Proteorhodopsin Overproduction Enhances the Long-Term Viability of Escherichia coli.

Genes encoding the photoreactive protein proteorhodopsin (PR) have been found in a wide range of marine bacterial species, reflecting the significant contribution that PR makes to energy flux and carbon cycling in ocean ecosystems. PR can also confer advantages to enhance the ability of marine bacteria to survive periods of starvation. Here, we investigate the effect of heterologously produced PR on the viability of Escherichia coli Quantitative mass spectrometry shows that E. coli, exogenously supplied with the retinal cofactor, assembles as many as 187,000 holo-PR molecules per cell, accounting for approximately 47% of the membrane area; even cells with no retinal synthesize ∼148,000 apo-PR molecules per cell. We show that populations of E. coli cells containing PR exhibit significantly extended viability over many weeks, and we use single-cell Raman spectroscopy (SCRS) to detect holo-PR in 9-month-old cells. SCRS shows that such cells, even incubated in the dark and therefore with inactive PR, maintain cellular levels of DNA and RNA and avoid deterioration of the cytoplasmic membrane, a likely basis for extended viability. The substantial proportion of the E. coli membrane required to accommodate high levels of PR likely fosters extensive intermolecular contacts, suggested to physically stabilize the cell membrane and impart a long-term benefit manifested as extended viability in the dark. We propose that marine bacteria could benefit similarly from a high PR content, with a stabilized cell membrane extending survival when those bacteria experience periods of severe nutrient or light limitation in the oceans.IMPORTANCE Proteorhodopsin (PR) is part of a diverse, abundant, and widespread superfamily of photoreactive proteins, the microbial rhodopsins. PR, a light-driven proton pump, enhances the ability of the marine bacterium Vibrio strain AND4 to survive and recover from periods of starvation, and heterologously produced PR extends the viability of nutrient-limited Shewanella oneidensis We show that heterologously produced PR enhances the viability of E. coli cultures over long periods of several weeks and use single-cell Raman spectroscopy (SCRS) to detect PR in 9-month-old cells. We identify a densely packed and consequently stabilized cell membrane as the likely basis for extended viability. Similar considerations are suggested to apply to marine bacteria, for which high PR levels represent a significant investment in scarce metabolic resources. PR-stabilized cell membranes in marine bacteria are proposed to keep a population viable during extended periods of light or nutrient limitation, until conditions improve.

Hipomagnesemia grave secundaria a inhibidores de la bomba de protones, dos casos clínicos / Severe hypomagnesaemia secondary to proton pump inhibitors: a presentation of two cases

Se describen dos casos clínicos de pacientes con hipomagnesemia grave secundaria a inhibidores de la bomba de protones. Los datos de laboratorio nos pueden ayudar a diferenciar entre la hipomagnesemia producida por pérdida intestinal de magnesio y la producida por pérdidas renales de magnesio. La hipomagnesemia asociada al uso prolongado de inhibidores de la bomba de protones es un efecto adverso que suele pasar inadvertido y que puede ocasionar manifestaciones clínicas graves, siendo conveniente realizar controles periódicos de magnesemia en pacientes que precisen de tratamiento prolongado con inhibidores de la bomba de protones, fundamentalmente en el uso concomitante de antiarrítmicos o diuréticos y en aquellos pacientes con hipocalcemia y/o hipopotasemia. La posibilidad de este y de otros efectos adversos es un motivo más para valorar periódicamente el tratamiento con inhibidores de la bomba de protones a largo plazo (AU)

Two clinical cases are presented on patients with severe hypomagnesaemia induced by proton pump inhibitors. Laboratory data can help us to differentiate between hypomagnesaemia caused by intestinal loss of magnesium and the one produced by renal magnesium losses. Hypomagnesaemia associated with a prolonged use of proton pump inhibitors is an inadvertent adverse effect that can lead to severe clinical manifestations, therefore it is advisable to perform periodic monitoring of magnesium in the blood of patients who require prolonged treatment with proton pump inhibitors, especially in the concomitant use of antiarrhythmic or diuretic drugs, and in those patients with hypocalcaemia and/or hypokalaemia. The possibility of this and other adverse effects is one more reason to periodically evaluate long-term proton pump inhibitors treatment (AU)

Riesgo de resultados negativos asociados a inhibidores de la bomba de protones: revisión de las prescripciones electrónicas en pacientes polimedicados / Risk of negative results associated with proton pump inhibitors: review of electronic prescription in polymedicated patients

Introducción: El elevado consumo de inhibidores de la bomba de protones (IBP) puede incrementar la probabilidad de aparición de interacciones clínicamente relevantes. Pacientes mayores, polimedicados y pluripatológicos representan un grupo de alto riesgo. Se espera que la revisión sistemática de las prescripciones electrónicas (PE) permita detectar potenciales interacciones farmacológicas. Material y métodos: Estudio retrospectivo, transversal y observacional: revisión de las PE de IBP dispensadas entre enero y diciembre de 2015 en una farmacia comunitaria rural. Resultados: 1.186 PE, 164 pacientes (edad 65,7±17,2). Mayor número de pacientes en rango de edad 71-80 (n=52). Medicamentos por paciente: 11,0±5,6. PE IBP sin indicación aprobada: 27%. Indicación mayoritaria: protección frente a gastrolesión (77%). 29 pacientes (30%) con riesgo de resultados negativos asociados a la medicación (RNM) por omeprazol, 15 de ellos sin indicación. Patologías concomitantes más prevalentes: hipertensión arterial (n=81), dislipemia (n=61) y diabetes (n=36). Principios activos implicados: acenocumarol, hierro, cianocobalamina, escitalopram, benzodiazepinas y clopidogrel. Discusión: El 80% de las PE de omeprazol corresponde a pacientes entre 61 y 90 años, la mayoría con comorbilidad y polifarmacia, y supera el tiempo de tratamiento recomendado. Relacionamos la cronificación y el aumento del riesgo de RNM con la ausencia de un seguimiento adecuado. Muchos fármacos corresponsables del riesgo tratan los problemas de salud (PS) más prevalentes de nuestra población: la probabilidad de interacción resulta independiente de la correcta indicación del IBP. Conclusiones: La revisión de las PE permite valorar el riesgo de RNM y evaluar la información básica relativa al riesgo de interacción. Se detectaron RNM de no necesidad y de inseguridad en proporciones comparables. Un número elevado de PE de omeprazol tienden a cronificarse. Las interacciones más relevantes registradas ocurren a nivel metabólico (AU)

Introduction: Extensive use of proton pump inhibitors (PPI) can result in an increased risk of drug interactions. Aged polypharmacy patients are a source of particular concern. A systematic electronic prescription (EP) review allows detection of potential drug - drug interactions. Material and methods: Retrospective, transversal, observational study: review of e-prescription orders received during 2015 in our community pharmacy. Results: 1186 EP dispensed to 164 patients (age 65.7±17.2), 52 patients in 71-80 range. 11.0±5.6 medicines per patient. 27% IBP EP with no approved indication. 77% EP used as gastroprotective agent. As far as omeprazole is concerned, risk of negative outcomes associated with medication (NOM) detected in 29 patients (30%), 15 of them taking the drug without approved indication. Most prevalent comorbidities: hypertension (n=81), dyslipidemia (n=61) and diabetes (n=36). Drugs responsible for potential interaction: acenocoumarol, iron, cyanocobalamin, escitalopram, benzodiazepines and clopidogrel. Discussion: 80% of omeprazole EP were dispensed to patients aged 61-90. Coupled with multimorbidity and polypharmacy, the duration of the treatment exceeded directions for use in most of the cases. Chronification and increase of NOM may be due to lack of an appropriate patient follow-up procedure. Many of the drugs responsible for omeprazole interactions were prescribed to treat most prevalent health problems. Thus, risk of NOM does not appear to depend on PPI appropriate indication. Conclusions: EP review let us to assess the risk of suffering from a NOM. Reviewing pharmacokinetic PPI interaction profile allows to depict the basics for a later intervention. During EP review, safety and necessity NOMs were recorded in similar percentages. Most relevant interactions found for omeprazole occur during metabolism of the drugs (AU)

Diagnosing gastro-oesophageal reflux disease or lactose intolerance in babies who cry a lot in the first few months overlooks feeding problems.

This paper explores two areas in which the translation of research into practice may be improved in the management of cry-fuss behaviours in the first few months of life. Firstly, babies who cry excessively are often prescribed proton pump inhibitors, despite evidence that gastro-oesophageal reflux disease is very rarely a cause. The inaccuracy of commonly used explanatory mechanisms, the side-effects of acid-suppressive medications, and the failure to identify treatable problems, including feeding difficulty when the diagnosis of 'reflux' is applied, are discussed. Secondly, crying breastfed babies are still prescribed lactase or lactose-free formula, despite evidence that the problem of functional lactose overload is one of breastfeeding management. The mechanisms and management of functional lactose overload are discussed. These two problems of research translation need to be addressed because failure to identify and manage other causes of cry-fuss problems, including feeding difficulty, may have adverse outcomes for a small but significant minority of families.

Increasing the duration of dual amoxicillin plus omeprazole Helicobacter pylori eradication to 6 weeks: a pilot study.

BACKGROUND AND AIM: Helicobacter pylori infections have become increasingly difficult to treat as antimicrobial resistance has increased. The aim of this study was to test the hypothesis that a 6-week dual regimen of amoxicillin 1 gm and omeprazole 20 gm therapy b.i.d. would cure at least 90% of treatment-naïve H. pylori infections. METHODS: This was an open-label prospective pilot study in which treatment-naïve subjects with active H. pylori infection (positive by two tests) received dual amoxicillin 1 g and omeprazole 20 mg, b.i.d. daily for 6 weeks. Success was accessed by urea breath test 4-6 weeks later. A tentatively effective therapy was defined as a per-protocol treatment success of 90% or greater; treatment success of 80% or less was prespecified as unacceptable. RESULTS: Sixteen patients were included in the study (14 men, two women) with an average age of 49 years. At 16 patients, the prespecified stopping rule of six treatment failures was achieved (i.e. the 95% confidence interval excluded achieving the required 90% success rate even if 50 patients were entered). As per protocol, enrollment was stopped. Per-protocol and intention-to-treat treatment success were both 62.5% (95% confidence interval, 35-84%). Compliance was greater than 99%. Five patients (31%) reported side-effects, all of which were mild and none interrupted therapy. CONCLUSION: Despite the theory and pre-existing data from Japan, in the USA, prolonging the duration of dual amoxicillin-PPI therapy did not improve treatment outcome in 90% or more of our patients.

Inhibidores de la bomba de protones y riesgo de infección / Proton pump inhibitors and infection risk

Los fármacos antisecretores gástricos, y en especial los inhibidores de la bomba de protones, se encuentran entre los fármacos más usados tanto en el medio ambulatorio como en el hospital, y su prescripción no siempre se ajusta a las indicaciones establecidas. Existen datos experimentales que sugieren que la inhibición de la secreción ácida gástrica y los efectos de estos fármacos sobre el sistema inmune pueden favorecer la aparición de infecciones. En los últimos años se han publicado un número de estudios observacionales que encuentran una asociación independiente entre el uso de inhibidores de la bomba de protones y un riesgo aumentado de infecciones gastrointestinales, incluyendo las causadas por Clostridium difficile, y de neumonía comunitaria y nosocomial. En esta revisión se discute la evidencia existente, se plantean los posibles mecanismos patogénicos implicados y se presentan recomendaciones para la investigación futura y la práctica clínica actual(AU)

Gastric antisecretory drugs, especially proton pump inhibitors, are among the most used drugs both in ambulatory and hospital settings, and prescription does not always follows approved indications. Experimental data suggest that gastric acid inhibition and the effects of proton pump inhibitors on the immune system can promote the development of infections. In recent years a number of observational studies have found an independent association between the use of proton pump inhibitors and an increased risk of gastrointestinal infections, including those caused by Clostridium difficile, and community and nosocomial pneumonia. This review discusses the current evidence, raises the potential pathogenic mechanisms involved and makes recommendations for current clinical practice and future research(AU)

Seguridad e interacciones de los IBP / Security and interactions of PPIs

Los IBP han demostrado ser fármacos relativamente seguros después de muchos años de una amplia utilización. Las reacciones adversas con las que más frecuentemente se han asociado son leves y con escasa repercusión clínica. Inducen hipergastrinemia pero esta no se ha relacionado con una capacidad para inducir lesiones malignas Parece que pueden facilitar determinadas infecciones bacterianas a nivel digestivo y del aparato respiratorio, aunque este hecho no limita su prescripción dada la facilidad de su tratamiento. Desde el punto de vista farmacocinético se han descrito la posibilidad de interacciones con otros fármacos a nivel del citocromo P450, pero ello no parece tener mayor trascendencia clínica y terapéutica en general. Sin embargo, recientemente se está incidiendo por las agencias reguladoras en la hipotética interacción de los IBP (sobre todo omeprazol) con el clopidogrel generando una reducción en su efecto antiagregante. Aunque se debe seguir esta recomendación, necesitaria ser evaluado de forma específica para poder determinar su realidad clínica y las posibles alternativas existentes en los pacientes con riesgo de sangrado gastrointestinal. En último lugar se revisa su administración en situaciones especiales, objeto de discusión, como en la mujer embarazada o durante la lactancia materna...

Poliposis gástrica secundaria a tratamiento con inhibidores de la bomba de protones / Gastric polyposis due to treatment with proton pump inhibitors

Los pólipos de glándulas fúndicas pueden aparecer en formas esporádicas o asociados a síndrome de poliposis adenomatosa familiar. Se ha descrito su asociación al tratamiento continuado con inhibidores de la bomba de protones (IBP), así como una regresión tras su retirada. No suelen asociar componente displásico.Se describen 4 casos de pacientes en tratamiento crónico con IBP, con endoscopia previa normal, en los que se detectó la presencia de múltiples pólipos de glándulas fúndicas, y se constató su desaparición a los 6 meses tras la supresión del tratamiento(AU)

Fundic gland polyps can appear sporadically or in association with familial adenomatous polyposis syndrome. An association between fundic gland polyps and prolonged treatment with proton pump inhibitors has been described, as has their regression after withdrawal of these inhibitors. Dysplastic components are not usually associated.We describe four patients who were receiving chronic treatment with proton pump inhibitors. The results of prior endoscopic analysis were normal. The presence of multiple fundic gland polyps was detected as was their disappearance 6 months after treatment cessation(AU)

Proton-pump inhibitor use and the risk for community-acquired pneumonia.

BACKGROUND: Recent studies suggest that proton-pump inhibitors (PPIs) may increase the risk for community-acquired pneumonia (CAP). OBJECTIVE: To examine the association between PPI use and CAP in adults followed in general practices in the United Kingdom. DESIGN: Nested case-control study. SETTING: The General Practice Research Database (1987 to 2002) in the United Kingdom. PARTICIPANTS: Patients age 18 years or older with at least 6 months of initial pneumonia-free follow-up in the database. Case patients (n = 80 066) were defined as those who received an incident diagnosis of CAP. Control participants (n = 799 881) were selected by using incidence density sampling, matching on practice site, calendar period, and follow-up duration. MEASUREMENTS: Use of PPIs within 30 days before the index date. Adjusted odds ratios (ORs) were estimated by using conditional logistic regression, adjusting for potential confounders. RESULTS: Overall, current PPI use was not associated with an increased risk for CAP (adjusted OR, 1.02 [95% CI, 0.97 to 1.08]) or risk for CAP that required hospitalization (adjusted OR, 1.01 [CI, 0.91 to 1.12]). There was a strong increase in risk for CAP associated with current use of PPI therapy that was started within the previous 2 days (adjusted OR, 6.53 [CI, 3.95 to 10.80]), 7 days (adjusted OR, 3.79 [CI, 2.66 to 5.42]), and 14 days (adjusted OR, 3.21 [CI, 2.46 to 4.18]), but there was no statistically significant association for longer-term current PPI therapy. A separate matched case-control analysis, which included the 3 strongest confounders as additional matching factors, yielded similar results as the primary analysis (adjusted OR, 0.96 [CI, 0.91 to 1.02]). LIMITATIONS: Adherence to PPI prescription was assumed to be 100%. No radiographic evidence was available to corroborate a diagnosis of CAP. CONCLUSION: Proton-pump inhibitor therapy started within the past 30 days was associated with an increased risk for CAP, whereas longer-term current use was not.

Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis.

BACKGROUND: Although some cases of collagenous colitis have been induced by lansoprazole (LPZ), the clinicopathologic features of LPZ-associated collagenous colitis have not been elucidated. OBJECTIVE: To elucidate the clinical, endoscopic, and histopathologic features of LPZ-associated collagenous colitis. DESIGN: Retrospective case study. PATIENTS: The subjects were 13 patients with collagenous colitis diagnosed during a period from 2002 to 2007. MAIN OUTCOME MEASUREMENTS: The colonoscopic and histopathologic findings were compared retrospectively between 9 cases of LPZ use (LPZ group) and 4 cases without the use of LPZ (non-LPZ group). RESULTS: A colonoscopy revealed a linear mucosal defect more frequently in the LPZ group (7 of 9 cases [78%]) than in the non-LPZ group (0 of 4 cases [0%], P = .02). Friable mucosa was also noted in 4 patients (44%) in the LPZ group but none in the non-LPZ group. The colonoscopic finding in the non-LPZ group was either normal mucosa or nonspecific minimal abnormalities, whereas patients in the LPZ group had either a linear mucosal defect, mucosal bleeding, or both (P = .001). On histologic examination, the subepithelial collagen band was thicker in patients in the LPZ group than in those in the non-LPZ group (median 45 vs 26.3 mum). All patients in the LPZ group recovered from diarrhea after discontinuance of LPZ. LIMITATION: A small number of patients. CONCLUSIONS: Linear mucosal defects and friable mucosa may be characteristic colonoscopic findings in cases of LPZ-associated collagenous colitis.

Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals.

BACKGROUND: Some studies have shown that short-term use of proton pump inhibitors decreases the absorption of vitamin B12, but the results of studies into long-term proton pump inhibitor use and vitamin B12 deficiency are inconsistent. AIM: To investigate whether long-term proton pump inhibitor use is associated with an abnormal vitamin B12 status in elderly individuals. METHODS: One hundred and twenty-five long-term (>3, years) proton pump inhibitor users aged 65, years and above were recruited from general practices. Their 125 partners (who did not use proton pump inhibitors) served as the reference group. Vitamin B12 status was determined by serum levels of vitamin B12 and homocysteine, and mean corpuscular volume. RESULTS: No differences in mean vitamin B12 levels were observed between the long-term proton pump inhibitor users and their partners [345 (s.d. 126), pm vs. 339 (s.d. 133), pm, P, =, 0.73], even after adjustment for age, gender, Helicobacter pylori status and C-reactive protein levels (P, =, 0.87). Four proton pump inhibitor users and three partners had vitamin B12 levels <150, pm (3% vs. 2%, P, =, 1.00). No differences between the groups were observed in homocysteine levels and mean corpuscular volume. CONCLUSIONS: No association between long-term proton pump inhibitor use and vitamin B12 status was observed. Regular testing for low vitamin B12 levels in elderly patients on long-term treatment with proton pump inhibitors is therefore not recommended.

Systematic review: Proton pump inhibitor-associated acute interstitial nephritis.

BACKGROUND: A number of recent case reports and case series suggest that proton pump inhibitors may cause acute interstitial nephritis. AIM: To establish the nature of the relationship (cause or association) between proton pump inhibitor use and development of interstitial nephritis. DATA COLLECTION: Two researchers independently searched electronic databases (MEDLINE, EMBASE, GOOGLE, LILACS, COCHRANE) for articles from 1970 to 2006, including all study designs, populations and languages. Two independent reviewers assessed study quality and collected the data. SELECTION CRITERIA: absence of baseline renal failure, development of interstitial nephritis after proton pump inhibitor exposure, nephritis confirmed by creatinine plus either renal biopsy or recurrence upon reinitiating proton pump inhibitor. RESULTS: Sixty four cases (60% females, mean age 78 years) of proton pump inhibitor-associated interstitial nephritis were found, 60 included in this review (59 confirmed by renal biopsy, one by recurrence upon reinitiating proton pump inhibitor). The most common symptoms were non-specific. The mean proton pump inhibitor treatment duration before diagnosing nephritis was 13 weeks, average recovery time was 35.5 weeks, one patient required permanent dialysis, there were no deaths. CONCLUSION: Proton pump inhibitor-related interstitial nephritis is rare, idiosyncratic and difficult to predict. It requires a high level of clinical suspicion. While there is not sufficient evidence to establish a causal relationship with certainty, there does appear to be a low-prevalence association.

Adherence to gastroprotection and the risk of NSAID-related upper gastrointestinal ulcers and haemorrhage.

BACKGROUND: Upper gastrointestinal (UGI) complications are a well-recognized risk of NSAID treatment, requiring preventive measures in high-risk patients. Adherence to gastroprotective agents (GPAs) in NSAID users has been suggested to be suboptimal. AIM: To investigate the association between adherence to GPAs (proton pump inhibitors or H(2)-receptor antagonists) and the risk of NSAID-related UGI ulcers or haemorrhage in high-risk patients. METHODS: A population-based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication, identified in the Dutch IPCI database during 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate odds ratios with 95% confidence intervals (95% CI). RESULTS: Fifteen percent of the non-selective NSAID users received GPAs. The risk of a NSAID-related UGI complication among NSAID users increased 16% for every 10% decrease in adherence. Compared to patients with a PDC of >80%, patients with PDCs of 20-80% and <20% had a 2.5-fold (95% CI: 1.0-6.7) respectively 4.0-fold (95% CI: 1.2-13.0) increased risk. CONCLUSION: There is a strong inverse relationship between adherence to GPAs and the risk of UGI complications in high-risk NSAID users.

Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants.

OBJECTIVES: After the withdrawal of some cyclooxygenase-2 (COX-2) selective inhibitors, traditional nonsteroidal anti-inflammatory drug (NSAID) use has increased, but without additional prevention strategies against upper gastrointestinal (GI) complications in many cases. Here, we report the effect of antisecretory drugs and nitrates on the risk of upper GI peptic ulcer bleeding (UGIB) associated with nonselective NSAIDs, aspirin, antiplatelet agents, and anticoagulants. METHODS: This case-control study matched 2,777 consecutive patients with UGIB (confirmed by endoscopy) with 5,532 controls (2:1). Adjusted relative risks (RR) of UGIB are reported. RESULTS: Proton pump inhibitors (PPIs) (RR 0.33, 95% confidence interval [CI] 0.27-0.39), H2-receptor antagonists (H2-RAs) (RR 0.65, 95% CI 0.50-0.85), and nitrates (RR 0.52, 95% CI 0.38-0.70) reduced UGIB risk. PPI use was associated with greater reductions among both traditional NSAID (RR 0.13, 95% CI 0.09-0.19 vs RR 0.30, 95% CI 0.17-0.53 with H2-RAs; RR 0.48, 95% CI 0.19-1.24 with nitrates) and low-dose aspirin users (RR 0.32, 95% CI 0.22-0.51 vs RR 0.40, 95% CI 0.19-0.73 with H2-RA; RR 0.69, 95% CI 0.36-1.04 with nitrates), and among patients taking clopidogrel (RR 0.19, 95% CI 0.07-0.49). For patients taking anticoagulants, use of nitrates, H2-RA, or PPIs was not associated with a significant effect on UGIB risk. CONCLUSION: Antisecretory agent or nitrate treatment is associated with reduced UGIB RR in patients taking NSAID or aspirin. Only PPI therapy was associated with a marked, consistent risk reduction among patients receiving all types of agents (including nonaspirin antiplatelet agents). Protection was not apparent in patients taking anticoagulants.