L selectin was blocked and hepatocellular damage after IRI was assessed to mechanistically define the role of the adhesion molecule. Results: Mice fed a HFD diet showed significant increase in body weight (42±1.2, vs. 24.6±0.6 grams; p<0.0001) and presence of hepatic steatosis by ORO stain. Splenocytes from HFD mice undergoing IRI demonstrated significant increase in CD4+ T cell activation markers, such as PD1

(p<0.0009), CD69(p<0.01), and CD62L(p<0.001), in addition to higher ALK inhibitor clinical trial levels of serum ALT and significant increase in hepatocellular necrosis. The T cell proliferation marker Ki67 (p<0.0089), was significantly higher in HFD IRI as compared to lean IRI. Expression levels of L-selectin (p<0.03) but not P or E-selectin were elevated in HFD IRI. Increased cytokines such as IFNγ, IL-1a, IL-10, IL-6 and IL-17, suggested a pro-inflammatory milieu in HFD IRI. Blockade of L-selectin, lead to a significant attenuation of hepatocellular injury. Conclusion: A steatotic liver undergoing IRI is associated with elevation of adhesion molecule L-se-lectin along with activation and proliferation of CD4+ T cells, and a pro-inflammatory

cytokine milieu. Blocking the adhesion molecule L-selectin leads to mitigation of hepatocellular injury, thus offering an important and clinically relevant therapeutic intervention in the increasingly prevalent clinical condition of IRI of fatty liver Selleck Temsirolimus disease. Disclosures: The following people have nothing to disclose: Vasantha L. Kolachala, Abramowsky Carlos, Ming Shen, Alayna Feng, Allan D. Kirk,

Nitika A. Gupta “
“From the mid-1950s, it was observed that liver injury by a variety of toxins greatly sensitized the host to the effects of administered lipopolysaccharide. In the nutritional cirrhosis of choline deficiency, and in acute toxic injury as well, the need for the presence of enteric endotoxin was demonstrated. The universality of this association was striking for almost all agents associated medchemexpress with liver injury. In addition, the presence of endotoxemia in human liver disease was documented in the 1970s, when the hypothesis was first proposed, and correlated with the severity of the disease. Despite imposing evidence of the critical role of enteric endotoxin in liver injury, it did not excite much interest in investigators until the 1980s. With the ability to study effects of alcohol in newer delivery systems, and an increased understanding of the role of Kupffer cells in the process, the original hypothesis has been accepted. This historical review details the progress of this novel concept of disease initiation and suggests future directions to bring potential therapies to the bedside. (HEPATOLOGY 2010.) Continuing work over the past several decades has further solidified the importance of intestinal endotoxins as critical cofactors in toxic liver injury by a number of agents.

Background.— European studies have demonstrated increased prevalence of headache of patients with celiac disease compared with controls. Methods.— Subjects took a self-administered survey containing clinical, demographic, and dietary data, as well as questions about headache type and frequency. The ID-Migraine screening tool and the Headache Impact

Test (HIT-6) were also used. Results.— Five hundred and two subjects who met exclusion criteria were analyzed – 188 with celiac disease, 111 with IBD, 25 with gluten sensitivity (GS), and 178 controls (C). Chronic headaches were reported by 30% of celiac disease, 56% of GS, 23% of IBD, and 14% of control subjects (P < .0001). On multivariate logistic MDX-010 regression, celiac disease (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.78-8.10), GS (OR 9.53, 95%CI 3.24-28.09), and IBD (OR 2.66, 95%CI 1.08-6.54)

subjects all had significantly higher prevalence of migraine headaches compared with controls. Female sex (P = .01), depression, and anxiety (P = .0059) were independent predictors of migraine headaches, whereas age >65 was protective (P = .0345). Seventy-two percent of celiac disease subjects graded their migraine as severe in impact, compared with 30% of IBD, Metformin 60% of GS, and 50% of C subjects (P = .0919). There was no correlation between years on gluten-free diet and migraine severity. Conclusions.— Migraine was 上海皓元医药股份有限公司 more prevalent in celiac disease and IBD subjects than in controls. Future studies should include screening migraine patients for celiac disease and assessing the effects of gluten-free diet on migraines in celiac disease. “
“There is a growing body of evidence supporting the efficacy of various complementary

and alternative medicine approaches in the management of headache disorders. These treatment modalities include nutraceutical, physical and behavioral therapies. Nutraceutical options comprise vitamins and supplements (magnesium, riboflavin, coenzyme Q10, and alpha lipoic acid) and herbal preparations (feverfew, and butterbur). Although controversial, there are some reports demonstrating the benefit of recreational drugs such as marijuana, lysergic acid diethylamide and psilocybin in headache treatment. Behavioral treatments generally refer to cognitive behavioral therapy and biobehavioral training (biofeedback, relaxation training). Physical treatments in headache management are not as well defined but usually include acupuncture, oxygen therapy, transcutaneous electrical nerve stimulation, occlusal adjustment, cervical manipulation, physical therapy, massage, chiropractic therapy, and osteopathic manipulation. In this review, the available evidence for all these treatments will be discussed. The use of complementary and alternative medicine (CAM) has been on the rise, as demonstrated by epidemiological studies in the USA and Europe over the past few decades.

The increased use of simpler metazoans with smaller genomes has, in recent years, played an increasingly important role in defining and dissecting a number of processes and key players of particular importance to biology. Already these are impacting on our understanding of liver development and Panobinostat order disease. The opportunities presented by the study of simpler organisms to dissect function and pathology are now growing. The use of nonvertebrate and lower vertebrate models provides researchers with a number of key advantages. These include

defined and relatively limited genomes, a short lifespan, ease of genetic manipulation, in some examples direct visualization of an organ or tissue, and of course homologous biological systems with higher vertebrates. Additionally, for these lower organisms, antisense or knockout strategies are easily deployed to dissect out multiple components of pathways of interest for pathological processes. Effectively, libraries of knockout or knockdown organisms can be created for the research community. For example, in the last few years, critical observations relating to liver biology and development have been driven selleck screening library by the zebrafish model. This includes the identification of the Wnt2b gene as critical for normal fish liver specification and development.3 Looking to the future, however, fish offer multicellular/multiorgan models for screening. Because the zebrafish embryo

is transparent and has relatively close homology with other higher vertebrates, it renders itself as an extraordinary yet simple multiorgan in vivo MCE model in which to screen drugs.4, 5 Fish can be created that incorporate reporter systems expressing

fluorescent protein when a target gene is transcribed. Multiwell plates in which each well contains a single transparent fish embryo can be exposed to novel therapies, and compounds regulating transcription in particular pathways may be rapidly identified. This opens the door to, for example, screening existing licensed drugs for novel indications. Additionally, because the array can take place in a 96-well plate format, literally thousands of compounds can be screened in a whole vertebrate organism in vivo assay. It is easy to see how organisms such as zebrafish, which possess a defined liver, might be used as models for hepatological research. It is less clear, though, for Drosophila (the fruit fly), which lacks a discrete organ homolog for the liver. Traditionally, the fat body, the major glycogen store in the fly, oriented in a segmental fashion during larval development, has been seen as being the equivalent of the liver for the fruit fly. However, current evidence suggests that Drosophila does not have a discrete organ ortholog to the liver, but rather that specific metabolic functions associated with the mammalian liver have evolved to be delivered by different tissues.

It increases the risk to gallbladder cancer. ● Diagnostic approach of Mirizzi usually begins with history taking, physical exam, lab exam, ultrasonography followed by cholangiography via endoscopic retrograde cholangiopancreatography, direct percutaneous cholangiography, or magnetic resonance cholangiography. ● Endoscopic treatment with or without electrohydraulic lithotripsy (EHL) considered to be effective as a temporizing measure before surgery like the one underwent in this case file. Surgery is the main therapy for Mirizzi syndrome, eliminating definitive pathomechanisms of this entity,

i.e., the inflamed gallbladder and the impacted stone. Surgical modalities depend on the type of Mirizzi syndrome, which range from laparoscopic, closure of fistula, cholodeochoplasty, and bilioenteric anastomosis. Fluorouracil order Key Word(s): 1. Mirizzi syndrome; 2. management; 3. diagnosis Presenting Author: SEOK JEONG Additional Authors: DON HAENG LEE, YONG WOON SHIN Corresponding Author: SEOK JEONG Affiliations: Inha University School of Medicine, Inha University School of Medicine Objective: The aim of this study is to estimate the safety, efficacy and photosensitizer stability of endobiliary PDT using PDT-stent in

swine model. Methods: Single session of endoscopic biliary in-stent PDT was performed with various energy amount

of laser after insertion of PDT-stent in the common bile duct (CBD) of twelve swine www.selleckchem.com/products/PLX-4032.html to determine proper energy level of laser for PDT. Two days later, bile ducts were extracted for pathologic examination. Biliary PDT with 70 J/cm 2, and cholangiogram were repeated at 2-week intervals over a period of 4 weeks or 8 weeks after PDT-stent insertion in 6 swine. Then the bile ducts and the inserted stent were obtained after two days for pathologic analysis and medchemexpress quantification of fluorescence intensity (FI) for Pheoporbide A (Pheo-A) remained from PDT-stent. Results: There was no evidence of bile duct perforation in all animals on follow up cholangiograms after single or repeated biliary PDT. Repeated PDT caused only surface mucosal necrosis in all animals and the degree of inflammation was constant irrespective of number of PDT session. The FI of Pheo-A from PDT-stent was reduced to 50 and 60% of baseline FI for 100 and 150 J/cm 2 group, respectively after single session of PDT. After 3 or 5 sessions of PDT with 70 J/cm 2, the FI of PDT-stents observed to be similar to that of the PDT-stent before laser irradiation. Conclusion: Endoscopic biliary PDT using the PDT-stent was safe, effective, and repeatable over a period of 8 weeks for the treatment of cholangiocarcinoma. Key Word(s): 1. cholangiocarcinoma; 2. photodynamic therapy; 3.

It increases the risk to gallbladder cancer. ● Diagnostic approach of Mirizzi usually begins with history taking, physical exam, lab exam, ultrasonography followed by cholangiography via endoscopic retrograde cholangiopancreatography, direct percutaneous cholangiography, or magnetic resonance cholangiography. ● Endoscopic treatment with or without electrohydraulic lithotripsy (EHL) considered to be effective as a temporizing measure before surgery like the one underwent in this case file. Surgery is the main therapy for Mirizzi syndrome, eliminating definitive pathomechanisms of this entity,

i.e., the inflamed gallbladder and the impacted stone. Surgical modalities depend on the type of Mirizzi syndrome, which range from laparoscopic, closure of fistula, cholodeochoplasty, and bilioenteric anastomosis. buy Y-27632 Key Word(s): 1. Mirizzi syndrome; 2. management; 3. diagnosis Presenting Author: SEOK JEONG Additional Authors: DON HAENG LEE, YONG WOON SHIN Corresponding Author: SEOK JEONG Affiliations: Inha University School of Medicine, Inha University School of Medicine Objective: The aim of this study is to estimate the safety, efficacy and photosensitizer stability of endobiliary PDT using PDT-stent in

swine model. Methods: Single session of endoscopic biliary in-stent PDT was performed with various energy amount

of laser after insertion of PDT-stent in the common bile duct (CBD) of twelve swine BMS-777607 concentration to determine proper energy level of laser for PDT. Two days later, bile ducts were extracted for pathologic examination. Biliary PDT with 70 J/cm 2, and cholangiogram were repeated at 2-week intervals over a period of 4 weeks or 8 weeks after PDT-stent insertion in 6 swine. Then the bile ducts and the inserted stent were obtained after two days for pathologic analysis and medchemexpress quantification of fluorescence intensity (FI) for Pheoporbide A (Pheo-A) remained from PDT-stent. Results: There was no evidence of bile duct perforation in all animals on follow up cholangiograms after single or repeated biliary PDT. Repeated PDT caused only surface mucosal necrosis in all animals and the degree of inflammation was constant irrespective of number of PDT session. The FI of Pheo-A from PDT-stent was reduced to 50 and 60% of baseline FI for 100 and 150 J/cm 2 group, respectively after single session of PDT. After 3 or 5 sessions of PDT with 70 J/cm 2, the FI of PDT-stents observed to be similar to that of the PDT-stent before laser irradiation. Conclusion: Endoscopic biliary PDT using the PDT-stent was safe, effective, and repeatable over a period of 8 weeks for the treatment of cholangiocarcinoma. Key Word(s): 1. cholangiocarcinoma; 2. photodynamic therapy; 3.

Recently, it was reported in Europe that a 10-day sequential strategy produced good outcomes. The aim of this study was to assess the efficacy of sequential therapy as first-line treatment for eradication of H. pylori in clinical practice in Korea. Materials and Methods:  A total of 98 patients (mean age 55.2 years and male 47, female 51) with proven H. pylori infection received 10-day sequential therapy LY2157299 supplier (20 mg of rabeprazole, and 1 g of amoxicillin, twice daily for the first 5 days, followed by 20 mg of

rabeprazole, 500 mg of clarithromycin, and 500 mg of metronidazole, twice daily for the remaining 5 days). Eradication was evaluated 4 weeks later, after completion of treatment by 13C-urea breath testing. Eradication rates were calculated by intention-to-treat (ITT) and by per protocol (PP). Compliance and adverse events were also assessed in study group. Results:  The eradication rate of sequential therapy was 91.8% (90/98) by ITT and same result

was reported by PP analysis (89/97). The study group consisted of 66 H. pylori associated gastritis, 7 gastric ulcer, and 25 duodenal ulcer patients (67.3%, 7.1%, 25.5%, respectively). Mild Romidepsin mw adverse events happened frequently (21.4%) but the treatment was well tolerable. The most common adverse event was a bitter taste (9.2%) followed by nausea and diarrhea (4.1%). Conclusions:  Ten-day sequential therapy is found to effectively eradicate H. pylori infection as first-line treatment in Korea. “
“Background: Helicobacter pylori infection is regarded as the major cause of various gastric diseases and induces the production of several cytokines including interleukin-17 (IL-17) recently recognized as an important player in the mammalian immune system. Objective:  This review deals

with the role of IL-17 on the H. pylori-induced infection and immunity in humans and experimental animals. Results: H. pylori infection increases IL-17 in the gastric mucosa of humans 上海皓元 and experimental animals. In humans, IL-17 induces the secretion of IL-8 by activating the ERK 1/2 MAP kinase pathway and the released IL-8 attracts neutrophils promoting inflammation. IL-23 is increased in patients with H. pylori-related gastritis and regulates IL-17 secretion via STAT3 pathway. Studies in H. pylori-infected mice indicate that IL-17 is primarily associated with gastric inflammation. The early events in the immune response of immunized and challenged mice include the recruitment of T cells and the production of IL-17. Neutrophil attracting chemokines are released, and the bacterial load is considerably reduced. IL-17 plays a dual role in infection and vaccination. In infection, T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL-17 thereby favoring bacterial persistence.

[59] Stool culture studies in patients with cirrhosis show an overgrowth of pathogenic E. coli and Staphylococcus species.[60] Studies on ascitic fluid, portal blood, mesenteric lymph nodes, and ileal contents have shown that bacterial translocation was more frequent in rats with ascites

and SBP than in rats with ascites but no SBP or in healthy rats[61]; the bacterial species isolated in mesenteric nodes or ascites were similar to those in the rat intestine, suggesting translocation of bacteria from gut as the source of SBP.[61, 62] Further, cirrhosis is associated with numerous defects in immune response, including impaired leukocyte function,[63, 64] low ascitic fluid levels of components of the complement system,[65] reduced phagocytic activity of reticuloendothelial cells,[66] reduced antibody-mediated and complement-dependent Talazoparib price bacterial killing,[67] and reduced proliferation and γ-interferon synthesis by intraepithelial lymphocytes[68]; these could contribute through reduced clearance

of translocated bacteria. HE encompasses a wide spectrum of abnormalities, ranging from subclinical alterations in neuropsychiatric tests (minimal HE) to overt neuropsychiatric manifestations of varying severity (clinical HE grade I–IV) in patients with Selleck Roxadustat acute or chronic liver failure. Pathogenesis of HE is poorly understood and appears to be multifactorial; several pieces of evidence support a role for gut microbes in this process.[69] Intraperitoneal administration of LPS in a mouse model of cirrhosis is associated with induction of pre-coma and worsening of cytotoxic brain edema.[70] Bacterial overgrowth is more common in patients with liver cirrhosis and minimal HE than in those without the latter.[51] Liu et al. reported an overgrowth of pathogenic E. coli and Staphylococcus species in patients with cirrhosis and minimal HE.[60] Administration

of probiotics and fermentable fiber resulted in an increase of non-urease-producing Lactobacilli over pathogenic bacteria with a significant reduction in blood levels of ammonia MCE and endotoxin, reversal of minimal HE, and improvement of Child–Pugh score. A meta-analysis of the effect of prebiotics, probiotics, or synbiotics, which modulate gut flora, has shown significant improvement in minimal HE.[71] Increased blood ammonia, leading to astrocyte swelling followed by brain edema, is believed to play a central role in the pathogenesis of HE. Ammonia is produced from catabolism of glutamine in the small bowel and that of undigested proteins and urea in the colon. Several other products of bacterial metabolism also have neurotoxic effects, and their levels are increased in persons with cirrhosis; these include phenols produced from aromatic amino acids such as phenylalanine mercaptans produced from sulfur-containing amino acids such as methionine, and short- and medium-chain fatty acids.

As depicted in Table 1, several gene sets selleckchem were significantly different in azaC-treated larvae, including IFN-γ-responsive genes and other inflammatory gene sets. Table

1 also shows that gene sets downstream of several transcription factors were significantly down-regulated, including genes regulated by Hnf6, shown previously to be important in biliary development in mammals29 and zebrafish.26 The gene profiling data suggested several mechanisms to account for biliary defects associated with inhibition of DNA methylation, including activation of the innate immune response and reduced activation of developmental signaling pathways. As histological analysis revealed no evidence of an inflammatory infiltrate in azaC-treated livers (Supporting Information Fig. S2), we hypothesize that activation of IFN-γ target genes, normally silenced by DNA methylation, could directly affect developing biliary epithelial cell survival and/or proliferation. Indeed, mammalian biliary cells express several inflammatory mediators, including the IFN-γ receptor, which mediate biliary cell proliferation and survival in models of biliary disease.40 The activation of IFN-γ-responsive genes was especially intriguing given the

importance of IFN-γ in mouse models of BA5 and in patients with BA.4 Although selleck kinase inhibitor extrahepatic defects are the hallmark of BA, progressive destruction of intrahepatic ducts following surgical relief of extrahepatic obstruction is the most important factor determining the eventual need for transplantation. Activation of IFN-γ signaling and intrahepatic biliary defects in azaC-treated zebrafish larvae suggests that they may be used to model BA progression. We attempted to rescue the biliary phenotype by treating azaC-injected larvae with the glucocorticoid prednisone, as prednisone has shown promise as a treatment for intrahepatic biliary defects in BA,41 and there is a currently a large national trial examining the effectiveness of prednisone

in treating ongoing intrahepatic biliary atresia medchemexpress (NIDDK NCT00294684). As depicted in Fig. 3, treatment of azaC-injected larvae with prednisone resulted in normalization of PED-6 gallbladder uptake, suggesting improved bile flow arising from rescue of intrahepatic biliary anatomy. Cytokeratin and 2F11 immunostaining of livers from 5 dpf larvae treated with azaC and prednisone demonstrates rescue of the defects seen in azaC-treated larvae (Fig. 3B-G). These results suggest that intrahepatic biliary defects elicited by chemical inhibition of DNA methylation can be prevented by glucocorticoid treatment. Based on well-established models of glucocorticoid mechanisms of action, this is probably not a result of a direct effect of prednisone on DNA methylation, but on gene expression changes elicited by the inhibition of DNA methylation.

It is also much more reliable than serum ferritin levels, which may be increased far beyond the real amount of iron excess in several common conditions such as metabolic abnormalities,24 excessive alcohol consumption,25 inflammatory syndrome, or increased serum transaminases levels. In the present study there was no statistical linear correlation between AIR and BMI in either sex, but in women we found a

BMI threshold of 28 kg/m2 beyond which almost all AIR values remained lower than 6 g. Despite this, when compared selleck chemicals llc to women with BMI <28 kg/m2, women with BMI ≥28 kg/m2 were older, were more often postmenopausal, and did not have more pregnancies, all conditions associated with increased body iron stores. Moreover, when taking into account these potential confounding factors and others in a multivariate model, we found that BMI remained as an independent explanatory variable of AIR together with expected variables including parameters of iron metabolism, ALT, and hemoglobin. Laine et al.15 demonstrated

lower C282Y homozygosity expression, defined as TS <45%, in overweight women when compared to normal and lean women in a Britton general population. In a much larger sample, the present study confirms that both serum iron and transferrin saturation are significantly lower in women with BMI ≥28 than in women with BMI <28 kg/m2, which suggests a lower bioavailability of systemic iron in case of significant overweight, and then a lower rate find more of iron loading. Such data could support the role of an increased production of hepcidin in lowering iron burden in overweight C282Y women. Indeed, metabolic syndrome is associated with a minimal chronic inflammatory state related to the synthesis of proinflammatory cytokines and adipokines,26 in particular interleukin (IL)-627 and leptin.28 These cytokines

are known to promote hepcidin gene transcription through the STAT3 pathway.29 Moreover, several studies have shown that there is an overexpression of hepcidin in obesity. Bekri et al.16 medchemexpress reported that subcutaneous and visceral adipose hepcidin messenger RNA (mRNA) expression was significantly higher in obese compared to lean women, while liver mRNA expression was similar. Tussing-Humphreys et al.30 confirmed this result in obese women, but reported that hepatic hepcidin mRNA expression was strongly correlated with serum hepcidin, but not adipose hepcidin mRNA.16, 30 In a small sample of patients, a study reported that there was no oversecretion of hepcidin by subcutaneous adipose tissue whether the patient was obese or lean.31 Thus, the relationship that we found between serum hepcidin level and BMI in C282Y homozygous women suggests that the overproduction of hepcidin could be responsible for lower disease penetrance in the overweight cases. However, the mechanism of such an overproduction remains unclear, especially with respect to the tissular origin of hepcidin.

Subjects with lower ABR reported better physical HRQoL. “
“Severe factor VIII (FVIII)-deficient patients with and without FVIII inhibitors cannot be distinguished using FVIII levels. The FVIII assay is sensitive to detect factor levels below 1%. While severe FVIII-deficient, non-inhibitor patients have FVIII < 1%, they may retain unmeasurable residual factor activity. In contrast,

inhibitor patients have a FVIII antibody that presumably fully eliminates FVIII activity. It is unknown whether thromboelastography (TEG) and thrombin generation assay (TGA) can differentiate between Copanlisib patients with FVIII < 1% with and without the presence of FVIII inhibitors. The primary objective was to discern whether TEG and TGA could differentiate between severe FVIII-deficient patients with and without the presence of FVIII inhibitors. A secondary objective was to correlate TEG and TGA to annualized bleeding rates. This observational Caspase-dependent apoptosis study performed TEG and TGA in healthy volunteers

(N = 15), severe FVIII-deficient (N = 15) and severe FVIII-deficient patients with inhibitors (N = 15). Kaolin-activated TEG was better at differentiating reaction time (31.3 vs. 120 min respectively, P = 0.004) and kinetics time (6.1 vs. 23.1 min respectively, P = 0.028) between the non-inhibitor and inhibitor patients. TEG activated by tissue factor in plasma-containing corn trypsin inhibitor failed to differentiate groups. The TGA failed to differentiate peak thrombin, medchemexpress endogenous thrombin potential and lag time between groups. There was no correlation between TEG and TGA with annualized bleeding rates. Kaolin-activated TEG, but not TGA, differentiated between severe FVIII-deficient patients with and without inhibitors. These assays did not find a correlation to annualized bleeding rate. “
“Summary.  Between 2000 and 2008, 11 major orthopaedic surgeries for 7 congenital haemophilia patients with inhibitors were performed by the first author as the primary doctor using recombinant

activated factor VII (rFVIIa). Orthopaedic surgical treatments were performed for six surgeries for four high-responder haemophilia A patients, three surgeries for two high-responder haemophilia B patients and two surgeries for one low-responder haemophilia B patient. This low-responder patient is allergic to factor IX products, so he usually uses rFVIIa as a haemostatic agent. All of the surgeries were major, such as joint arthroplasty, arthroscopic synovectomy, and a combination of both, and excellent surgical results were achieved. Seven cases were controlled by bolus infusion of rFVIIa, and the other four cases were controlled by combined bolus and continuous infusion of rFVIIa. An anti-fibrolytic agent was used for all cases. There were no thrombogenic adverse effects, only two bleeding episodes. As for haemostatic control, nine surgeries were excellent, one was good and one was fair.