Profound Acid Research Articles

Novel oceanic cyanobacterium isolated from Bangaram island with profound acid neutralizing ability is proposed as Leptolyngbya iicbica sp. nov. strain LK

An acid-neutralizing, filamentous, non-heterocytous, marine cyanobacterium named 'LK' has been isolated from the seashore of Bangaram Island, an atoll of Lakshadweep, India, and is described here as a novel species. LK has been characterized using morphological, ecological, and genomic features. Based on 16S rRNA, whole-genome sequencing, and marker gene-based analysis, LK has been identified as a new species. LK clustered with Leptolyngbya-like strains belonging to the LPP group but diverged from Leptolyngbya sensu stricto, indicating the polyphyletic nature of the Leptolyngbya genus. Leptolyngbya sp. SIOISBB and Halomicronema sp. CCY15110 were identified as LK's two closest phylogenetic neighbors in various phylogenetic studies. The analysis of 16S rRNA, ITS secondary structures, and genome relatedness indices such as AAI, ANI, and gANI strongly support LK as a novel species of the Leptolyngbya genus. The mechanism behind acid neutralization in LK has been delineated, attributing it to a surface phenomenon most likely due to the presence of salts of calcium, magnesium, sodium, and potassium. We name LK as Leptolyngbya iicbica strain LK which is a novel species with prominent acidic pH-neutralizing properties.

The diversification of the antimicrobial peptides from marine worms is driven by environmental conditions

Antimicrobial peptides (AMPs) play a key role in the external immunity of animals, offering an interesting model for studying the influence of the environment on the diversification and evolution of immune effectors. Alvinellacin (ALV), arenicin (ARE) and polaricin (POL, a novel AMP identified here), characterized from three marine worms inhabiting contrasted habitats (‘hot’ vents, temperate and polar respectively), possess a well conserved BRICHOS domain in their precursor molecule despite a profound amino acid and structural diversification of the C-terminal part containing the core peptide. Data not only showed that ARE, ALV and POL display an optimal bactericidal activity against the bacteria typical of the habitat where each worm species lives but also that this killing efficacy is optimal under the thermochemical conditions encountered by their producers in their environment. Moreover, the correlation between species habitat and the cysteine contents of POL, ARE and ALV led us to investigate the importance of disulfide bridges in their biological efficacy as a function of abiotic pressures (pH and temperature). The construction of variants using non-proteinogenic residues instead of cysteines (α-aminobutyric acid variants) leading to AMPs devoid of disulfide bridges, provided evidence that the disulfide pattern of the three AMPs allows for a better bactericidal activity and suggests an adaptive way to sustain the fluctuations of the worm's environment. This work shows that the external immune effectors exemplified here by BRICHOS AMPs are evolving under strong diversifying environmental pressures to be structurally shaped and more efficient/specific under the ecological niche of their producer.

How We Approach Difficult to Eradicate Helicobacter pylori

How We Approach Difficult to Eradicate Helicobacter pylori

A Comparative Study between Nissen's Fundoplication with or without Endoscopic Mucosal Resection in the Treatment of Barrett’s Oesophagus: a Meta-Analysis

Abstract Background It is already known that Barrett’s esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the distal esophagus is replaced by columnar epithelium (intestinal metaplasia or gastric metaplasia) due to GERD. Most observers believe that there is a progression from intestinal metaplasia to low-grade dysplasia (LGD) to highgrade dysplasia (HGD) to cancer. The relative risk of developing esophageal adenocarcinoma in patients with BE appears to be 30-fold higher. Conventional therapies include medical treatment (profound acid inhibition), endoscopic treatment (like endoscopic mucosal resection) and surgical treatment (fundoplication). Methodology Types of studies: Published studies about the efficacy of Nissen’s Fundoplication with or without Endoscopic Mucosal Resection in the treatment of Barrett’s Oesophagus (carried out in the period between 2015 – 2020), types of participants Patients with clinically proven Barrett’s Oesophagus diagnosed by endoscopy and biopsy, types of interventions Nissen’s Fundoplication (Open or Laparoscopic) with or without Endoscopic Mucosal Resection, types of outcome measures Outcome of treatment in the form of Complete Remission of Columnar Metaplasia of the oesophageal mucosa or regression in recurrence rate as proved by follow-up endoscopy. Results The strategy of endoscopic therapy for Barrett’s metaplasia, dysplasia and/or intramucosal cancer along with fundoplication results in similar durability and recurrence rates when compared to patients being managed with PPIs following endoscopic therapy. However, fundoplication along with endoscopic therapy is superior to either of them alone in preventing further progression of disease and the development of cancer, particularly in refractory patients. Fundoplication is an important strategy along with endoscopic therapy for Barrett’s to achieve and maintain CR-IM, and to facilitate the eradication of persistent dysplasia. Conclusion Endoscopic mucosal resection after Nissen's Fundoplication is a safe modality, with high rate of success in complete eradication of BE in symptomatic GERD patients, especially those with severe anatomical impairment in distal esophageal segment. As a concurrent procedure, endoscopic procedures may be beneficial in the terms of reducing the early recurrence rates, which seems to be important issue during the management of BE. By doing synchronous endoscopic procedures and fundoplication, one might observe a true anatomy of esophagogastric junction in its entirety and might be able to truly observe the distal extent of columnar esophagus.

Vonoprazan-based triple therapy is effective for Helicobacter pylori eradication irrespective of clarithromycin susceptibility.

Helicobacter pylori causes peptic ulcers and accounts for over 90% of gastric cancers; however, eradication rates have been declining due to antimicrobial resistance. Vonoprazan (VPZ), a potassium-competitive acid blocker, produces rapid and profound gastric acid suppression and has shown promising effects in the improvement of H. pylori eradication rates. The efficacy and safety of VPZ-based triple therapy as a first-line regimen for H. pylori eradication and its relationship with clarithromycin (CAM) susceptibility were evaluated. From May 2015 to September 2017, H. pylori-infected patients who underwent esophagogastroduodenoscopy with CAM susceptibility testing were prospectively enrolled. Patients received a 7-day triple therapy regimen (VAC) of VPZ (20mg), amoxicillin (750mg), and CAM (200mg) twice daily. Eradication rates, demographics, CAM susceptibility, and safety profiles were assessed. VAC was administered to 146 patients (median age: 63, range: 22-85years) (60% of whom were females) who underwent CAM susceptibility testing, and 131 patients underwent 13C-urea breath testing to evaluate eradication success. The prevalence of CAM resistance was 34.2%. The overall eradication rates of VAC in per protocol (PP) and "intention to treat" (ITT) analyses were 90.8% (n = 131) and 81.5% (n = 146), respectively. In PP analysis for CAM susceptibility, the eradication rates of VAC were comparable between CAM-sensitive (91.6%, n = 83) and CAM-resistant (89.4%, n = 47) strains. The corresponding rates from the ITT analysis were 80.0% (n = 95) and 84.0% (n = 50), respectively. No adverse events requiring discontinuation of VAC were observed. CAM-resistant H. pylori was prevalent in one-third of patients in the Tokyo metropolitan area. VPZ-based triple therapy was highly effective and well-tolerated irrespective of CAM susceptibility. Therefore, it could be a valuable first-line treatment regimen for H. pylori infection.

TGFβ Signaling Increases Net Acid Extrusion, Proliferation and Invasion in Panc-1 Pancreatic Cancer Cells: SMAD4 Dependence and Link to Merlin/NF2 Signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related death, with a 5-year survival of <10% and severely limited treatment options. PDAC hallmarks include profound metabolic acid production and aggressive local proliferation and invasiveness. This phenotype is supported by upregulated net acid extrusion and epithelial-to-mesenchymal transition (EMT), the latter typically induced by aberrant transforming growth factor-β (TGFβ) signaling. It is, however, unknown whether TGFβ-induced EMT and upregulation of acid extrusion are causally related. Here, we show that mRNA and protein expression of the net acid extruding transporters Na+/H+ exchanger 1 (NHE1, SLC9A1) and Na+, HCO cotransporter 1 (NBCn1, SLC4A7) are increased in a panel of human PDAC cell lines compared to immortalized human pancreatic ductal epithelial (HPDE) cells. Treatment of Panc-1 cells (which express SMAD4, required for canonical TGFβ signaling) with TGFβ-1 for 48 h elicited classical EMT with down- and upregulation of epithelial and mesenchymal markers, respectively, in a manner inhibited by SMAD4 knockdown. Accordingly, less pronounced EMT was induced in BxPC-3 cells, which do not express SMAD4. TGFβ-1 treatment elicited a SMAD4-dependent increase in NHE1 expression, and a smaller, SMAD4-independent increase in NBCn1 in Panc-1 cells. Consistent with this, TGFβ-1 treatment led to elevated intracellular pH and increased net acid extrusion capacity in Panc-1 cells, but not in BxPC-3 cells, in an NHE1-dependent manner. Proliferation was increased in Panc-1 cells and decreased in BxPC-3 cells, upon TGFβ-1 treatment, and this, as well as EMT per se, was unaffected by NHE1- or NBCn1 inhibition. TGFβ-1-induced EMT was associated with a 4-fold increase in Panc-1 cell invasiveness, which further increased ~10-fold upon knockdown of the tumor suppressor Merlin (Neurofibromatosis type 2). Knockdown of NHE1 or NBCn1 abolished Merlin-induced invasiveness, but not that induced by TGFβ-1 alone. In conclusion, NHE1 and NBCn1 expression and NHE-dependent acid extrusion are upregulated during TGFβ-1-induced EMT of Panc-1 cells. NHE1 upregulation is SMAD4-dependent, and SMAD4-deficient BxPC-3 cells show no change in pHi regulation. NHE1 and NBCn1 are not required for EMT per se or EMT-associated proliferation changes, but are essential for the potentiation of invasiveness induced by Merlin knockdown.

Novel Therapies for Gastroesophageal Reflux Disease: Beyond Proton Pump Inhibitors.

Despite the many areas of unmet needs in gastroesophageal reflux disease (GERD), proton pump inhibitors (PPIs) remain the cornerstone of medical therapy. However, since their introduction, the therapeutic limitations of PPIs in GERD management have been increasingly recognized. In this review we discuss the new medical, endoscopic, and surgical therapeutic modalities that have been developed over the last decade. They include the potassium-competitive acid blockers (P-CABs) which provide a rapid onset, prolonged, and profound acid suppression, mucosal protectants which promote the physiological protective barrier of the esophageal mucosa, new prokinetics and neuromodulators. There are growing numbers of novel therapeutic endoscopic techniques that are under investigation or were recently introduced into the market, further expanding our therapeutic armamentarium for GERD. The development of diverse therapeutic modalities for GERD, despite the availability of PPIs, suggests that there are many areas of unmet need in GERD that will continue and drive future exploration for novel therapies.

Characterization of envelope sequence of HIV virus in children infected with HIV in Vietnam.

Background:HIV is characterized by high levels of genetic variability, including increased numbers of heterogeneous sequences of the envelope region. Therefore, studying genetic variability of HIV in relation to viral replication might facilitate prognosis of disease progression.Methods:The study was designed as cross-sectional; data and samples of participants collected and analyzed env genes were obtained from 23 children enrolled by Vietnam National Children’s Hospital.Results:Substantial mutations in the C2 region were found in patients with high levels of viral replication while changes in the C3 region were mostly found in patients with low viral load. In the V1 region, we found profound amino acid modifications in patients with low HIV viral loads in contrast to the V2 sequence, where we identified single point mutations in patients with increased HIV viral load. The V3 region was relatively homogeneous, while profound deletions in the V4 region were detected in patients with increased viral replication.Conclusion:Our results suggest that genetic variations in different regions of the HIV envelope sequence, including both conserved C2 and C3 and variable V1/V2 and V4 regions, might be involved in increased viral infectivity and replication capacity. Such knowledge might help improve prediction of HIV progress and treatment in patients.

Synthesis and properties of 1D Sm-doped CeO2 composite nanofibers fabricated using a coupled electrospinning and sol–gel methodology

Ce1−xSmxO2(x=0, 0.2, 0.5 and 0.8) nanofibers (NFs) were synthesized by coupling sol–gel with electrospinning and using poly-vinyl pyrrolidone (PVP) as the polymer medium, in an ethanol/water mixture. Control over the fabrication conditions was achieved through analysis of the most key synthetic factors, which include: (i) the applied field strength; (ii) the solution feed rate and (iii) the PVP content in the electrospinning solution. The optimum microstructural fiber morphology (high quality beeds-free fibers) was achieved using the following electrospinning parameters: an applied voltage of 18.5kV, a 7ml/h of solution feed rate and a 12% (w/w) of PVP composition. Morphological features of the resulting fibers were examined by scanning electron microscopy (SEM). The average fiber diameter was typically found to be in the range of 200–1100nm and 50–300nm, before and after calcination at 500°C, respectively. X-ray diffraction (XRD) results showed that the fluorite cubic structure was preserved for the entire Ce1−xSmxO2 compositional range studied, while elemental analysis using EELS and X-ray photoelectron spectroscopy (XPS) confirmed the purity of the bulk and surface composition of the fibers. Selected area electron diffraction (SAED) and high resolution transmission electron microscopy (HRTEM) proved that the NFs are highly crystalline. The thermal stability of the composite (polymer/inorganic nitrate salts) NFs was further investigated in an inert atmosphere (N2) using thermogravimetric analysis (TGA), which allowed the transformation process of the NFs from composite to oxide to be monitored. The reducibility of the metal oxide NFs (mobility of oxygen species in the fluorite cubic lattice) as well as their thermal stability in successive oxidation–reduction cycles was evaluated using temperature-programmed reduction in a H2 atmosphere (H2-TPR). Acidic–basic features of the NFs and powder surfaces were studied through temperature programmed desorption (TPD) using NH3 and CO2 as probe molecules, where weak, medium and strong acid sites were successfully traced with profound differences depending on the morphology. The NFs' potential performance towards NH3 oxidation was also evaluated. Two types of basic sites, hydroxyl groups and surface lattice oxygen are present on the NFs, as probed by CO2 adsorption. Pyridine adsorption followed by infrared spectroscopy (Py-FT-IR) studies unveiled the more profound Lewis acid presence in Ce0.5Sm0.5O2 NFs compared to bulk powder Ce0.5Sm0.5O2.

Gastric Hypersecretory States: Investigation and Management.

Hypersecretory conditions affecting the stomach account for significant morbidity and mortality manifested in some cases with peptic ulcer, gastrointestinal hemorrhage, and/or gastroesophageal reflux disease (GERD). The diagnosis of gastric acid hypersecretory states can be challenging and relies on the use of quantitative assays to measure gastric acid secretion and serum gastrin. The most common etiology for hypergastrinemia is the use of potent gastric acid inhibitors such as the proton pump inhibitors. The differential diagnosis of this condition is of critical importance, and will dictate management decisions. Conditions such as atrophic gastritis are relatively benign and can lead to hypergastrinemia without the presence of gastric acid hypersecretion. Zollinger-Ellison syndrome, on the other hand, causes hypergastrinemia with profound gastric acid hypersecretion [1]. More common causes of hypergastrinemia include gastric outlet obstruction, ileus, and chronic renal failure [2]. In most cases, proton pump inhibitors will be used to manage these conditions. In some instances, surgical therapy may be required. This chapter will review the important clinical causes of gastric acid hypersecretion and provide insights to the best medical management options to better care for patients with these disorders.

Sa1135 Acceleration of Gastric Ulcer Healing by Carbon Monoxide Releasing Molecule-2 (CORM-2), a Carbon Monoxide Donor. Role of Heme Oxygenase-1, Endogenous Prostaglandins and Lipid Peroxidation

rary endoscopic hemostasis followed by high-dose PPI infusion, although most rebleeding occurs within the first 72 hours, a significant proportion of patients experience a later rebleed. Data are too few and heterogeneous to confidently identify predictors of delayed rebleeding. These require further characterization and may justify a more tailored approach to using second-look endoscopy, while justifying the need for future studies that assess the duration of post-hemostasis profound acid suppression.

Chronic Proton Pump Inihibitor Therapy and Calcium Metabolism

Proton pump inhibitors (PPIs) have been widely used since their introduction in the late 1980s because they are highly effective for acid-related conditions. However, some recent epidemiological studies have suggested a positive association between PPI therapy and the risk of osteoporotic fractures. The potential mechanisms underlying this association may be related to the physiologic effects of chronic acid suppression on calcium metabolism. First, chronic hypergastrinemia induced by PPI therapy may lead to parathyroid hyperplasia, resulting in increased loss of calcium from the bone. Second, profound gastric acid suppression may reduce the bioavailability of calcium for intestinal absorption. I will review the published evidence regarding these potential links and discuss their clinical implications.

P3-16-18: Phase 2, Open-Label Study of EZN-2208 (PEG-SN38) in Patients with Previously Treated Metastatic Breast Cancer.

Abstract Background EZN-2208 is a water-soluble PEGylated conjugate of SN38 that results in parenteral delivery, increased solubility, higher exposure, and longer apparent half-life of SN38, as well as more profound deoxyribonucleic acid (DNA) damage and inhibition of angiogenesis. EZN-2208 results in prolonged exposure of tumors to SN38 via preferential accumulation of EZN-2208 in the tumor and prolonged release of SN38 in the blood. Methods: This trial evaluated EZN-2208 delivered as a 1-h IV infusion weekly for 3 wks in 4-wk cycles. The primary objective was to determine the overall response rate (RR) in female patients with metastatic breast cancer (MBC) who had received prior adjuvant or metastatic therapy with either 1) anthracycline and taxane (AT) or 2) anthracycline, taxane, and capecitabine (Xeloda®) (ATX). Secondary objectives included evaluation of RR based on tumor receptor status, duration of response, progression-free survival (PFS), overall survival (OS), and safety and toxicity. Response was evaluated using RECIST (v1.1). Results: 148 patients received EZN-2208 in the AT (n=65; median age = 56 y [31-84 y]) or ATX (n=83; median age = 55 y [36-83 y]) cohorts. All 65 patients in the AT cohort had received 0–2 lines of prior cytotoxic therapy for MBC; for the ATX cohort, 31 patients (37%) had received 0–2 prior lines of cytotoxic therapy for MBC, 50 patients (60%) had received 3–4 prior lines, and 2 patients (2%) had received 5 prior lines. Preliminary results follow; final data will be presented at the meeting. Median (range) cycles of EZN-2208 was 2.3 (0.3-14) for AT and 2 (0.3-15) for ATX. Best overall response is shown in the table. RR (PR+uPR) was 22% for AT and 10% for ATX. Median (95% CI) time to progression was 3.8 mo (3.6−7.4) for AT and 3.3 mo (1.8−3.7) for ATX. Median (95% CI) duration of response was 4.0 mo (3.7−5.6) for AT and 5.2 mo (1.9-..) for ATX. 6-mo PFS (95% CI) was 34% (19%-50%) for AT and 19% (9%-29%) for ATX. Median PFS (95% CI) was 3.8 mo (2.7−5.6) for AT and 2.9 mo (1.83.7) for ATX. Median OS (95% CI) was 9.1 mo (6.1−12.7) for AT and 7.9 mo (6.4−12.9) for ATX. Grade 3 or 4 drug-related adverse events (&amp;gt;10% of patients in either arm) included neutropenia (43%, 33%), diarrhea (11%, 8%), and leukopenia (11%, 6%). Conclusions: EZN-2208 is active in patients with previously treated MBC. The activity is similar regardless of ER status and is promising in the TNBC population. The safety profile of EZN-2208 is acceptable with good tolerability in most patients. Further evaluation of EZN-2208 in this population is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-18.

Lysosomal pH and analysis of the counter ion pathways that support acidification

Lysosomes serve multiple degradative functions that are potentiated by a profound luminal acid pH generated by an electrogenic proton pump. This proton transport requires charge compensation, and chloride has long been assumed to be the primary counter ion. In this Journal Club, we review the recent

Esomeprazole for the treatment of peptic ulcer bleeding

Peptic ulcer bleeding is the most common cause of acute bleeding in the upper GI tract. The incidence of peptic ulcer bleeding has slowly decreased and endoscopic treatment options have improved; nevertheless, it remains a very common condition with a 7–15% mortality. Acidic environments have a negative effect on hemostasis. Therefore, acid inhibitors have been applied in the adjuvant treatment of peptic ulcer bleeding, both in preventing rebleeding and in treating the underlying cause. This requires profound acid suppressive therapy aiming for a rapid onset of effect and a persistent intragastric pH above 6. This can only be achieved by proton pump inhibitors (PPIs). Esomeprazole is the S-isomer of omeprazole, and the first PPI to consist of only the active isomer. A number of studies have compared esomeprazole with other PPIs, demonstrating a faster and more persistent increase in intragastric pH with the use of esomeprazole than with other agents. Continuous high-dose intravenous treatment with esomeprazole decreases rebleeding, surgery, transfusion rates and hospital days in peptic ulcer bleeding.

Improved characterization of visible vessels in bleeding ulcers by using magnification endoscopy: results of a pilot study

Not all exposed vessels carry the same risk of recurrent bleeding, and sometimes endoscopic therapy may not be warranted in the setting of profound acid inhibition therapy. To investigate the role of magnification endoscopy (ME) in improving the characterization of exposed vessels in ulcer hemorrhage. Prospective study. Single-center teaching hospital. Diagnostic accuracy and safety of ME in patients with bleeding peptic ulcers. A total of 43 patients were studied. Exposed vessels were initially categorized as high risk (protuberant, translucent, or pale) in 25 and low risk (nonprotruding through the ulcer floor, pigmented, or dark red) in 18 cases. ME was subsequently performed, and the operator was asked to reclassify the vessel into 1 of these 2 categories. A magnified view provided a clear image of the vessel and allowed visualization of the artery, the site of rupture, and the presence of a clot plugging the hole. In 6 cases previously categorized as low risk, ME clearly showed the 2 ends of the vessel, the longitudinal tear in the vessel wall, and a protuberant aspect that was not seen with standard view. The lesion was then reclassified as high risk (diagnostic gain 33%). The mean procedure time for ME inspection was 7 +/- 4 minutes. No complications occurred. Absence of controls. In patients with peptic ulcer bleeding and exposed vessels, ME allows clear visualization of the vessel wall and provides detailed clues to further characterize the lesion.

417 Effect of Esomeprazole On Sleep Quality in Patients with Gastroesophageal Reflux Disease (GERD)-Related Sleep Disturbances

Small intestinal bacterial overgrowth occurs often in patients treated with PPI, because of profound acid suppression, but its clinical significance, particularly after long-term treatment, needs yet to be clarified. Glucose H-breath test (GHBT) is the most accurate non invasive tool to diagnose SIBO. AIM: To clarify clinical significance and risk factors for SIBO in patients treated with PPI for long-term. MATERIAL AND METHOD: 450 patients were studied: 200 on PPI for at least 2 months (mean age 39±18 y;M 120;median treatment: 36 months, at full dose for at least 3⁄4 of the time); 200 with IBS, as “pathologic” controls (IBSc), in absence of PPI treatment for at least 3 years (mean age 37±19 y; M 102); 50 “normal” controls (N-c), in absence of PPI for at least 10 years (mean age 35±16 y; M 29). Patients on antibiotics in the last 6 months, on eucinetics or submitted to colonoscopy or barium enema in the last month before test were excluded. Neoplasia, malabsorption diseases, previous G-I surgery, metabolic/hormonal disturbances were also excluded. Each patient was submitted to GHBT (Gastrolyzer, Bedfont Sc. Ldt, England). Symptoms Index (S.I.) was rated as mild (0-5), moderate (6-10) or severe (11-15) on the basis of frequency, duration and severity of pain, constipation /diarrhoea, and “gassy bowel” symptom (by simply adding all parameter scores, each from 0 to 3). Patients affected by SIBO were treated with Rifaximin 400 mg tid for 2 wks. RESULTS: GHBT POSITIVE FOR SIBO: Pts on PPI: 50%. IBS-c:24.5% . N-c:6% (P<0.001) PREVALENCE OF SYMPTOMS SIBO-RELATED in PPI and IBS group respectively:1)Gassy bowel:64% VS 35%; 2)Diarrhoea:41% VS 30%; 3)Constipation:26% VS 19% HEALING OF SIBO: in PPI group: 87%. In IBS group:91%. HEALING OF SIBO IN RELATION TO PPI TREATMENT DURATION: Months 2-12: 93%;More than 13 months: 86%. CONCLUSIONS:1)SIBO is more frequent in patients on long term treatment with PPI than in healthy controls and in IBS controls, in a statistically significant way. 2) Prevalence and Severity of PPI-related SIBO increases with the duration of therapy. 3) “Gassy bowel” is more frequent and more severe in PPI-SIBO than in IBS-SIBO. 4) Healing of SIBO with Rifaximin is satisfactory, being more successful in patients on PPI less than 12 months. Severity of SIBO in relation to PPI-therapy duration

416 PPI-Realted SIBO: Clinical Significance and Risk Factors

Small intestinal bacterial overgrowth occurs often in patients treated with PPI, because of profound acid suppression, but its clinical significance, particularly after long-term treatment, needs yet to be clarified. Glucose H-breath test (GHBT) is the most accurate non invasive tool to diagnose SIBO. AIM: To clarify clinical significance and risk factors for SIBO in patients treated with PPI for long-term. MATERIAL AND METHOD: 450 patients were studied: 200 on PPI for at least 2 months (mean age 39±18 y;M 120;median treatment: 36 months, at full dose for at least 3⁄4 of the time); 200 with IBS, as “pathologic” controls (IBSc), in absence of PPI treatment for at least 3 years (mean age 37±19 y; M 102); 50 “normal” controls (N-c), in absence of PPI for at least 10 years (mean age 35±16 y; M 29). Patients on antibiotics in the last 6 months, on eucinetics or submitted to colonoscopy or barium enema in the last month before test were excluded. Neoplasia, malabsorption diseases, previous G-I surgery, metabolic/hormonal disturbances were also excluded. Each patient was submitted to GHBT (Gastrolyzer, Bedfont Sc. Ldt, England). Symptoms Index (S.I.) was rated as mild (0-5), moderate (6-10) or severe (11-15) on the basis of frequency, duration and severity of pain, constipation /diarrhoea, and “gassy bowel” symptom (by simply adding all parameter scores, each from 0 to 3). Patients affected by SIBO were treated with Rifaximin 400 mg tid for 2 wks. RESULTS: GHBT POSITIVE FOR SIBO: Pts on PPI: 50%. IBS-c:24.5% . N-c:6% (P<0.001) PREVALENCE OF SYMPTOMS SIBO-RELATED in PPI and IBS group respectively:1)Gassy bowel:64% VS 35%; 2)Diarrhoea:41% VS 30%; 3)Constipation:26% VS 19% HEALING OF SIBO: in PPI group: 87%. In IBS group:91%. HEALING OF SIBO IN RELATION TO PPI TREATMENT DURATION: Months 2-12: 93%;More than 13 months: 86%. CONCLUSIONS:1)SIBO is more frequent in patients on long term treatment with PPI than in healthy controls and in IBS controls, in a statistically significant way. 2) Prevalence and Severity of PPI-related SIBO increases with the duration of therapy. 3) “Gassy bowel” is more frequent and more severe in PPI-SIBO than in IBS-SIBO. 4) Healing of SIBO with Rifaximin is satisfactory, being more successful in patients on PPI less than 12 months. Severity of SIBO in relation to PPI-therapy duration

Response to Lin

To the Editor: We thank Dr Lin for his interest in our article and for the several points raised in his letter (1). Dr Lin's main concern is the fact that we did not check intragastric pH in our patients with bleeding peptic ulcers, given that the presumptive aim of pharmacological treatment in such cases is to increase intragastric pH above the proteolytic range of pepsin. In vitro, fibrin clots are dissolved when pH falls below 4, and platelet aggregation is totally inhibited when pH falls below 5.9. Previous evidence has sustained the claim that profound acid suppression is essential for a favorable outcome in peptic ulcer bleeding cases. Obviously, the in vitro–generated hypothesis that optimizing intragastric pH during acute peptic ulcer bleeding might reduce patients' risk of morbidity and mortality had to be validated in vivo. Indeed, all in vitro data represent only surrogate end points, whereas in vivo data are the essential outcome measures on which clinical decisions should be based. In our head-to-head comparison of standard bolus vs. an intensive regimen of proton pump inhibitor administration after successful endoscopic hemostasis, the former regimen proved as effective as the high-dose infusion in terms of preventing peptic ulcer rebleeding (2). A recent trial from Hong Kong reported results similar to ours (3). Ulcer healing is a complex process, and it is likely that factors in addition to high pH level contribute to the cessation of ulcer bleeding, as this usually occurs without intervention.

Proton Pump Inhibitor Therapy and Osteoporosis

Osteoporotic fractures, particularly hip fractures, can have a devastating impact on the well-being of the elderly population. Recently, two population-based observational studies reported a highly important association between the use of potent acid suppressive therapy and an increased risk of hip fractures. The mechanisms underlying such an association are not clear. However, a careful review of the existing evidence seems to suggest that the main physiologic consequences of proton pump inhibitor therapy may each have a theoretical influence on bone metabolism. Specifically, inhibition of the osteoclastic proton pumps may reduce bone resorption, while profound acid suppression could potentially hamper intestinal calcium absorption, and secondary hypergastrinemia may enhance bone resorption through the induction of parathyroid gland hyperplasia. However, the existing data are clearly too limited for us to draw any definitive conclusions, and more studies are urgently needed to delineate the physiologic relevance of these theoretical mechanistic links, individually and collectively.