Chronic gastritis – An update

Helicobacter pylori is the main aetiologic factor for chronic gastritis worldwide. The degree of inflammation and the evolution of this form of chronic gastritis can vary largely depending on bacterial virulence factors, host susceptibility factors and environmental conditions. Autoimmune gastritis is another cause of chronic inflammation in the stomach, which can occur in all age groups. This disease presents typically with vitamin B12 deficiency and pernicious anaemia. The presence of anti-parietal cell antibodies is highly specific for the diagnosis. The role of H. pylori as a trigger for autoimmune gastritis remains uncertain.Other rare conditions for chronic gastritis are chronic inflammatory conditions such as Crohn's disease or on the background of lymphocytic or collagenous gastroenteropathies.     

Inflammatory muscle disease – An update

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of inflammatory myopathies whose common feature is immune-mediated muscle injury. There are distinct subgroups including dermatomyositis (DM), polymyositis (PM), inclusion body myositis, and immune-mediated necrotizing myopathy. Antisynthetase syndrome is also emerging as a distinct subgroup with its unique muscle histopathological characteristic of perifascicular necrosis. While the newly updated EULAR/ACR Classification Criteria for IIM have brought advancements in diagnosis and the exclusion of mimickers, the use of only one autoantibody in the derivation of the schema limits its use. Similarly, while the advent of multiple novel therapeutics in the treatment of myositis has been exciting, it has also highlighted the scarcity of validated outcome measures. The purpose of our review is to highlight the updated classification criteria of myositis, newly reported clinical phenotypes associated with myositis autoantibodies, the measurement of outcomes, and emerging treatments in the field.     

Mitochondrial DNA damage and repair during ischemia–reperfusion injury of the heart

Ischemia–reperfusion (IR) injury of the heart generates reactive oxygen species that oxidize macromolecules including mitochondrial DNA (mtDNA). The 8-oxoguanine DNA glycosylase (OGG1) works synergistically with MutY DNA glycosylase (MYH) to maintain mtDNA integrity. Our objective was to study the functional outcome of lacking the repair enzymes OGG1 and MYH after myocardial IR and we hypothesized that OGG1 and MYH are important enzymes to preserve mtDNA and heart function after IR. Ex vivo global ischemia for 30 min followed by 10 min of reperfusion induced mtDNA damage that was removed within 60 min of reperfusion in wild-type mice. After 60 min of reperfusion the ogg1^−/− mice demonstrated increased mtDNA copy number and decreased mtDNA damage removal suggesting that OGG1 is responsible for removal of IR-induced mtDNA damage and copy number regulation. mtDNA damage was not detected in the ogg1^−/−/myh^−/−, inferring that adenine opposite 8-oxoguanine is an abundant mtDNA lesion upon IR. The level and integrity of mtDNA were restored in all genotypes after 35 min of regional ischemia and six week reperfusion with no change in cardiac function. No consistent upregulation of other mitochondrial base excision repair enzymes in any of our knockout models was found. Thus repair of mtDNA oxidative base lesions may not be important for maintenance of cardiac function during IR injury in vivo. This article is part of a Special Issue entitled \"Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease.\"     

Tuberculous liver abscesses and venous thromboembolism – An unusual association

A rare association of tuberculous liver abscesses with bilateral transudative pleural effusion, ascites and venous thromboembolism in a 22-year-male is reported. While the BACTEC culture and polymerase chain reaction of the aspirate from liver abscess were positive for mycobacterium tuberculosis, all the reports of pleural fluid and ascitic fluid were negative. The bilateral pleural effusion and the ascites may be due to a non-tuberculous cause like hypoalbuminaemia. The finding of venous thromboembolism was incidental.     

Mitochondrial DNA gene therapy: a gene therapy for aging?

Mutations in mitochondrial DNA cause a group of diverse diseases that affect an estimated half a million people worldwide. These disorders are remarkably resistant to conventional treatments, and thus several gene therapy approaches are being explored. As some of these approaches develop towards maturity, one can't help thinking that some day they may be used against a much more common health problem currently affecting about 6 billion people- aging, which also has been quite resistant to treatment. Unfortunately, we still do not know whether mtDNA mutations significantly contribute to the aging process or not. The prospect of success in mtDNA gene therapy makes getting the answer a high priority.     

An 8-oxo-guanine repair pathway coordinated by MUTYH glycosylase and DNA polymerase λ

Reactive oxygen species (ROS) interact with DNA, frequently generating highly mutagenic 7,8-dihydro-8-oxoguanine (8-oxo-G) lesions. Replicative DNA polymerases (pols) often misincorporate adenine opposite 8-oxo-G. The subsequent repair mechanism allowing the removal of adenine and formation of C:8-oxo-G base pair is essential to prevent C:G to A:T transversion mutations. Here, we show by immunofluorescence experiments, in cells exposed to ROS, the involvement of MutY glycosylase homologue (MUTYH) and DNA pol λ in the repair of A:8-oxo-G mispairs. We observe specific recruitment of MUTYH, DNA pol λ, proliferating cell nuclear antigen (PCNA), flap endonuclease 1 (FEN1) and DNA ligases I and III from human cell extracts to A:8-oxo-G DNA, but not to undamaged DNA. Using purified human proteins and a DNA template, we reconstitute the full pathway for the faithful repair of A:8-oxo-G mispairs involving MUTYH, DNA pol λ, FEN1, and DNA ligase I. These results reveal a cellular response pathway to ROS, important to sustain genomic stability and modulate carcinogenesis.     

On the “struggle between chemistry and biology during aging” – implications for DNA repair, apoptosis and proteolysis, and a novel route of intervention

The possible effects of specificspontaneous changes in protein chemistry onage-related homeostatic dysfunction arediscussed. Spontaneous racemization andisomerization of aspartic acid and deamidationof asparagine to four possible forms ofaspartic acid in caspases and their substratescould profoundly alter apoptotic activity.Deamidation of asparagine residues atcritically important sites of DNA glycosylasescould compromise base excision repairactivity. Furthermore, as oxidative damage mayenhance asparagine/aspartate instability inproteins, and erroneously-synthesized proteins show increased susceptibility tooxidative attack, it is beginning to appearthat the aberrant protein forms thataccumulate during ageing are possiblyinterrelated. The role of cell growth rates incontrolling constitutive proteolyticelimination of various forms of aberrantpolypeptides is then discussed. Finally, it ispointed out that three recently describedagents that delay senescence in cultured cells(aminoguanidine, N-t-butylhydroxylamine andkinetin) resemble carnosine in that they arealso likely to react with glycoxidisedproteins, as well as possess anti-oxidant activity. These observations suggest thatpluripotency may be a necessary pre-requisitefor effective anti-ageing activity.     

High-density lipoprotein and coronary heart disease – an update

There is increasing evidence for a protective effect of high density lipoprotein (HDL) on the cardiovascular system. Patients with low concentrations have been shown to be at an increased risk of coronary heart disease, and there is evidence that high concentrations confer a degree of protection. But there is uncertainty about when HDL should be measured, its role in the assessment of patients and its relative importance in making decisions about therapy. This review presents recent epidemiological findings and discusses the possible mechanisms of action of HDL. Insights from disease states are presented, and the results of intervention studies are discussed. Recent guidelines for the use of HDL in patient assessment are discussed, together with the options for therapy aiming to increase HDL concentrations. There are studies underway which should provide more information about the effects of current therapy, and perhaps lead to the development of new treatment options, and these are briefly summarised.     

Anemia and digestive diseases： An update for the clinician

Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease （IBD）. However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are： （1） anemia is quite common in IBD; （2） although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; （3） anemia, and also iron deficiency without anemia, have important consequences in the clinical status and quality of life of the patient; （4） oral iron can lead to gastrointestinal intolerance and failure of treatment; （5） intravenous iron is an effective and safe way to treat iron deficiency; （6） erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice.     

Preterm birth in women with inflammatory bowel disease – the association with disease activity and drug treatment

Background: The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) have been associated with an increased risk of preterm birth.

Material and methods: We identified all 246 singleton preterm births among women with IBD between July 2006 and December 2010 as cases and an equal number of controls with IBD from the Swedish national health registers, matched by maternal age, parity and IBD diagnosis (CD/UC). From register data and medical charts, we obtained information on reproductive history, comorbidity, disease activity and drug treatment (corticosteroids, 5-aminosalicylates, sulfasalazine, thiopurines and anti-TNF) as risk factors for preterm birth. Associations were estimated using conditional logistic regression and results were presented as odds ratios (OR) with 95% confidence intervals (CI).

Results: Previous preterm birth was more common among cases, OR 6.13 (95%CI: 2.51–15.01). Significant activity at any time during pregnancy (OR: 2.20; 95%CI: 1.37–3.53), and in particular both in early and in late pregnancy, was more common for cases (OR: 4.78 95%; CI: 2.10–10.9). The OR for immunosuppressive treatment with thiopurines or anti-TNF was 1.88 (1.04–3.39) without significant activity and 12.78 (95%CI: 3.68–44.72) with. The risk for women who discontinued thiopurines was 6.56 (1.44–29.82).

Conclusions: Significant activity and immunosuppressive treatment was associated with preterm birth, particularly in women with both. The existing recommendations to aim at maintaining quiescent disease during pregnancy, even if it means continuing immunosuppressive treatment, are rational.     

Risk factors and chemoprevention in Barrett's esophagus – an update

Abstract

Objective. Barrett's esophagus (BO) is a precursor of esophageal adenocarcinoma (OAC), a cancer with a poor prognosis and an increasing incidence. Hence there is an interest in mapping causal factors underlying BO and finding strategies to reduce the risk of dysplasia progression in patients with BO. Here we review current knowledge on established as well as less risk factors for the development of BO. Additionally, we summarize today's status on the use of chemoprevention aiming to reduce the risk of cancer progression in BO patients. Methods. We searched Medline and the Cochrane Library using the MeSH terms “Barrett's esophagus” and “Barrett esophagus,” both alone and combined with the terms “risk factor,” “aetiology,” “diet,” or “prevention.” Focus was on original contributions, systematic reviews, and meta-analyses. Results. Established risk factors for the development of BO include gastro-esophageal reflux, obesity, male gender, Caucasian ethnicity, and increasing age. Smoking might increase the risk of BO, while aspirin/NSAIDs, Helicobacter pylori infection, and specific “healthy” dietary factors may lower the risk. The potential value of using chemoprevention with proton pump inhibitors, aspirin/NSAIDs, or statins is still uncertain. Conclusions. There is today a substantial knowledge of risk factors of BO. Certain diet may be protective of BO, albeit yet to be proven. The efficiency of chemoprevention in BO is currently addressed further in randomized clinical trials.     

Non-alcoholic fatty liver disease and the metabolic syndrome： An update

Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic in westernized countries, subsequently increasing the risk for developing the metabolic syndrome and nonalcoholic fatty liver disease （NAFLD）. NAFLD is estimated to affect approximate 30% of the general US population and is considered the hepatic manifestation of the metabolic syndrome. Recent findings linking the components of the metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis （NASH） will be reviewed; in particular, the role of visceral adipose tissue, insulin resistance, and adipocytokines in the exacerbation of these conditions. While no therapy has been proven effective for treating NAFLD/NASH, common recommendations will be discussed.     

Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.     

An OTC deficiency ‘phenocopy’ in association with Klinefelter syndrome

Summary  Late-onset urea cycle disorder in a 20-month-old boy is unusually associated with Klinefelter syndrome with a 47XXY karyotype. We record the typical clinical and biochemical findings of ornithine transcarbamylase (OTC) deficiency in a young boy with a short history of recurrent vomiting, self mutilating behaviour, lethargy, ataxia and seizures. Laboratory studies showed hyperammonaemia and orotic aciduria, with normal citrulline and other urea cycle amino acids. Unfortunately, a liver biopsy for OTC activity measurement was refused by the parents. A rapid reversal of phenotype was seen on the introduction of a low-protein diet with accompanying benzoate and phenylbutyrate administration. Linkage studies suggested the inheritance of two X chromosomes, which was confirmed by karyotype analysis. Sequencing of all exons and immediate splice site regions revealed no sequence alterations in these sections of the OTC gene. A search for skewing of X-inactivation in the liver was not possible but we did show a random pattern of X-inactivation in leukocytes. The possibility of maternal X chromosome iso-disomy in our patient was discounted by microsatellite analysis, which revealed the inheritance of two independent X chromosomes. Mutation analysis in the OTC gene has shown that approximately 20% of patients with liver biopsy confirmed OTC deficiency do not have mutations in the coding or immediate splice-site sequences of this gene. Their classification as OTC phenocopies remains speculative, awaiting clarification of the underlying DNA alteration. We report on the novel association of OTC deficiency and Klinefelter syndrome with the additional interest of a probable unusual genetic defect underlying the OTC abnormality. Electronic Supplementary Material  Supplementary material is available for this article at Communicating editor: Verena Peters