Prospects for nucleic acid-based therapeutics against hepatitis C virus

In this review,we discuss recent advances in nucleic acid-based therapeutic technologies that target hepatitis C virus(HCV)infection.Because the HCV genome is present exclusively in RNA form during replication,various nucleic acid-based therapeutic approaches targeting the HCV genome,such as ribozymes,aptamers,siRNAs,and antisense oligonucleotides,have been suggested as potential tools against HCV.Nucleic acids are potentially immunogenic and typically require a delivery tool to be utilized as therapeutics.These limitations have hampered the clinical development of nucleic acid-based therapeutics.However,despite these limitations,nucleic acid-based therapeutics has clinical value due to their great specificity,easy and large-scale synthesis with chemical methods,and pharmaceutical flexibility.Moreover,nucleic acid therapeutics are expected to broaden the range of targetable molecules essential for the HCV replication cycle,and therefore they may prove to be more effective than existing therapeutics,such as interferon-αand ribavirin combination therapy.This review focuses on the current status and future prospects of ribozymes,aptamers,siRNAs,and antisense oligonucleotides as therapeutic reagents against HCV.     

Functional gastrointestinal disorders and gut-brain axis: What does the future hold?

Despite their high prevalence, lack of understanding of the exact pathophysiology of the functional gastrointestinal disorders has restricted us to symptomatic diagnostic tools and therapies. Complex mechanisms underlying the disturbances in the bidirectional communication between the gastrointestinal tract and the brain have a vital role in the pathogenesis and are key to our understanding of the disease phenomenon. Although we have come a long way in our understanding of these complex disorders with the help of studies on animals especially rodents, there need to be more studies in humans, especially to identify the therapeutic targets. This review study looks at the anatomical features of the gut-brain axis in order to discuss the different factors and underlying molecular mechanisms that may have a role in the pathogenesis of functional gastrointestinal disorders. These molecules and their receptors can be targeted in future for further studies and possible therapeutic interventions. The article also discusses the potential role of artificial intelligence and machine learning and its possible role in our understanding of these scientifically challenging disorders.     

Non-invasive detection of vulnerable coronary plaque

Critical coronary stenosis have been shown to contribute to only a minority of acute coronary syndromes and sudden cardiac death.Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis.Consequently,a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease.Recent advances in invasive and non-invasive imaging techniques have shown the potential to identify these high-risk plaques.Non-invasive imaging with magnetic resonance imaging,computed tomography and positron emission tomography holds the potential to differentiate between low-and highrisk plaques.There have been significant technological advances in non-invasive imaging modalities,and the aim is to achieve a diagnostic sensitivity for these technologies similar to that of the invasive modalities.Molecular imaging with the use of novel targeted nanoparticles may help in detecting high-risk plaques that will ultimately cause acute myocardial infarction.Moreover,nanoparticle-based imaging may even provide non-invasive treatments for these plaques.However,at present none of these imaging modalities are able to detect vulnerable plaque nor have they been shown to definitively predict outcome.Further trials are needed to provide more information regarding the natural history of high-risk but non-flow-limiting plaque to establish patient specific targeted therapy and to refine plaque stabilizing strategies in the future.     

New techniques in the tissue diagnosis of gastrointestinal neuromuscular diseases

Gastrointestinal neuromuscular diseases are a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular （including interstitial cell of Cajal） dysfunction. Common to most of these diseases are symptoms of impaired motor activity which manifest as slowed or obstructed transit with or without evidence of transient or persistent radiological visceral dilatation. A variety of histopathological techniques and allied investigations are being increasingly applied to tissue biopsies from such patients. This review outlines some of the more recent advances in this field, particularly in the most contentious area of small bowel disease manifesting as intestinal pseudo-obstruction.     

New therapeutic opportunities for hepatitis C based on small RNA

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy.     

Contribution of genetics to a new vision in the understanding of inflammatory bowel disease

Inflammatory bowel diseases (IBD), such as Crohn' s disease (CD) and ulcerative colitis (UC), are chronic inflammatory autoimmune conditions of the gastrointestinal tract. Other organs, such as the eyes, skin and articulations, are often affected and IBD may be accompanied by other diseases of autoimmune origin. There is no single etiological factor responsible for the onset of IBD. Recent advances in genetics and in the molecular mechanisms of the proteins coded by these genes have given rise to a new vision in understanding these complex diseases. Activation of specific genes that affect antigen presentation and the handling of cells by innate immunity may lead to autoimmunity with the consequent activation of the major histocompatibility complex (MHC) and multiple cytokines involved in the regulation of acquired immunity. In this review IBD is described as a constellation of diseases that can best be classified as barrier diseases. This vision, developed by Kiel in Germany, includes the idea that changes in our environment due to the westernization of civilization have not been met with adaptation of the innate immune system, and this has given rise to autoimmune diseases. These diseases affect 1-5 of 1000 individuals and represent a major burden on the national health systems of many countries on different continents. On a world scale, a major challenge is to generate interventions to prevent the development of these diseases in Asia, Latin America and Africa.     

Appendectomy and Clostridium difficile colitis: Relationships revealed by clinical observations and immunology

Advances in understanding the interaction between the human immune system and the microbiome have led to an improved understanding of the function of the vermiform appendix as a safe-house for beneficial bacteria in the colon.These advances have been made despite long standing clinical observations that the appendectomy is a safe and effective procedure.However,more recent clinical data show that an appendectomy puts patients at increased risk for recurrent Clostridium difficile(C.difficile)-associated colitis,and probably other diseases associated with an altered microbiome.At the same time,appendectomy does not apparently put patients at risk for an initial onset of C.difficile-associated colitis.These clinical observations point toward the idea that the vermiform appendix might not effectively protect the microbiome in the face of broad spectrum antibiotics,the use of which precedes the initial onset of C.difficile-associated colitis.Further,these observations point to the idea that historically important threats to the microbiome such as infectious gastrointestinal pathogens have been supplanted by other threats,particularly the use of broad spectrum antibiotics.     

Update and actual trends on bacterial infections following liver transplantation

Recent advances in effective antimicrobial prophylactic strategies have led to a decline in the incidence of opportunistic infections in liver transplant recipients. However, morbidity and mortality due to infectious diseases remain as major problems. Bacterial infections occurring early after transplant are mainly related to the technical aspects of the procedure. By contrast, after the first postoperative days and beyond, the nature and variety of infectious complications change. Opportunistic bacterial infections are uncommon after 6 mo in patients receiving stable and reduced maintenance doses of immunosuppression with good graft function and little is documented about these cases in the literature. Transplant recipients may be more susceptible to some pathogens, such as the Nocardia species, Legionella species, Listeria monocytogenes , Mycoplasma species, Salmonella species or Rhodococcus equi. Respiratory infections due to capsulated bacteria, such as Streptococcus pneumoniae and Haemophilus intTuenza, can be life- threatening if not promptly treated in this population. These late bacterial infections may be very difficult to recognize and treat in this population. In this article, we review what has been described in the literature with regards to late bacterial infections following liver transplantation.     

Imaging biomarkers for the treatment of esophageal cancer

Esophageal cancer is known as one of the malignant cancers with poor prognosis.To improve the outcome,combined multimodality treatment is attempted.On the other hand,advances in genomics and other“omic”technologies are paving way to the patient-oriented treatment called“personalized”or“precision”medicine.Recent advancements of imaging techniques such as functional imaging make it possible to use imaging features as biomarker for diagnosis,treatment response,and prognosis in cancer treatment.In this review,we will discuss how we can use imaging derived tumor features as biomarker for the treatment of esophageal cancer.     

Esophageal squamous cell carcinoma - precursor lesions and early diagnosis

Squamous cell carcinoma of the esophagus (SCCE) carries a poor prognosis due to late diagnosis.Early detection is highly desirable,since surgical and endoscopic resection offers the only possible cure for esophageal cancer.Population screening should be undertaken in high risk areas,and in low or moderate risk areas for people with risk factors (alcoholics,smokers,mate drinkers,history of head and neck cancer,achalasia and lye stricture of the esophagus).Esophageal balloon cytology is an easy and inexpensive sampling technique,but the current methods are insufficient for primary screening due to sampling errors.Conventional endoscopy with biopsy remains the standard procedure for the identification of pre-malignant and early malignant changes in esophageal mucosa and endoscopic detection.It may be enhanced by several techniques such as dye and optic chromoendoscopy,magnifying endoscopy,and optical-based spectroscopic and imaging modalities.Since more than 80% of SCCE deaths occur in developing countries,where expensive techniques such as narrow band imaging (NBI) and autofluorescence imaging are unavailable,the most cost-effective tool for targeting biopsies may be Lugol dye chromoendoscopy,since it is easy,accurate,inexpensive and available worldwide.In ideal conditions,or in developed countries,is it reasonable to think that optimal detection will require a combination of techniques,such as the combination of Lugol’s chromoendoscopy and NBI to identify esophageal areas that require further characterization by a high resolution technique.The efficacy and cost-effectiveness will determine whether these modalities will become part of standard endoscopy practice.     

New technologies for the evaluation of esophageal motility disorders: impedance, high-resolution manometry, and intraluminal ultrasound

New technologies have been introduced for studying esophageal function, including intraluminal impedance and ultrasound, whereas conventional techniques, such as manometry, have undergone substantial upgrades because of advances in transducer technology, computerization, and graphic data presentation. Although these techniques provide both novel and more detailed information regarding esophageal function, it is still unclear whether they have improved the ability to diagnose and treat patients more effectively. Regardless, they are innovative research tools and they have added substantially to the understanding of the pathophysiology of dysphagia and esophageal motor dysfunction. This article describes the technical aspects of each of these technologies and the potential benefits they offer over conventional techniques for the evaluation of esophageal motor diseases.     

Evaluation of esophageal motor disorders in the era of high-resolution manometry and intraluminal impedance

The past few years were an exciting time in the study of esophageal motor disorders because new technologies emerged to study esophageal motor function and bolus transit. Although conventional manometry was long considered the “gold standard” for defining esophageal motor disorders, many technologic improvements occurred due to advances in transducer technology, computerization, and graphic data presentation. In addition, a relatively new technology, intraluminal impedance, was incorporated into manometric modalities. The most sophisticated systems now include combined high-resolution manometry with high-resolution impedance. Although these techniques provide more detailed information about esophageal function, whether they improve our ability to diagnose and treat patients more effectively is debatable. However, more recent data support that these advances actually improve our ability to diagnose and treat esophageal motor disorders. This article provides an update on these technologies in clinical practice and how they may be helpful in the future.     

Current and future techniques in the evaluation of dysphagia

Dysphagia is common in the general population, and is generally due to either mechanical obstruction or dysmotility. Patient demographics and symptom evaluation are often useful in determining the likely cause, and guide subsequent investigation and management. Oropharyngeal dysphagia is usually caused by neurological conditions where treatment options are limited. Conversely, many of the esophageal causes of dysphagia are amenable to therapy. Gastroscopy is often the first test of choice, given its diagnostic and therapeutic potential, especially when mechanical causes are concerned. Esophageal motor function can be assessed by a variety of techniques, ranging from radiology such as barium swallow, to dedicated motility tests such as manometry and impedance monitoring. The choice of test relies on the clinical indication and the results should be interpreted in conjunction with the patients' symptoms. High-resolution manometry with topography is now the new benchmark for motility studies. Several new techniques for motility testing have also become available, such as esophageal ultrasound and functional lumen imaging probe, but are currently limited to the research setting.     

Utility of Esophageal High-Resolution Manometry in Clinical Practice: First,Do HRM

Esophageal high-resolution manometry (HRM) has advanced the understanding of esophageal motor function and the ability to diagnose and manage disorders of esophageal motility. In this review, we describe the indications for and the technical performance of HRM. The Chicago classification of esophageal motor function, now in its third iteration, streamlines and standardizes the nomenclature and basic interpretation of HRM data depicted as Clouse topographic plots. In clinical practice, HRM is an important diagnostic test for patients with dysphagia as well as patients with suspected gastroesophageal reflux disease (GERD), particularly in those patients with a suboptimal symptomatic response to antisecretory therapy. HRM can support diagnoses such as achalasia, as well as provide evidence for behavioral disorders such as rumination syndrome or supragastric belching with the assistance of postprandial HRM with impedance. Further, the GERD classification of motor function introduces a three-part hierarchical evaluation of esophageal motor function in GERD, highlighting the value of assessment of esophageal contractile reserve through provocative maneuvers during HRM such as multiple rapid swallows.     

Esophageal testing: What we have so far

Gastroesophageal reflux disease(GERD) is a common disorder of the gastrointestinal tract. In the last few decades, new technologies have evolved and have been applied to the functional study of the esophagus, allowing for the improvement of our knowledge of the pathophysiology of GERD. High-resolution manometry(HRM) permits greater understanding of the function of the esophagogastric junction and the risks associated with hiatal hernia. Moreover, HRM has been found to be more reproducible and sensitive than conventional water-perfused manometry to detect the presence of transient lower esophageal sphincter relaxation. Esophageal 24-h p H-metry with or without combined impedance is usually performed in patients with negative endoscopy and reflux symptoms who have a poor response to anti-reflux medical therapy to assess esophageal acid exposure and symptom-reflux correlations. In particular, esophageal 24-h impedance and p H monitoring can detect acid and non-acid reflux events. Endo FLIP is a recent technique poorly applied in clinical practice, although it provides a large amount of information about the esophagogastric junction. In the coming years, laryngopharyngeal symptoms could be evaluated with up and coming non-invasive or minimally invasive techniques, such as pepsin detection in saliva or pharyngeal p H-metry. Future studies are required of these techniques to evaluate their diagnostic accuracy and usefulness, although the available data are promising.     

Physiopathologic approach in esophageal motor disorders: from the diagnosis to therapeutic implications

Motor disorders are an important chapter in esophageal pathology; from a clinical point of view, these disorders are characterised by dysphagia, non-cardiac chest pain, pyrosis and regurgitation. It is important to underline that chest pain and dysphagia are not specific to motility disorders; in fact, they are also present in other pathologies like peptic or infective esophagitis. In order to attribute these symptoms to a functional cause, it is first of all is necessary to exclude an organic pathology; this can be done with the help of radiological and endoscopical examination when the symptoms are dysphagia, pyrosis and regurgitation, or with electrocardiography or angiography, when the symptom is chest pain. The functional pathology is marines studied by manometric and pH-metric techniques. The manometric technique represents an important instrument for diagnosing esophageal motor disease. The aim of this study, after a review of the literature, is to describe the principal esophageal motor disorders and the physiopathological approach, that have important implications in diagnosis and therapy.     

Endoscopic dilation for treatment of esophageal motility disorders

Esophageal dilation is an important therapeutic strategy in patients with esophageal motility disorders. Patients with achalasia have for many years benefited from pneumatic dilation as a definitive form of therapy, which is superior to botulinum toxin injection and equivalent in efficacy to surgical myotomy. Optimal performance of pneumatic dilation ensures maximum efficacy and reduced complication of perforation. Esophageal dilation also plays a crucial role in esophagogastric junction outflow obstruction due to strictures or prior surgical interventions as well as in esophageal hypercontractile states such as spastic disorders or in those with nonobstructive dysphagia. In this section, we will review the clinical evidence of esophageal dilation in achalasia, esophagogastric junction outflow obstruction, esophageal spastic disorders and in patients with dysphagia and nonobstructive dysphagia. We will outline specific techniques currently recommended and employed in esophageal dilations for these disorders and provide relative efficacy to other forms of therapy.     

Esophageal motor dysfunction years after radiation therapy

Well-known complications of radiation to the esophagus are acute esophagitis and strictures. Although radiologic studies have demonstrated motor abnormalities after radiation treatment, clinical aspects have not been described adequately, nor have manometric evaluations been reported. Clinical presentation of dysphagia long after treatment also has not been reported.We describe herein three patients who presented with dysphagia years after radiation therapy. Radiographic, endoscopic, histologic, and manometric studies supported our conclusion that these patients suffered from radiation-induced esophageal motor dysfunction.This report indicates the need, in the proper setting, to consider radiation-induced motor dysfunction as a cause of dysphagia even decades after radiation treatment.     

Swallowing and Esophageal Function in Parkinson's Disease

Dysphagia and drooling of saliva are frequent symptoms in Parkinson's disease (PD), occurring in one-half and three-quarters of all patients, respectively. Aspiration related to swallowing is a major cause of morbidity and mortality in PD. Defects in oral, pharyngeal, and esophageal phases of swallowing have been documented in patients with PD, and these defects precede symptoms. This paper reviews the current knowledge concerning swallowing abnormalities in PD.
The pathogenesis of dysphagia and drooling of saliva is multifactorial, involving cognitive and psychological changes in addition to abnormalities of the extra-pyramidal and autonomic nervous systems. Videofluoro-scopic imaging of the upper esophageal sphincter and pharynx during mastication and swallowing has been the basis of our understanding of the mechanical malfunction present in patients with PD. Manometric abnormalities of the esophageal body and lower esophageal sphincter have also been documented. The use of combined manofluoroscopy to examine the upper esophageal sphincter and pharynx in PD offers great promise both in understanding the defects and directing therapy. Voluntary airway protection techniques may reduce aspiration, but they need to be tested in a clinical study. Such maneuvers may reduce the morbidity seen in PD.     

Premature Lower Esophageal Sphincter Closure as a Cause of Dysphagia

Impaired lower esophageal sphincter (LES) relaxation is highly correlated with dysphagia. A variation of the impaired relaxation of the LES of achalasia has been described, characterized by premature closure after normal relaxation. With a microtransducer system, standard manometric testing followed by food ingestion identified 33 patients (12 male, 21 female, 18–79 yr old) who exhibited premature LES closure. Twenty-three (70%) of these patients had a presenting complaint of dysphagia. Of these, seven (30%) experienced dysphagia during food ingestion. Manometry documented a concurrent motor abnormality in the esophageal body in 28 (85%) patients. Of the five remaining patients who did not have a concurrent motor abnormality, all had a presenting complaint of dysphagia, and three (60%) experienced dysphagia during food ingestion. The incidence of dysphagia during testing reported by patients with premature LES closure is comparable to that reported by patients with achalasia (45%) or diffuse esophageal spasm (38%) who have been studied during food ingestion in our laboratory.