The 2018 ISDE achalasia guidelines

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Maxillary sinus floor elevation using a tissue-engineered bone complex with OsteoBone and bMSCs in rabbits.

OBJECTIVES: To evaluate the effects of maxillary sinus floor elevation by a tissue-engineered bone complex with OsteoBone(trade mark) and bone marrow stromal cells (bMSCs) in rabbits. MATERIAL AND METHODS: Autologous bMSCs from adult New Zealand rabbits were cultured and combined with OsteoBone(trade mark) at a concentration of 20 x 10(6) cells/ml in vitro. Twenty-four animals were used and randomly allocated into groups. For each time point, 16 maxillary sinus floor elevation surgeries were made bilaterally in eight animals and randomly repaired by bMSCs/material (i.e. OsteoBone), material, autogenous bone and blood clot (n=4 per group). A polychrome sequential fluorescent labeling was also performed post-operatively. The animals were sacrificed 2, 4 and 8 weeks after the procedure and evaluated histologically as well as histomorphometrically. RESULTS: New bone area significantly decreased from weeks 2 to 8 in the blood clot group, while bone area in the autologous bone reduced from weeks 4 to 8. In both groups, a significant amount of fatty tissue appeared at week 8. Accordingly, augmented height in both groups was also significantly decreased from weeks 2 to 8. The bone area in the material-alone group as well as in the bMSCs/material group, on the other hand, increased over time. Significantly more newly formed bone area and mineralization was observed in the center of the raised space in the bMSCs/material group than in the material-alone group. The augmented height was maintained in these two groups throughout the course of this study. CONCLUSION: These results suggest that OsteoBone can successfully be used as a bone graft substitute and that the combination of this material with bMSCs can effectively promote new bone formation in sinus elevation.

The use of tissue-engineered bone with human bone morphogenetic protein-4-modified bone-marrow stromal cells in repairing mandibular defects in rabbits.

In this study, the capacity of hBMP-4 gene therapy combined with tissue-engineering techniques to improve the repair of mandibular osseous defects in rabbits was explored. A mammalian plasmid vector expressing enhanced green fluorescent protein-human bone morphogenetic protein-4 (pEGFP-hBMP-4) was initially constructed through subcloning techniques. Bone-marrow stromal cells (bMSCs) from New Zealand White rabbits were cultured and either transfected with pEGFP-hBMP-4 or pEGFP, or left untransfected in vitro. Once the transfer efficiency was determined through the expression of EGFP, cells from the three groups were combined with natural non-organic bone (NNB) at a concentration of 50 x 10(6)cells/ml and placed in 15 mm x 6 mm bilateral, full-thickness, mandibular defects surgically made in 12 rabbits. Together with NNB control, there were six samples per group. Four weeks after surgery, the implants were harvested and evaluated histomorphologically. Under optimal experimental conditions, gene transfer efficiency reached a maximum of 38.2+/-9.4%. While the percentage of new bone area in the NNB control group was 8.8+/-3.1%, in the untransfected bMSC group 22.5+/-8.2%, and in the pEGFP group 18.1+/-9.0%, a significantly higher amount of 32.5+/-6.1% was observed in the pEGFP-hBMP-4 group. These results suggest that transfection of bMSCs with hBMP-4 enhances their inherent osteogenic capacity for maxillofacial bone tissue-engineering applications.

Growth factor delivery for bone tissue engineering.

Bone is a dynamic tissue that undergoes significant turnover during the life cycle of an individual. Despite having a significant regenerative capability, trauma and other pathological scenarios commonly require therapeutic intervention to facilitate the healing process. Bone tissue engineering, where cellular and biological processes at a site are deliberately manipulated for a therapeutic outcome, offers a viable option for the treatment of skeletal diseases. In this review paper, we aim to provide a brief synopsis of cellular and molecular basis of bone formation that are pertinent to current efforts of bone healing. Different approaches for engineering bone tissue were presented with special emphasis on the use of soluble (diffusible) therapeutic agents to accelerate bone healing. The latter agents have been used for both local bone repair (i.e. introduction of agents directly to a site of repair) as well as systemic bone regeneration (i.e. delivery for regeneration throughout the skeletal system). Critical drug delivery and targeting issues pertinent for each mode of bone regeneration are provided. In addition, future challenges and opportunities in bone tissue engineering are proposed from the authors' perspective.

Post-lesion lateralisation shifts in a computational model of single-word reading.

The mechanisms underlying lateralisation of language are incompletely understood. Existing data is inconclusive, for example, in determining which underlying asymmetries in hemispheric anatomy/physiology lead to lateralisation, the precise role of interhemispheric connections in this process, and exactly how and why lateralisation can shift following focal brain damage. Although these issues will ultimately be settled by experimentation, it is likely that computational modelling can be used to suggest, focus, and even interpret such empirical work. We have recently studied the emergence of lateralisation in an artificial neural network model having paired cerebral hemispheric regions, as the model learned to generate the correct pronunciation for simple words. In this paper we extend this previous work by examining the immediate and longer-term changes in lateralisation that occur following simulated acute hemispheric lesions. Among other things, the results demonstrate that the extent to which the non-lesioned model hemispheric region contributes to recovery is a function of lesion size, prelesion lateralisation, and assumptions about the excitatory/inhibitory influences of the corpus callosum. The relevance of these results to the currently controversial suggestion that language lateralisation shifts following focal damage to language areas, and that the unlesioned hemisphere contributes to recovery from stroke-induced aphasia in adults, is discussed.