This patient, FR06, had received transarterial chemoembolization

(TACE) treatment, but as the other two TACE-treated patients did not present such Ixazomib molecular weight a profile we cannot make any conclusion on the effect of TACE on ABC expression. Second, we were able to demonstrate that in the 16 untreated patients the expression of 10 ABC transporters was significantly up-regulated in HCC compared with paired AHL samples. In untreated patients, only up-regulation of ABCC1 has been shown to be associated with a more aggressive HCC phenotype.10 To our knowledge this is the first publication reporting up-regulation of a broad range of ABC transporters in untreated HCC patients. This includes eight ABC genes: ABCA2, ABCB6, ABCC2, ABCC3, ABCC5, ABCC10, ABCC11, and ABCE1, whose association with HCC has not been reported

so far. Due to the size of some subpopulations, the described associations between ABC profile and clinical parameters will have to be confirmed on a larger patient population. Nevertheless, find more the results of the ABC profiling raise the question of the possible regulation pathways implicated in the phenomenon of ABC genes up-regulation. We chose to further investigate the possibility of miRNA-mediated ABC gene regulation in association with HCC. So far only miR-203 has been reported to specifically target ABCE127 but its implication in HCC still needs to be determined. Our miRNA screen in 10 HCC patients identified significant changes in expression of 90 miRNAs, including 11 up-regulated miRNAs and 79 down-regulated miRNAs, of which 25 had predicted ABC targets. Interestingly, 97% of the dysregulated miRNAs were highly conserved in mammals (up to the mouse), indicating their possible association with HCC, as has been shown for several diseases.31 Seventy-nine of 90 dysregulated miRNAs are down-regulated and this is in agreement with the evidence that miRNAs are generally down-regulated in cancer.32 Many miRNAs identified during the current screen confirmed findings obtained with larger

sample sets or sample sets coming from patients with a different medchemexpress cancer etiology. Similar to other publications, we observed down-regulation of miR-101,33 miR-122,34-37 miR-125a,37, 38 miR-130a,34, 39 miR-145,39-41 miR-199a,33, 36, 38, 39 miR-199b,38, 40 and up-regulation of miR-21.33-37, 40-42 Seventy-four percent of our patients had alcoholic cirrhosis, and ethanol-treatment has been linked in the literature to the miR-199 family.43 However, no correlation between the miRNA profiles and viral HCC etiology could be determined, probably due to the small patient size (14 alcohol, three HCV, one HBV, and one alcohol/HCV). Our screen also identified 12 miRNAs with predicted ABC targets that have not been previously associated with HCC. Down-regulated miRNAs were reported to be repressed by oncogenes: miR-145 by Ras,44 and miR-26a and miR-195 by Myc45 as well as let-7.

This patient, FR06, had received transarterial chemoembolization

(TACE) treatment, but as the other two TACE-treated patients did not present such MG-132 manufacturer a profile we cannot make any conclusion on the effect of TACE on ABC expression. Second, we were able to demonstrate that in the 16 untreated patients the expression of 10 ABC transporters was significantly up-regulated in HCC compared with paired AHL samples. In untreated patients, only up-regulation of ABCC1 has been shown to be associated with a more aggressive HCC phenotype.10 To our knowledge this is the first publication reporting up-regulation of a broad range of ABC transporters in untreated HCC patients. This includes eight ABC genes: ABCA2, ABCB6, ABCC2, ABCC3, ABCC5, ABCC10, ABCC11, and ABCE1, whose association with HCC has not been reported

so far. Due to the size of some subpopulations, the described associations between ABC profile and clinical parameters will have to be confirmed on a larger patient population. Nevertheless, GSK3235025 order the results of the ABC profiling raise the question of the possible regulation pathways implicated in the phenomenon of ABC genes up-regulation. We chose to further investigate the possibility of miRNA-mediated ABC gene regulation in association with HCC. So far only miR-203 has been reported to specifically target ABCE127 but its implication in HCC still needs to be determined. Our miRNA screen in 10 HCC patients identified significant changes in expression of 90 miRNAs, including 11 up-regulated miRNAs and 79 down-regulated miRNAs, of which 25 had predicted ABC targets. Interestingly, 97% of the dysregulated miRNAs were highly conserved in mammals (up to the mouse), indicating their possible association with HCC, as has been shown for several diseases.31 Seventy-nine of 90 dysregulated miRNAs are down-regulated and this is in agreement with the evidence that miRNAs are generally down-regulated in cancer.32 Many miRNAs identified during the current screen confirmed findings obtained with larger

sample sets or sample sets coming from patients with a different 上海皓元医药股份有限公司 cancer etiology. Similar to other publications, we observed down-regulation of miR-101,33 miR-122,34-37 miR-125a,37, 38 miR-130a,34, 39 miR-145,39-41 miR-199a,33, 36, 38, 39 miR-199b,38, 40 and up-regulation of miR-21.33-37, 40-42 Seventy-four percent of our patients had alcoholic cirrhosis, and ethanol-treatment has been linked in the literature to the miR-199 family.43 However, no correlation between the miRNA profiles and viral HCC etiology could be determined, probably due to the small patient size (14 alcohol, three HCV, one HBV, and one alcohol/HCV). Our screen also identified 12 miRNAs with predicted ABC targets that have not been previously associated with HCC. Down-regulated miRNAs were reported to be repressed by oncogenes: miR-145 by Ras,44 and miR-26a and miR-195 by Myc45 as well as let-7.

A study by Sibon and Orgogozo17 demonstrated that 4.5% of strokes were related to recent discontinuation of antiplatelet agents but all events occurred between 6 and 10 days after discontinuation of antiplatelet drugs. Since most peptic ulcer rebleeding occurs within the first 3 days of presentation,18,19 resuming antiplatelet agents at 3–5 days after the last dosing is a reasonable strategy in the management of bleeding ulcer patients with high-risk stigmata of recent hemorrhage (Fig. 1).20 However, patients with low-risk stigmata of recent hemorrhage or clean-base ulcers can keep taking antiplatelet agents immediately

following R788 endoscopy.21 It merits noting that stent thrombosis is a life-threatening complication of coronary artery stent implantation. Dual antiplatelet therapy with aspirin and clopidogrel is recommended for at least 12 months after drug-eluting stent implantation compared with 4 weeks after placement of bare-metal stent.22 Discontinuation of antiplatelet therapy (particularly clopidogrel) is a crucial independent factor for the development of stent thrombosis. A recent study showed that the incidence of major cardiovascular

events was significantly higher if dual antiplatelet therapy was discontinued within one month of bare-metal stent, 3 months of Sirolmus drug-eluting stent and 6 months of Paclitaxel drug-eluting stent placement.23 Because the risk of stent thrombosis with removal of antiplatelet agents is high within the critical MCE periods following selleck kinase inhibitor percutaneous coronary intervention,

and antiplatelet effects of aspirin and clopidogrel may last at least a few days after cessation, resuming antiplatelet therapy at 3 days after the last dosing is recommended for the bleeding ulcer patients undergoing recent coronary stenting (Fig. 1). Currently, the best initial treatment of low-dose aspirin-related peptic ulcer remains unclear. Although the discontinuation of aspirin use during the period of ulcer healing may avoid further GI injury, the withdrawal of the antiplatelet agent could potentially precipitate an ischemic vascular event, particularly in high-risk patients with acute coronary syndrome. In contrast, continued use of aspirin may prevent CV events but the antiplatelet agent could potentially hinder ulcer healing and precipitate bleeding in ulcer patients. As mentioned in the previous section, the initial step in reducing GI risk of antiplatelet therapies is to assess whether the patient has a continued need of antiplatelet therapy (Fig. 2). Depending on the indication for antiplatelet therapy, some patients may be able to withdraw antiplatelet agents after consultation with cardiologists or neurologists.

A study by Sibon and Orgogozo17 demonstrated that 4.5% of strokes were related to recent discontinuation of antiplatelet agents but all events occurred between 6 and 10 days after discontinuation of antiplatelet drugs. Since most peptic ulcer rebleeding occurs within the first 3 days of presentation,18,19 resuming antiplatelet agents at 3–5 days after the last dosing is a reasonable strategy in the management of bleeding ulcer patients with high-risk stigmata of recent hemorrhage (Fig. 1).20 However, patients with low-risk stigmata of recent hemorrhage or clean-base ulcers can keep taking antiplatelet agents immediately

following Torin 1 endoscopy.21 It merits noting that stent thrombosis is a life-threatening complication of coronary artery stent implantation. Dual antiplatelet therapy with aspirin and clopidogrel is recommended for at least 12 months after drug-eluting stent implantation compared with 4 weeks after placement of bare-metal stent.22 Discontinuation of antiplatelet therapy (particularly clopidogrel) is a crucial independent factor for the development of stent thrombosis. A recent study showed that the incidence of major cardiovascular

events was significantly higher if dual antiplatelet therapy was discontinued within one month of bare-metal stent, 3 months of Sirolmus drug-eluting stent and 6 months of Paclitaxel drug-eluting stent placement.23 Because the risk of stent thrombosis with removal of antiplatelet agents is high within the critical MCE periods following Bafilomycin A1 datasheet percutaneous coronary intervention,

and antiplatelet effects of aspirin and clopidogrel may last at least a few days after cessation, resuming antiplatelet therapy at 3 days after the last dosing is recommended for the bleeding ulcer patients undergoing recent coronary stenting (Fig. 1). Currently, the best initial treatment of low-dose aspirin-related peptic ulcer remains unclear. Although the discontinuation of aspirin use during the period of ulcer healing may avoid further GI injury, the withdrawal of the antiplatelet agent could potentially precipitate an ischemic vascular event, particularly in high-risk patients with acute coronary syndrome. In contrast, continued use of aspirin may prevent CV events but the antiplatelet agent could potentially hinder ulcer healing and precipitate bleeding in ulcer patients. As mentioned in the previous section, the initial step in reducing GI risk of antiplatelet therapies is to assess whether the patient has a continued need of antiplatelet therapy (Fig. 2). Depending on the indication for antiplatelet therapy, some patients may be able to withdraw antiplatelet agents after consultation with cardiologists or neurologists.

65 High drug trough levels in the setting of treatment failure may be explained by alternative pathways of inflammation being responsible for the active disease (Fig. 1). Alternatively, non-inflammatory causes, such as fibrotic strictures or concurrent irritable bowel syndrome, may account for continuing symptoms. Large multicentre registries such as the TREAT registry,66 prospective cohorts67 and post marketing surveillance have provided clinicians with a combined anti-TNF experience of hundreds of thousands of patient-years. Despite the heterogeneity of these sources, they provide invaluable information regarding

safety and adverse selleck products events. In discussions with the patient, these risks must be weighed against the potential benefits of anti-TNF therapy. Infections.  There is increased risk of incidental infections associated with the EPZ-6438 diagnosis of IBD, associated malnutrition and the use of other immunosuppressive agents. The risk of infection is likely to be higher in patients using anti-TNF in IBD compared with other inflammatory diseases because poorly controlled intestinal ulceration provides a ready source of intra-abdominal

sepsis. Anti-TNF agents also convey a risk of opportunistic infections, among which tuberculosis (TB) is the most clearly associated. TNF is a key cytokine involved in maintenance of granulomatous compartmentalization of Mycobacterium tuberculosis.68 The risk of infection increases with the use of corticosteroids, narcotic analgesics, disease severity, thiopurines, and anti-TNF agents. The odds ratio for opportunistic

infections when using anti-TNF agents is approximately fourfold (Table 2).69 The risk increases strikingly to 14.5 when combination therapy with two or three agents is given. These figures, however, can be contrasted to other studies quoting minimal increased risk of opportunistic medchemexpress infection for those on infliximab monotherapy.67 Combination therapies that include corticosteroids appear to be those that result in the highest risk of opportunistic infections.69 Activation of latent TB and acquisition of primary TB are both more likely in patients treated with anti-TNF agents.70 Post-marketing reports suggest a fourfold increase in the risk of TB illness.68 Screening for TB prior to commencing anti-TNF therapy provides a 74% reduction in TB rates.71 In addition to a meticulous history and a chest X-ray, an interferon-γ (IFN-γ) release assay (such as QuantiFERON-TB Gold assay) or tuberculin skin test (> 1 cm Mantoux wheal) isused for TB screening.72 IFN-γ release assays are not reactive against Bacillus Calmette-Guérin (BCG) vaccines and hence are more specific.73 Specific management of established or suspected latent TB infection is covered elsewhere.

65 High drug trough levels in the setting of treatment failure may be explained by alternative pathways of inflammation being responsible for the active disease (Fig. 1). Alternatively, non-inflammatory causes, such as fibrotic strictures or concurrent irritable bowel syndrome, may account for continuing symptoms. Large multicentre registries such as the TREAT registry,66 prospective cohorts67 and post marketing surveillance have provided clinicians with a combined anti-TNF experience of hundreds of thousands of patient-years. Despite the heterogeneity of these sources, they provide invaluable information regarding

safety and adverse see more events. In discussions with the patient, these risks must be weighed against the potential benefits of anti-TNF therapy. Infections.  There is increased risk of incidental infections associated with the NVP-AUY922 mouse diagnosis of IBD, associated malnutrition and the use of other immunosuppressive agents. The risk of infection is likely to be higher in patients using anti-TNF in IBD compared with other inflammatory diseases because poorly controlled intestinal ulceration provides a ready source of intra-abdominal

sepsis. Anti-TNF agents also convey a risk of opportunistic infections, among which tuberculosis (TB) is the most clearly associated. TNF is a key cytokine involved in maintenance of granulomatous compartmentalization of Mycobacterium tuberculosis.68 The risk of infection increases with the use of corticosteroids, narcotic analgesics, disease severity, thiopurines, and anti-TNF agents. The odds ratio for opportunistic

infections when using anti-TNF agents is approximately fourfold (Table 2).69 The risk increases strikingly to 14.5 when combination therapy with two or three agents is given. These figures, however, can be contrasted to other studies quoting minimal increased risk of opportunistic MCE infection for those on infliximab monotherapy.67 Combination therapies that include corticosteroids appear to be those that result in the highest risk of opportunistic infections.69 Activation of latent TB and acquisition of primary TB are both more likely in patients treated with anti-TNF agents.70 Post-marketing reports suggest a fourfold increase in the risk of TB illness.68 Screening for TB prior to commencing anti-TNF therapy provides a 74% reduction in TB rates.71 In addition to a meticulous history and a chest X-ray, an interferon-γ (IFN-γ) release assay (such as QuantiFERON-TB Gold assay) or tuberculin skin test (> 1 cm Mantoux wheal) isused for TB screening.72 IFN-γ release assays are not reactive against Bacillus Calmette-Guérin (BCG) vaccines and hence are more specific.73 Specific management of established or suspected latent TB infection is covered elsewhere.

Results: The frequency of C carrier was higher in UC patients than in healthy controls (66.7% vs. 53.3%, P = 0.005, OR = 1.75, 95% CI: 1.18–2.60),

and associated with extensive colitis (P = 0.029). PTPN22 mRNA levels were elevated in UC patients than in healthy controls (P < 0.001). Among UC patients, PTPN22 mRNA expression levels were higher in biopsies of inflamed colonic tissue compared Romidepsin research buy with non-inflamed tissue (P < 0.001), and were correlated with CRP levels (r = 0.578, P < 0.001). PTPN22 mRNA expression levels were elevated in extensive colitis compared to proctitis (P = 0.008) and to left sided colitis (P = 0.029), and were higher in moderate Opaganib cell line and severe disease than in mild disease (P = 0.005). Conclusion: Our study showed the potential association between PTPN22 −1123G/C polymorphism and UC in central China. PTPN22 mRNA levels were highly expressed in UC, especially in active disease, and were correlated with CRP levels, disease location and disease severity in UC patients. Key Word(s): 1. ulcerative

colitis; 2. PTPN22; 3. polymorphism; 4. expression; Table 1 Distribution of PTPN22 -1123G/C, +1858C/T and +788G/A allele and genotype frequencies in patients with ulcerative colitis (UC) and healthy controls   UC n = 165 (%) Healthy Controls n = 300 (%) UC vs. healthy controls: Table 2 Association between −1123G/C polymorphism of PTPN22 gene and disease characteristics in patients with ulcerative colitis   GG n = 55 (%) −1123G/C C carrier n = 110(%) MCE *P = 0.029, OR = 2.38, 95% CI: 1.08–5.23 Presenting Author: LI ZHAOSHEN Additional Authors: SUJUN KAI, SU JUN, ZOUDUO WU, GAOHAI LLIAN, ZHANG LING, LIU JIE Corresponding Author: LI ZHAOSHEN Affiliations: Changhai Hospital, Second Military Medical University Objective: As estrogen increasees visceral hypersensitivity (VH) induced by water avoidance stress in female rats, further evaluated whether NR2B are involved in the estrogen contribution to stress-induced VH. Methods: Healthy adult female Wistar rats were bilaterally ovariectomized,

implantation of cannula into lateral cerebroventricle and equipped with electrodes in the abdominal muscles for electromyography recording 5 days, and then exclude the rats with abnormal behavior and electromyography. There are 48 rats were eligible, and submitted to water avoidance stress (WAS). Visceromotor response (VMR) to 20, 40, 60 and 80 mmHg colorectal distension (CRD) was recorded in rats intracerebroventricular-infused with either 17β-estradiol, normal saline, AP5(NMDA receptor-antagonist) or Ro25-6981(NR2B antagonist). NR2B mRNA in anterior cingulate cortex or dorsal root ganglia were compared by real-time PCR between the rats treated with 17β-estradiol and that with noormal saline.

In a selected cohort with biliary atresia requiring LT, there were no perioperative cardiac complications, although the cardiac lesions (e.g., ventricular septal defect [VSD], ASD, and pulmonary stenosis) were incidental. The overall recipient and graft survival at 1 and 5 years were both 100%.38 Manzoni et al. compared outcomes after LT in patients with cirrhosis and CHD (61% with Alagille syndrome) and a group undergoing LT without CHD (86% with biliary atresia).37 In this group of patients with

“mild” deficits attributable to their CHD, rates of mortality (7% versus 8%), recovery, and retransplantation were similar. However, patients with CHD that required corrective cardiac surgery KU-57788 clinical trial and patients with liver masses were excluded. Furthermore, only a subset of CHD defects with mild severity were included (e.g., patent foramen ovale and pulmonary artery

stenosis). A separate analysis by the same group demonstrated that living donor LT can be safely performed in hemodynamically stable patients with small- to large-sized ASD. However, once again, it must be borne in mind that these were less-severe defects. Hence, the available evidence as to the efficacy of LT is patients with severe CHD remains sparse. In adults, significant cardiopulmonary disease is a relative contraindication to LT, and the presence of significant pulmonary hypertension is associated with poor outcomes.39 In pediatric patients with Selleckchem MLN0128 hypoxemia resulting from intrapulmonary shunting, as in adult patients with hepatopulmonary syndrome, a Pa02 value <50 mmHg is associated with significant mortality (33%). The decrease in systemic vascular resistance after reperfusion may lead to further intracardiac shunting (right to left), leading to hypoxia.37 Most adult patients with failing Fontans have significantly elevated right atrial pressures. At our center, however, we consider right atrial pressures greater than 15 mmHg as a relative contraindication to isolated LT. The potential for air embolism during the LT procedure (leading to either pulmonary embolism or

paradoxical emboli and cerebral infarction) and the risk of infective endocarditis need to be considered.29, 37 Patients with CHD have tenuous hemodynamics 上海皓元 and may be at a higher risk for hypotension, arrythmias, and bleeding. Postoperatively, hepatic congestion resulting from right-sided failure may occur, and one must bear in mind that the eventual progression of cardiac disease may ensue.38 There are limited data on CHLT in patients with congenital heart disease.40-42 The procedure has been performed in selected cases at a handful of centers and may be an option for heart transplant candidates with cirrhosis or for patients with liver failure or HCC secondary to cardiac cirrhosis. The most common indication for CHLT in the United States is amyloidosis (30%).

Both von Willebrand and Jurgens had suggested that the VWD patients had signs of vessel and platelet function defects. A possible Lenvatinib research buy platelet defect in addition to a deficiency of FVIII was also found in later studies in Åland [12]. However, the platelet function tests were rather non-specific. Together with Dag Nyman, working in Stockholm, and Aldur Eriksson, a geneticist from Åland now working in Amsterdam, I investigated four different families, including the original family S, thought to have VWD [13–15] and we found that: the original family (family S) had decreased levels of FVIII and VWF and a prolonged bleeding time; one family had a ‘pure’ platelet dysfunction, cyclo-oxygenase defect; one family had a mixture of

these two defects; and one family had a platelet selleck compound dysfunction of the so-called ‘aspirin’ type. Later I started to collaborate with the geneticist Maria Anvret also at the Karolinska Institutet. We performed coagulation investigations in 25 patients with severe, type 3, VWD. Nine of the probands and their families were further investigated with DNA linkage analyses. The findings sugggested homozygosity in five families and compound heterozygosity or a new mutation in the proband of three families [16]. Significantly, we also found that the heterozygotes, which we called type I VWD, mostly had a bleeding tendency and an increased FVIII/VWFAg ratio (>1.6). Examples are found

in reference 16. All except one of seven type 1 VWD patients were with blood group O. In 1990, Zhiping Zhang from China started genetic investigations in our laboratories and even tried gene therapy constructs, later publishing 10 papers. Zhiping Zhang [17,18] sequenced the whole VWF gene in 28 上海皓元 Swedish patients with severe VWD and found that the probands of two families were homozygous for an exon 28 mutation – these were Finnish speaking families who had immigrated from Finland; two probands were homozygous for an exon 32 mutation; and 15 probands from 14 families were homozygous for the exon 18 mutation. In addition, there were several probands with combined heterozygous mutations. In 1992,

Zhiping Zhang and I made the third trip to the Åland Island to obtain samples for investigation of the DNA mutations in the VWD families, working together with Dag Nyman, now living in his home country, the Åland islands (Fig. 4). The exon 18 mutation was found in those with bleeding symptoms from the original family (S) and all were heterozygous [17]. We also found the exon 18 mutation in the hair of a 2-year boy with severe VWD and who was homozygous – his parents were heterozygous for the mutation. This patient is now an 18-year old and a good football player. The family, family 1, had recently moved from the north of Finland to Åland and was related to two of the families with VWD in Åland dating back to 1650. In the original Åland family S, Gerda (no. 2 from the right in Åland family S Fig.

Mucosal PGE2 contents were also increased by luminal perfusion of ATP, reduced by P2Y receptor antagonists, NADPH oxidase inhibitors, or cPLA2 inhibitors, further supporting our hypothesis that ATP-P2Y signal-induced H2O2 production increases PGE2 synthesis, augmenting HCO3− secretion. H2O2 increases electrogenic Cl− secretion via PGE2 synthesis in rat colon[32] and in primary inner medullary collecting duct cells,[33] consistent with

our results. Luminal acid exposure increases HCO3− secretion accompanied by increased H2O2 output into the perfusate, inhibited by co-perfusion of P2Y receptor antagonists or NADPH oxidase inhibitors. Furthermore, acid-induced HCO3− secretion was reduced by inhibition www.selleckchem.com/products/lgk-974.html of cPLA2 without affecting H2O2 output. Acid-augmented mucosal PGE2 content was also reduced by these inhibitors, suggesting that the duodenal mucosa exposed to luminal ATP or acid generates H2O2 and PGE2 via the same pathway. Therefore, acid exposure triggers ATP-P2Y signals, which activate Nutlin-3 order Duox2 to generate extracellular H2O2, which activates epithelial cPLA2, which increases PGE2 synthesis via COX, followed by EP4 receptor activation, intracellular cAMP increase, and cystic

fibrosis transmembrane conductance regulator (CFTR) activation, augmenting the rate of luminal HCO3− secretion (Fig. 2). This sequential pathway may explain the fundamental question of how luminal acid augments PG synthesis. Duodenal epithelial cells possess high catalase activity,[34-36] which may protect them from self-generated H2O2. Luminal exposure to H2O2 ≤ 0.3 mmol/L dose-dependently increased HCO3− secretion without epithelial injury or increasing mucosal permeability,[18] consistent with the effect of H2O2 on rat colonic Cl− secretion.[32] In contrast, 0.5 mmol/L H2O2 inhibits cAMP-induced or Ca2+-dependent Cl− secretion in colonic T84 cells.[37, 38] H2O2 also increases epithelial permeability

and cellular toxicity at higher concentration (≥ 0.5 mmol/L),[39, 40] suggesting that the effect of luminal H2O2 is dependent on whether its concentration is in the physiological or pathological ranges. Since generation of H2O2 by Duox2 requires sufficient luminal O2, and since activation of HCO3− secretion MCE consumes intracellular ATP, epithelial O2 consumption may be increased during acid exposure. We reported that post-prandial epithelial hypoxia was present in duodenal villous cells, induced by acid exposure, and inhibited by pretreatment with proton pump inhibitor (PPI) or oral catalase.[41] Since duodenal hypoxia increases hypoxia-inducible factor-2α signaling, enhancing iron absorption,[42, 43] and since PPI treatment decreased COX expression in the duodenal mucosa,[41] acid exposure may maintain mucosal integrity by inducing villous hypoxia. This mechanism may be implicated in the clinical observation of PPI-induced iron deficiency.