIONS: Cricoid pressure applied before insertion hampered proper placement of the ProSeal LMA. Temporary cricoid pressure release during insertion allowed the device to be advanced to the proper position. After correct placement of the ProSeal LMA, application of cricoid pressure did not change tidal volume, but produced a significant increase in peak inspiratory pressure.

Apoptosis induction by avian reovirus through p53 and mitochondria-mediated pathway.

Although induction of apoptosis by avian reovirus has been demonstrated in primary chicken embryonic fibroblast and several cell lines, to date, the potential significance of avian reovirus (ARV)-induced apoptosis and its pathways in cultured cells are still largely unknown. We now provide the first evidence of upregulation of p53 and Bax and specifically for Bax translocation from cytosol to mitochondria following infection with a cytoplasmically replicating RNA virus. Bax translocation to the mitochondria led to the release of mitochondrial proapoptic factors cytochrome c and Smac/DIABLO from mitochondria to the cytosol, but not the release of apoptosis-inducting factor. Activation of caspases-9 and -3 which cleaves the enzyme poly(ADP-ribose) polymerase in ARV-infected BHK-21 cells was also detected. Internucleosomal DNA cleavage was prevented by caspase inhibitors, further demonstrating that ARV-induced apoptosis was executed through caspase-dependent mechanisms. Stable expression of human bcl-2 in BHK-21 cells not only blocked ARV-induced apoptosis and DNA fragmentation but also reduced the level of infectious virus production and its spread in BHK-21 cells infected with ARV at a low multiplicity of infection. All our data suggest that p53 and the mitochondria-mediated pathway played an important regulatory role in ARV-induced apoptosis in BHK-21 cells. To further study the pathogenesis of ARV infection, a dual-labeling assay was used for the simultaneous detection of cells containing viral antigen and apoptotic cells. Dual-labeling assay revealed that the majority of antigen-expressing cells were not apoptotic. Remarkably, some apoptotic but non-antigen-expressing cells were frequently located in the vicinity of antigen-expressing cells. Syncytium formation in ARV-infected BHK-21 cells undergoing apoptosis, was apparent in large syncytia at late infection times, indicating a correlation between virus replication and apoptosis in cultured cells.