Infection by CagA-Positive Helicobacter pylori Strains and Bone Fragility: A Prospective Cohort Study

Helicobacter pylori (HP) infection is a common and persistent disorder acting as a major cofactor for the development of upper gastrointestinal diseases and several extraintestinal disorders including osteoporosis. However, no prospective study assessed the effects of HP on bone health and fracture risk. We performed a HP screening in a population-based cohort of 1149 adults followed prospectively for up to 11 years. The presence of HP infection was assessed by serologic testing for serum antibodies to HP and the cytotoxin associated gene-A (CagA). The prevalence of HP infection did not differ among individuals with normal bone mineral density (BMD), osteoporosis, and osteopenia. However, HP infection by CagA-positive strains was significantly increased in osteoporotic (30%) and osteopenic (26%) patients respect to subjects with normal BMD (21%). Moreover, anti-CagA antibody levels were significantly and negatively associated with lumbar and femoral BMD. Consistent with these associations, patients affected by CagA-positive strains had a more than fivefold increased risk to sustain a clinical vertebral fracture (HR 5.27; 95% CI, 2.23–12.63; p < .0001) and a double risk to sustain a nonvertebral incident fracture (HR 2.09; 95% CI, 1.27–2.46; p < .005). Reduced estrogen and ghrelin levels, together with an impaired bone turnover balance after the meal were also observed in carriers of CagA-positive HP infection. HP infection by strains expressing CagA may be considered a risk factor for osteoporosis and fractures. Further studies are required to clarify in more detail the underlying pathogenetic mechanisms of this association. © 2020 American Society for Bone and Mineral Research (ASBMR).     

慢性胃炎中医证侯与胃窦十二指肠运动及胃炎程度的相 …

研究慢性胃炎中医辩证分型与幽门螺杆菌（Ｈｐ）感染、胃粘膜炎症程度以及胃窦十二指肠消化间期移行性运动复合波之间的关系。将慢性胃炎１１７例,按中医辩证分为实证和虚证,实施包括脾胃湿热型３７例和肝胃不和型３４例,虚证包括脾胃虚型２６例和胃阴不足型２０例。均进行内镜、Ｈｐ及病理检查,分型统计并进行显著性检验。其中３８例用腔内测压法分别测定其消化间期移行性运动复合波（ＭＭＣ）。实证组Ｈｐ阳性率高于虚证组,依     

High Prevalence of Helicobacter pylori in Liver Cirrhosis (Relationship with Clinical and Endoscopic Features and the Risk of Peptic Ulcer)

In 153 consecutive patients with cirrhosis weassessed: (1) the prevalence of IgG to Helicobacterpylori and compared it with that found in 1010 blooddonors resident in the same area; and (2) therelationships of IgG to Helicobacter pylori with clinical andendoscopic features and with the risk of peptic ulcer.The IgG to Helicobacter pylori prevalence of cirrhoticswas significantly higher than in blood donors (76.5% vs 41.8%; P < 0.0005) and was notassociated with sex, cirrhosis etiology, Child class,gammaglobulins and hypertensive gastropathy. In bothgroups, the prevalence of IgG to Helicobacter pylori was significantly higher in subjects over 40. Amongpatients with cirrhosis a significantly higherprevalence of Helicobacter pylori was found in patientswith previous hospital admission (P = 0.02) and/or upper gastrointestinal endoscopy (P = 0.01) andpatients with peptic ulcer (P = 0.0004). Multivariateanalysis identified increasing age and male sex as riskfactors for a positive Helicobacter pylori serology and no independent risk factors for pepticulcer. The high prevalence of Helicobacterpylori-positive serology found in the present series isrelated to age and sex and might also be explained byprevious hospital admissions and/or uppergastrointestinal endoscopy. Our results do not confirmthe role of Helicobacter pylori as risk factor forpeptic ulcer in patients with liver cirrhosis.     

Delayed Gastric Emptying by Helicobacter pylori Lipopolysaccharide in Conscious Rats

The present study was carried out to investigatethe possibility that lipopolysaccharide deprived fromHelicobacter pylori may alter gastric motility. Toaddress the question, we examined the effect of H. pylori lipopolysaccharide on gastricemptying in conscious rats. Gastric emptying wasevaluated by the phenol red method. Time-course anddose-related effects of intraperitoneal administrationof H. pylori lipopolysaccharide were investigated.Intraperitoneal injection of H. pylorilipopolysaccharide significantly suppressed gastricemptying of a liquid meal in a dose-dependent manner.The inhibitory action of H. pylori lipopolysaccharide wasobserved 2, 4, 8, or 12 hr after the injection. Theseresults suggest for the first time that H. pylorilipopolysaccharide may suppress gastric emptying in along-lasting fashion. It is also suggested that H. pylorimay influence gastric function through its cell wallstructure named lipopolysaccharide.     

Augmented Eradication Rates of Helicobacter pylori by New Combination Therapy with Lansoprazole, Amoxicillin, and Rebamipide

The aim of the present study was to determinethe efficacy of a new combination regimen including anantioxidant, a proton pump inhibitor, and antibioticsagainst Helicobacter pylori and to document the changes of oxidative stress and cytokinesinvolved in H. pylori-associated gastric inflammation.From 57 patients with endoscopically diagnosed gastricand/or duodenal ulcers associated with H. pylori infection five gastric antral biopsy specimenswere taken for the diagnosis of H. pylori and for theexperimental measures. The patients were then treatedeither with lansoprazole 30 mg + amoxicillin 1.5 g (LAgroup; 21 patients) or lansoprazole 30 mg amoxicillin1.5 g + rebamipide 300 mg (LAM group; 36 patients) fortwo weeks. Four weeks after the initiation of treatment,the patients were endoscoped again and biopsy specimens were obtained. Mucosalmalondialdehyde (MDA) levels; myeloperoxidase (MPO)activities; superoxide dismutase; catalase; glutathioneperoxidase; cytokines IL-1, IL-6, TNF-; andchemokines IL-8, GRO-, RANTES (regulated onactivation normal T expressed and secreted) weremeasured. Using paraffin-embedded tissue sections, insitu terminal deoxyribonucleotide transferase (TdT)mediated dUTP nick end labeling (TUNEL) for apoptosisand immunohistochemical staining for inducible nitricoxide synthase (iNOS) were performed. Two weeks oftreatment with the LA regimen resulted in 57.4%eradication rates of H. pylori, whereas two weeks oftreatment with the LAM regimen resulted in 75.0%eradication rates. Eradication rates between these twogroups were statistically significantly different (P< 0.05). Mucosal MDA levels and MPO activities weresignificantly lower in the LAM group than the LA group.Mucosal levels of cytokines IL-1, IL-6, and TNF-and of chemokines IL-8, GRO-, and RANTES were all significantly decreased after the treatmentof H. pylori, especially so in the LAM group. Theapoptotic index and iNOS score were significantlyreduced after the eradication of H. pylori. The addition of an antioxidative drug to the eradicationregimen against H. pylori has advantages either inaugmenting the eradication rates of H. pylori or indecreasing the oxidative stress and cytokines levelsgenerated by H. pylori infection.     

Ammonia and gastric acid secretion: a key to understanding activity and regulation of the H+,K+-ATPase

Ammonia is a cytotoxic substance liberated during Helicobacter pylori infection that may be responsible, in part, for the significant reduction in gastric acid secretion in human patients. However, it is not clear how ammonia blocks acid secretion. Here, we investigate several potential pathways for ammonia blockade in gastric oxyntic cells.___TAGSTART___BR___TAGEND___ Methods: Stomachs from the bullfrog, Rana catesbeiana, were stripped and mounted in Ussing chambers. Four possible pathways of blockade were investigated: (1) blockade of basolateral K⁺-channel activity, (2) blockade of ion transport activity, (3) neutralization of secreted H⁺ or (4) ATP depletion.___TAGSTART___BR___TAGEND___ Results: Addition of nutrient 10 mM NH₄Cl at pH 7.4, yielding 92.5 M NH₃ and 9.91 mM NH₄ ⁺, abolished acid secretion within 30 min. Inhibition of acid secretion did not occur by blockade of basolateral K⁺-channel activity or ion transport activity, nor did NH₄ ⁺ enter cells by substituting for Na⁺ or K⁺ on individual ion transporters. Furthermore, neutralization of the luminal solution by NH₃ and/or ATP depletion cannot account for the total reduction in acid secretion. We demonstrate that NH₄Cl acts specifically on stimulated tissues.___TAGSTART___BR___TAGEND___ Conclusions: We show that small concentrations of ammonia completely block gastric acid secretion. We propose that inhibition of acid secretion occurs by blockade of an apical K⁺-channel, specifically inwardly rectifying K⁺-channels. Our data suggest that apical K⁺-channel activity may be essential for the regulation of acid secretion and could be a new therapeutic target for acid inhibitory drugs.     

Asymptomatic Helicobacter pylori Gastritis Is Associated with Increased Sucrose Permeability

Our aim was to investigate whether there arechanges in permeability to sucrose in asymptomaticHelicobacter pylori gastritis. Nineteen asymptomaticsubjects with Helicobacter pylori associated gastritis with no or mild mucosal atrophy and 19 age- andsex-matched normal controls were studied by peroral loadof sucrose (100 g). The fraction of the given oral doseof sucrose excreted in urine was increased in subjects with Helicobacter pylori gastritis(median 0.08% versus 0.04% in controls). Sucroseexcretion was not related to atrophy, intestinalmetaplasia, or inflammation in the gastric mucosa.However, sucrose permeability was related to the degreeof inflammatory (neutrophil) activity, since moderateactivity was associated with higher sucrose excretionthan mild activity (median 0.13% vs 0.07% ).Asymptomatic Helicobacter pylori gastritis was associatedwith an increased sucrose permeability, which could bea sign of gastric mucosal leakage. This could haveimplications for the diseases and complicationsassociated with Helicobacter pylori infection.     

Potential Relevance of Agmatine as a Virulence Factor of Helicobacter pylori

The polyamine agmatine is able to increasegastric acid secretion. Therefore, we investigatedwhether Helicobacter pylori is able to form and releaseagmatine in vitro and in the human stomach in vivo , and if so, whether a relationship exists amongagmatine concentration in gastric juice, H. pyloriinfection, and gastroduodenal lesions. Agmatine wasdetermined by means of HPLC. In the supernatant of H. pylori cultures, agmatine concentrations up to1500 ng/ml (~12 M) were determined, depending on thenumber of the bacteria in the individual cultures.Agmatine concentration in gastric juice from H. pylori-positive patients was higher than inthat from H. pylori-negative patients. Gastrin in bloodwas elevated in H. pylori-positive patients comparedwith H. pylori-negative patients. Agmatine concentration in gastric juice and serum gastrin levelappeared to be related. In conclusion, H. pylori is ableto form and to release agmatine in vitro and in vivo.This may be assumed to be relevant in vivo, since higher amounts of agmatine are present ingastric juice from H. pylori-positive than from H.pylori-negative patients. Accordingly, agmatine producedby H. pylori may be a virulence factor of this bacterium and may be involved in the pathogenesis ofgastroduodenal lesions.     

Lansoprazole Decreases Peripheral Blood Monocytes and Intercellular Adhesion Molecule-1-Positive Mononuclear Cells

We examined the effects of lansoprazole, aproton-pump inhibitor, on peripheral blood mononuclearcells in healthy subjects in comparison with ranitidine.Ten healthy volunteers were randomly divided into two groups and given either lansoprazole (30 mgdaily for 2 days) or ranitidine (150 mg daily for 21days). Peripheral blood was collected before and 7, 14,and 21 days after the start of treatment. Mononuclear cells were isolated by densitometriccentrifugation and were examined for adhesion molecules(ICAM-1, VLA4, SLe^x), membrane markers of themonocyte/macrophage series, and lymphocyte phenotypes.The number of cells expressing adhesion molecules, thenumber of monocytes/macrophages, and lymphocytephenotypes were the same in Helicobacter pylori-positiveand-negative subjects. The number of cells expressing ICAM-1 was significantly decreased seven daysafter the start of lansoprazole treatment, and thischange persisted until day 14, while ranitidine had noeffect. The number of monocytes (identified by Leu-M3 positivity) was decreased seven days after thestart of treatment in both groups, but predominantly inthe lansoprazole group. No other changes were observedon administration of either drug. These results suggest that short-term treatment withlansoprazole causes persistent inhibition ofinflammatory responses irrespective of the presence ofH. pylori infection. This effect may indicate a possiblenew mechanism of action of proton-pump inhibitors other thaninhibition of acid secretion.     

Mucosal Ulcerogenic Action of Monochloramine in Rat Stomachs (Effects of Polaprezinc and Sucralfate)

Effects of a novel zinc compound polaprezinc[N-(3-aminopropionyl)-L-histidinatozinc] and sucralfateon the mucosal ulcerogenic responses induced bymonochloramine (NH₂Cl) were examined in ratstomachs. Oral administration of NH₂Cl (60mM) produced severe lesions in unanesthetized ratstomachs, with concomitant increase of lipidperoxidation. These lesions were aggravated by sensorydeafferentation but not affected by pretreatment with indomethacinor L-NAME. The mucosal ulcerogenic response toNH₂Cl was significantly inhibited by oralpretreatment with either dmPGE₂ (10g/kg), capsaicin (30 mg/kg), or NOR-3 (3 mg/kg), the NO donor. Gastriclesions induced by NH₂Cl were also inhibitedby prior oral administration of polaprezinc (3-30 mg/kg)as well as sucralfate (30 and 100 mg/kg). The protectiveeffect of polaprezinc was not affected by anypretreatments such as indomethacin, L-NAME, or sensorydeafferentation, while that of sucralfate wassignificantly mitigated in the presence of eitherindomethacin or L-NAME. On the other hand, mucosal exposureto NH₂OH (60 mM) caused a marked PD reductionin ex vivo stomachs made ischemic by bleeding from thecarotid artery, followed by severe gastric lesions.These ulcerogenic and PD responses caused by NH OHplus ischemia were also attenuated by prior applicationof polaprezinc, while dmPGE₂ and sucralfateprevented such lesions without affecting the reduced PDresponse. These results suggest that: (1)NH₂Cl generated either exogenously orendogenously damages the gastric mucosa, (2) bothpolaprezinc and sucralfate protect the stomach againstinjury caused by NH₂Cl, and (3) the mechanisms underlying the protectiveaction of sucralfate may be partly mediated by bothendogenous PGs and NO but may be different from those ofpolaprezinc.