Andrea Ottonello

The appropriate use of proton pump inhibitors (PPIs): Need for a reappraisal

The advent of powerful acid-suppressive drugs, such as proton pump inhibitors (PPIs), has revolutionized the management of acid-related diseases and has minimized the role of surgery. The major and universally recognized indications for their use are represented by treatment of gastro-esophageal reflux disease, eradication of Helicobacter pylori infection in combination with antibiotics, therapy of H. pylori-negative peptic ulcers, healing and prophylaxis of non-steroidal anti-inflammatory drug-associated gastric ulcers and control of several acid hypersecretory conditions. However, in the last decade, we have witnessed an almost continuous growth of their use and this phenomenon cannot be only explained by the simple substitution of the previous H2-receptor antagonists, but also by an inappropriate prescription of these drugs. This endless increase of PPI utilization has created an important problem for many regulatory authorities in terms of increased costs and greater potential risk of adverse events. The main reasons for this overuse of PPIs are the prevention of gastro-duodenal ulcers in low-risk patients or the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anticoagulant treatment without risk factors for gastro-duodenal injury, the overtreatment of functional dyspepsia and a wrong diagnosis of acid-related disorder. The cost for this inappropriate use of PPIs has become alarming and requires to be controlled. We believe that gastroenterologists together with the scientific societies and the regulatory authorities should plan educational initiatives to guide both primary care physicians and specialists to the correct use of PPIs in their daily clinical practice, according to the worldwide published guidelines.

The natural history of gastro-esophageal reflux disease: a comprehensive review.

Gastroesophageal reflux disease (GERD) is a common disorder of the upper gastrointestinal tract which is typically characterized by heartburn and acid regurgitation. These symptoms are widespread in the community and range from 2.5% to more than 25%. Economic analyses showed an increase in direct and indirect costs related to the diagnosis, treatment and surveillance of GERD and its complications. The aim of this review is to provide current information regarding the natural history of GERD, taking into account the evolution of its definition and the worldwide gradual change of its epidemiology. Present knowledge shows that there are two main forms of GERD, that is erosive reflux disease (ERD) and non-erosive reflux disease (NERD) and the latter comprises the majority of patients (up to 70%). The major complication of GERD is the development of Barrett esophagus, which is considered as a pre-cancerous lesion. Although data from medical literature on the natural history of this disease are limited and mainly retrospective, they seem to indicate that both NERD and mild esophagitis tend to remain as such with time and the progression from NERD to ERD, from mild to severe ERD and from ERD to Barretts esophagus may occur in a small proportion of patients, ranging from 0 to 30%, 10 to 22% and 1 to 13% of cases, respectively. It is necessary to stress that these data are strongly influenced by the use of powerful antisecretory drugs (PPIs). Further studies are needed to better elucidate this matter and overcome the present limitations represented by the lack of large prospective longitudinal investigations, absence of homogeneous definitions of the various forms of GERD, influence of different treatments, clear exclusion of patients with functional disorders of the esophagus.

In vitro modulation of gamma amino butyric acid (GABA) receptor expression by bone marrow stromal cells.

Bone marrow stromal cells (BMSC) have the capability to undergo a change of morphology, reminiscent of neuronal cells, after exposure to an inductive medium. These induced BMSC-derived neuron-like (BDNL) cells express several neuronal markers, including Microtubule-Associated Protein Tau, Neurofilament M, and Nestin as revealed by immunocytochemistry analysis. To assess whether the induction process has possible functional relevance, we have focused our attention on the expression of neurotransmitter receptors. In particular, we show that the expression of GABA(A) subunits alpha1, beta2/3, epsilon and GABA(B1) mRNAs is greatly enhanced in BMSC by the induction treatment. Similar results were obtained from rat skin fibroblasts subjected to the same induction protocol, with the exception for the GABA(B2) transcript that was expressed only by BMSC and BDNL. The presence of both GABA(B1) and GABA(B2) subunits in BDNL cells suggests that functional GABA(B) receptors might be assembled: we indeed found that a functional GABA(B) receptor, negatively linked to cyclic AMP production, is expressed in BDNL. Therefore, we suggest that BMSC can be converted into cells equipped with appropriate receptors coupled to transduction mechanisms, potentially responding to a specific neurotransmitter.

Ilaprazole for the treatment of gastro-esophageal reflux.

ABSTRACT Introduction: Despite the undoubted benefit of proton pump inhibitors (PPIs), they have several shortcomings, such as a slow onset of action and a remarkable inter-individual variability, that limit the complete success of these drugs. Recently, a new PPI, ilaprazole, has been developed and used in GERD patients. Areas covered: The present review provides an update on the following points: current knowledge of GERD mechanisms; limitations of actual therapies; pharmacokinetic profile and metabolism of ilaprazole; initial studies on the therapeutic efficacy of ilaprazole in GERD. Expert opinion: Compared with all other approved PPIs, ilaprazole has shown an extended plasma half-life, a metabolism not significantly influenced by CYP2C19 genetic polymorphism and similar safety. This characteristics account for a low inter-individual variability, particularly in Asian populations, a higher suppression of gastric acid secretion, a more rapid acid control and consequent quicker symptom relief and a better effect on nocturnal acidity. However, clinical investigations assessing the efficacy of ilaprazole in the management of GERD are lacking and therefore the potential improvements achievable with ilaprazole in the current standard of care for acid-suppressing treatment must be confirmed in large and randomly controlled clinical trials enrolling patients with both erosive and non-erosive reflux disease.

Novel insights into esophageal diagnostic procedures

The 21st century offers new advances in diagnostic procedures and protocols in the management of esophageal diseases. This review highlights the most recent advances in esophageal diagnostic technologies, including clinical applications of novel endoscopic devices, such as ultrathin endoscopy and confocal laser endomicroscopy for diagnosis and management of Barretts esophagus; novel parameters and protocols in high‐resolution esophageal manometry for the identification and better classification of motility abnormalities; innovative connections between esophageal motility disorder diagnosis and detection of gastroesophageal reflux disease (GERD); impedance–pH testing for detecting the various GERD phenotypes; performance of distensibility testing for better pathophysiological knowledge of the esophagus and other gastrointestinal abnormalities; and a modern view of positron emission tomography scanning in metastatic disease detection in the era of accountability as a model for examining other new technologies. We now have better tools than ever for the detection of esophageal diseases and disorders, and emerging data are helping to define how well these tools change management and provide value to clinicians. This review features novel insights from multidisciplinary perspectives, including both surgical and medical perspectives, into these new tools, and it offers guidance on the use of novel technologies in clinical practice and future directions for research.

It is Time to Re-Think the Role of Small Intestinal Bacterial Overgrowth in IBS Patients

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Neurofibromas of the Oral Cavity: Clinical Aspects, Treatment, and Outcome

OBJECTIVE This study aimed to evaluate the efficacy of diode laser for the surgical treatment of neurofibromas (NF), in terms of clinical outcome and therapeutic success. BACKGROUND DATA The NF is a benign tumor of the peripheral nerve sheath, characterized by the proliferation of Schwann cells, perineural cells, and endoneural fibroblasts. NF may occur as a solitary lesion, or as part of a generalized neurofibromatosis syndrome; much more rarely it occurs in the form of multiple neurofibromas with no associated syndrome. Two distinct variants of neurofibromatosis have been described: types I and II. METHODS Ten cases are reported (6 women and 4 men, age range 43-70 years) with smooth, painful, or painless lesions of the oral mucosa. Lesions were completely excised using a diode laser at 980 nm wavelength, average power 2.0 W, in continuous wave mode, with 320 μm optical fibers, for 45 sec average time. RESULTS Complete healing occurred within 20 days. There were no adverse effects; patients were carefully followed up and there have been no recurrences after an interval of 3 months to 3 years. CONCLUSIONS The results of this diode laser treatment of NF demonstrate good effectiveness of this novel therapy, which may replace conventional surgical procedures.

Advanced 3D Models Cultured to Investigate Mesenchymal Stromal Cells of the Human Dental Follicle

The human dental follicle (hDF) contains the developing tooth and is involved in regulating tooth maturation and eruption. To investigate the mesenchymal stromal cells of the dental follicle, 2 three-dimensional (3D) culture models were used, based on a dynamic bioreactor: the Rotary Cell Culture System (RCCS™) and the 3D culture of precursor cells isolated from follicular tissue (human dental follicle cells [hDFCs]). The hDFCs were obtained from impacted third molars of 20 patients. Two 3D culture models were tested. In the first model, intact hDF explants were cultured in 3D conditions, preserving the original tissue architecture; they were studied using histomorphological and molecular analyses. The second model involved the 3D culture of hDFCs, which were characterized to evaluate their multipotency in terms of differentiation capability. Of the biomarkers known to characterize hDFCs, hDF precursors were selected for our study. The immunophenotype and in situ immunocytochemistry were evaluated for mar...

Alveolar ridge expansion by implants with osteodistractive function: A clinical report

The edentulous areas of the jaws, especially suffering from bone atrophy, still represent a prosthetic challenge for dental implants placement. For this reason, distraction osteogenesis is gaining more ground in dentistry, particularly in dental implants treatment, offering the possibility to restore and rehabilitate edentulous ridges with insufficient dimensions. The aim of the present report is to introduce the employment of dental implants with horizontal osteodistractive function to restore the dimensions of resorbed alveolar ridges without resorting to osteotomies or bone distractors. With such technique, a total of 25 patients have been treated, with edentulous premolar and/or molar regions receiving a total of 67 implants. Results and controls at 3, 6, 12 and 24 months are encouraging and show optimum implants osteointegration. The horizontal expansion technique that employs the same implants as a tool for distraction osteogenesis helps obtaining horizontal alveolar ridge expansion with a single surgical appointment which reduces significantly the risk of fracture and fenestration. Correspondence to: Andrea Ottonello, Department of Integrated Diagnostic and Surgical Sciences, Università degli studi di Genova, L.go Rosanna Benzi 8, 16132 Genova, Italia,Tel: +393384793547, +390103537433, Fax: +39010532524, E-mail: andrea.ottonello@unige.it Received: November 10, 2016; Accepted: November 23, 2016; Published: November 26, 2016 Introduction Osteointegrated implants are considered to date a solid prosthetic replacement for missing teeth, now with a history of decades of predictability [1,2]. It has been demonstrated that the functional load of the implants reduces bone resorption [3]. On the other hand, there are minimum dimensional requirements for horizontal width and vertical height of the alveolar ridge necessary for placement of a successful dental implant [4,5]. In this latter regard, a protocol for a surgical technique that guarantees a reliable and optimal rehabilitation by dental implants prosthetics is yet to be developed. Despite the continual optimization of the implant materials [6], their surface characteristics and the prosthetics they receive, challenges such as technical, functional and esthetic limitations still exist [7-10]. Consistent progress has been reported in the literature regarding the pre-implantation surgical techniques, often necessary, and regarding attempts to improve the initial anatomy of the edentulous ridge, usually suffering from atrophy and inadequacy to receive a dental implant [11]. The evolution of surgical techniques and the development of osteotomy prophylometric implant morphology have extended the indications of dental implants employment even in cases that were completely contraindicated from implants therapy in the past or the ones that were subject to several guided bone regeneration (GBR) procedures before implants placement [12]. In fact, it has been confirmed that the implants should be inserted according to a precise prosthetic stent even in the absence of adequate bone support or with sub-ideal 3D skeletal relationships. This modern approach by prosthetic dental implants assumes not only the necessity of having adequate bone width obtained by distraction, reconstruction or regeneration techniques but also to surgically adjust the undesirable bone morphologic changes related to resorption following the loss of teeth [13,14]. Accordingly, it is now feasible for a dental implant team to plan and implement adequate ridge volume and morphology for optimum implant insertion [15]. Coined since decades, distraction osteogenesis is a technique that targets the entire or partial elongation of a bone segment via surgical separation while leaving intact all associated soft tissue [16]. Such technique has found wide application in maxillofacial surgery and dental implants to restore edentulous alveolar ridges of inadequate horizontal and vertical dimensions [17-20]. The aim of this report is hence to introduce the employment of dental implants with horizontal osteodistractive function to restore the dimensions of resorbed edentulous alveolar ridges. Materials and methods 25 patients aged between 46 and 71 years (mean age 57.4) 14 females and 11 males participated in our study; each one had previously signed an informed consent. We have excluded from the study patients who had denied consent, patients with poor oral hygiene having full mouth Plaque Score (FMPS) ≥ 20% before surgery, patients with compromised periodontium or local soft tissue infections, patients with psychiatric illnesses and pregnant women. All patients were edentulous in their premolar and/or molars regions with ridge width between 3 and 5 mm in at least one of the designated sites for implant placement (Figure 1). All cases received a total of 67 implants with bone distraction function in the coronal area of the alveolar ridge without crestal opening or any kind of osteotomies (Figure 2). When necessary, in cases with ridge width less than 3 mm on the vestibular cortex (9 out of 25), bone augmentation took place by OsteoBiol Putty® bone grafting material (Figure 3). In every patient the alveolar crest has been exposed by a horizontal full thickness crestal incision. An initial osteotomy of diameter 1.2 mm Maltagliati A (2016) Alveolar ridge expansion by implants with osteodistractive function: A clinical report Volume 2(6) Dent Oral Craniofac Res, 2016 doi: 10.15761/DOCR.1000184 was drilled and enlarged to 2.0 mm then to 2.5-3.0 mm to receive the dental implant. We put implants Tekka In-Kone® Universal switch platform of 10 and 11.5 mm, characterized by a 2.5 mm collar and a conical spiral with cylindrical profile and a self-tapping apex. Therefore, ridge extension has been performed without osteotomy or bone distraction. All implants have been inserted with a protocol consisting of 3-step osteotomy drilling without using neck drills and screwed intermittently every 5 turns to recuperate the elastic memory of the cortical bone. The implants have been inserted at 1.5/2.5 mm beyond the alveolar crest. Before closing by full-thickness suture with horizontal mattress technique, we proceeded with full flap passivation, in order to guarantee the best graft vascularization. Then all incisions have been closed and the actual functional implant load took place 3 months post-operative – 4 months in cases treated with regeneration (Figures 4 and 5). All cases have been monitored and checked up at 3, 6, 12 and 24 months. Results All implants have been osteointegrated at the last check at 2 months, as confirmed by probing and radiographs. We report a selected case of a 62 y.o. female patient, treated in the edentulous area 4.4-4.5-4.6 (Figure 6), to which all pictures are referred. The use of dental implants with such technique guarantees the ridge expansion without additional osteotomies or distractors: the implant itself is the necessary and sufficient tool to obtain the sought bone distraction by a series of simple steps highly predictable and repeatable. The gradual helices in the implants allow the operator to reduce the time between surgeries and after the final surgery waiting for the eventual complete regeneration of the implants sites. The switch platform protocol allows the insertion below the bone crest even more that 2 mm with the necessity of some bone recontouring which is regarded as a natural protective mode for the neck of the implant especially since when it is not preceded with the insertion of transmucosal collar. Figure 1. Bone crest exposure after full-thickness flap elevation. Figure 2. Implants insertion. Figure 3. Bone regeneration with Osteobiol Putty. Figure 4. Re-opening of the site at 4 months. Figure 5. Abutments. Figure 6. Panoramic radiograph of a case of a 62 y.o. female patient, treated in the edentulous area 4.4-4.5-4.6. Maltagliati A (2016) Alveolar ridge expansion by implants with osteodistractive function: A clinical report Volume 2(6) Dent Oral Craniofac Res, 2016 doi: 10.15761/DOCR.1000184 Conclusion Today dental implants combined to pre-insertion surgical techniques such as ridge distraction present an optimal modality to restore the lost dentition in patients suffering from alveolar atrophy. To date, the available literature even from the broader field of orthopedic and maxillofacial surgery, has demonstrated that through distraction osteogenesis techniques it is possible to give way to neo-formation of bone tissue that have similar characteristics of the original bone, hence favoring the successful insertion and integration of dental implants [21-23]. The horizontal distraction technique, matter of this paper, that employs the very same implants as a distraction tool, allows the augmentation of the alveolar ridge horizontal dimensions with one single surgical step, hence reducing to the minimum the biological and financial cost for the patient. In most of the cases with mandibular atrophy, mainly bone of type D1 or D2 are encountered complicating any surgical approach [24] the use of implants with bone distraction ability reduces significantly fracture and fenestration risks, which are undesirable but frequent events occurring with traditional surgical techniques. Besides, bone distraction implants increase the comfort of the patient who otherwise would have to face several traumatic surgeries. Finally, the prosthetic connection with switch platform, when permitting the insertion of the implant 2 mm below the alveolar crest, prevents peri-implant conical resorption which favours reliable long term reproducibility of such technique. Conflicts of interest The authors declare that they have no conflict of interest. Financial disclosure The authors declare that this work was not supported by any funding source.

Letter: proton pump inhibitor-responsive oesophageal eosinophilia – more than just gastro-oesophageal reflux disease. Authors' reply

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