The current method of treatment for persistent internal rotation due to the medial rotation contracture in patients with obstetric brachial plexus injury is humeral derotational osteotomy. While this procedure places the arm in a more functional position, it does not attend to the abnormal glenohumeral joint. Poor positioning of the humeral head secondary to elevation and rotation of the scapula and elongated acromion impingement causes functional limitations which are not addressed by derotation of the humerus. Progressive dislocation, caused by the abnormal positioning and shape of the scapula and clavicle, needs to be treated more directly.Four patients with Scapular Hypoplasia, Elevation And Rotation (SHEAR) deformity who had undergone unsuccessful humeral osteotomies to treat internal rotation underwent acromion and clavicular osteotomy, ostectomy of the superomedial border of the scapula and posterior capsulorrhaphy in order to relieve the torsion developed in the acromio-clavicular triangle by persistent asymmetric muscle action and medial rotation contracture.Clinical examination shows significant improvement in the functional movement possible for these four children as assessed by the modified Mallet scoring, definitely improving on what was achieved by humeral osteotomy.These results reveal the importance of recognizing the presence of scapular hypoplasia, elevation and rotation deformity before deciding on a treatment plan. The Triangle Tilt procedure aims to relieve the forces acting on the shoulder joint and improve the situation of the humeral head in the glenoid. Improvement in glenohumeral positioning should allow for better functional movements of the shoulder, which was seen in all four patients. These dramatic improvements were only possible once the glenohumeral deformity was directly addressed surgically. Obstetric brachial plexus injury (OBPI) has been described as a discrete entity since 1754 . The medThe current surgical approach to treating persistent MRC in OBPI patients is derotational humeral osteotomy -12 or anScapular hypoplasia, elevation and rotation (SHEAR) deformity  is the uThe presentation of weakness of the deltoid and external shoulder rotators caused by the common C5 injury seen in OBPI immediately affects growth of both the muscles and bones. Formation of contractures and consequent asymmetric muscle action on the developing bony elements of the shoulder results in bone deformation of the scapula and humerus. The scapula not only elevates and rotates laterally, but also becomes hypoplastic with flattening of the glenoid fossa and hooking of the acromion process. The clavicle and acromion process impinge upon the humeral head due to the abnormal positioning of the scapula and associated acromio-clavicular triangle (ACT), with its sides defined by the clavicular shaft and the acromion process and its base by an imaginary line connecting their medial ends. Functionally debilitating effects include medial rotation and posterior and inferior subluxation of the humerus within the glenoid fossa.The abnormal migration of the scapula disrupts the normal anatomic relationships of the humeral head, the glenoid fossa and the acromio-clavicular triangle. Impingement of the distal acromio-clavicular triangle against the humeral head limits external rotation of the arm and shoulder. Without addressing the joint derangement, procedures such as humeral osteotomy are likely to fail or have significant rates of recurrence. To our knowledge there is no published method for correcting recurrence of the medial rotation contracture other than repeated humeral osteotomy.A novel osseous procedure, named the "Triangle Tilt," releases and tilts the acromio-clavicular plane back to neutral thus relieving the impingement of the acromio-clavicular triangle on the humeral head. The humeral head may now reposition passively into the neutral position within the glenoid fossa. Here we report the use of this technique to treat 4 children who had undergone unsuccessful humeral osteotomies.During a 10 month period between October 2005 and August 2006, 73 obstetric brachial plexus patients with persistent internal rotation underwent Triangle Tilt surgery. Four of these patients had undergone previous humeral osteotomy (performed by board-certified pediatric orthopedic surgeons) with complete failure of the procedure. All 4 had residual MRC with SHEAR deformity, and underwent Triangle Tilt surgery as a salvage procedure for unsuccessful humeral osteotomy.The presence of SHEAR deformity was determined by physical examination and confirmed by 3D-CT (computed tomography) if possible . ElevatiVersion and subluxation were measured on axial CT or MRI images. A scapular line was drawn connecting the medial margin of the scapula to the middle of the glenoid fossa on transverse CT or MRI (magnetic resonance imaging) images at the mid-glenoid level. The glenoscapular angle between the scapular line and a line connecting the base of the anterior labrum and posterior labrum was measured according to Friedman et al. . 90° werTwo of the patients were girls, ages 7.9 and 10.4 years, and 2 were boys, ages 10.4 and 11.9 years at the time of surgery. Two patients had undergone nerve surgery in infancy. Prior to humeral osteotomy, all 4 had undergone muscle contracture release, tendon transfers, and decompression of the axillary nerve at the quandrangular space -19. ImprShoulder movements were assessed preoperatively and postoperatively by evaluating video recordings of standardized movements according to the modified Mallet classification . AdditioThe Triangle Tilt surgery consisted most importantly of four components. First, osteotomy separated the clavicle at the junction of the middle and distal thirds. Second, osteotomy of the acromion process at its junction with the spine of the scapula was performed. Then, thirdly, ostectomy of the superomedial angle of the scapula was enacted. Finally, the extremity was splinted in adduction, 5° of external rotation and full forearm supination (90°). Splinting was maintained for 6 weeks after which time the splint was worn only at night for an additional 3 months.Minor elements of the procedure included bone grafting of the acromion process osteotomy site, and semi-rigid fixation of the clavicular osteotomy segments to prevent nonunion. Since all four of these children had proven shoulder instability, particularly subluxation, diagnosed by CT or positional MRI imaging, posterior glenohumeral capsulorrhaphy was performed.The same surgeon performed all surgical procedures (RKN).The preoperative and postoperative Mallet scores for these patients are presented in Table The developmental consequences of an obstetric brachial plexus injury, medial rotation contracture and progressive posterior dislocation of the shoulder, have serious consequences for shoulder function. Most commonly, the treatment method is humeral osteotomy, which places the arm in a more functional, externally rotated position. Though this procedure can give functional improvement, a significant proportion of children are not helped by this salvage procedure due to the fact that it does not address the bone deformities at the root of the progressive posterior dislocation and poor shoulder movement. The presence of unaddressed SHEAR deformity guarantees the continued impingement of the acromion upon the humeral head which can lead to recurrence of the debilitating internal rotation. Only in the absence of significant SHEAR is humeral osteotomy a viable treatment option.The improvements possible with the Triangle Tilt surgery are clear from the preoperative and postoperative photographs shown in Figure The degree of torsion caused by contractures around the shoulder is manifest during surgery, and observation of how the bones respond during surgery reveals the forces still acting on the glenohumeral joint after humeral osteotomy. When released by Triangle Tilt, the highly abnormal bony framework around the injured shoulder and the significant intraosseous torque results in immediate clavicular and acromial movements. Separation of the distal acromio-clavicular triangle from the abnormal medial structures relieves the torsion developed over time.The clavicle is abnormally twisted due to scapular migration, and the distal and proximal clavicle segments are intraoperatively observed to rapidly unwind after osteotomy. Significant movement also follows osteotomy of the acromion process, with the body of the acromion process and the medial margin of the acromion rapidly separating, and the distal segment moving both inferiorly and posteriorly. The distal acromio-clavicular triangle becomes normalized, and so does the humeral head through its relationship to the lateral structures. With the release of the abnormal torque and the leveling of the acromio-clavicular triangle, the glenohumeral axis returns towards neutral. This improves clinical arm positioning and movement possibilities.The four patients presented here demonstrate how important it is to recognize and treat the bone deformity. If SHEAR is present, it must be accounted for in the surgical plan. The design of the Triangle Tilt procedure aims at improving the position of the humeral head in the glenoid fossa by eliminating the impingement occurring in the SHEAR deformity. Long-term improved function of the shoulder is the expected consequence of improved glenohumeral anatomy. Only months after surgery, these four patients who had Triangle Tilt surgery to address the SHEAR as well as the medial rotation contracture show dramatically improved function.The authors declare that they have no competing interests.RKN conceived of the study, performed all surgeries, and edited the manuscript. MP collected and analysed data, created figures, and edited the manuscript. SEM collected and analysed data, and drafted the manuscript.


We present a case of a young-adult patient who was diagnosed with Askin’s tumor, with central nervous system lesions suspected as metastases. The patient achieved complete response after chemotherapy, and the question of consolidation radiotherapy to the CNS is discussed. Brain metastases from sarcomas are relatively uncommon and data are limited. The management of brain metastatic sarcoma patients is challenging since these lesions are often refractory to treatment and there are no currently accepted guidelines or consensus of the role of surgery, chemotherapy and radiation in the treatment of brain metastasis -4. PeripThe patient was a 28-year-old male from Jewish-Ethiopian descent, with no history of chronic diseases. He presented with right eye pain lasting for three weeks and loss of vision in the same eye. Fundoscopy showed bilateral papilledema and unknown cells within the vitreous. A brain MRI showed enhancement of the pituitary infundibulum and thickening of the optic nerves and optic chiasm, as well as an enhancing lesion in the pineal gland . Whole bOn presentation, the patient was started on high doses of steroids with immediate improvement of his eyesight. After histological evidence of PNET, chemotherapy was started with etoposide-ifosfamide alternating with vincristine, doxorubicin and cyclophosphamide cycles. A brain MRI on the 4th day of the first chemotherapy cycle (and after two weeks of steroid treatment) revealed disappearance of the lesion in the pineal gland and partial resolution of the other CNS sites. The chest wall lesion regressed significantly after chemotherapy.After the 4th chemotherapy cycle the patient underwent thoracotomy with resection of the chest wall lesion; pathological examination revealed complete remission. The patient completed a year of chemotherapy treatment as noted above.In a retrospective study of CNS involvement in children with sarcoma, 11 of 19 patients included in the study had Ewing's sarcoma . VariousConsolidation radiotherapy following a chemotherapy response in a young patient with otherwise good performance status, oligometastatic disease, and controlled primary site is often the treatment of choice. If the reported patient actually had involvement of the vitreous and intracranial disease, craniospinal irradiation (CSI) and orbital irradiation may be indicated due to the risk of leptomeningeal dissemination. CSI is technically challenging because of the planning target volume (PTV) length and the vital organs exposed. Nowadays, innovative techniques, such as three-dimensional conformal radiotherapy, proton beam, intensity modulated techniques, and tomotherapy, can be applied with great precision , 10. HowAfter consulting with a highly regarded overseas center, it was decided not to irradiate the CNS and to follow with brain MRI and ophthalmological examination every three months. An evaluation performed six months after completion of treatment indicated that the patient's eyesight was stable, his eye exam was unremarkable, and there was no evidence of chest wall recurrence and or of CNS disease on brain MRI.The presented case raises the following dilemmas: How much to risk a patient to obtain a tissue diagnosis from the intracranial lesion? Assuming the lesions were metastases, is consolidation treatment after complete response necessary? Most importantly and finally, should the craniospinal axis be irradiated?


This paper describes the intervention planning process for the Home and Online Management and Evaluation of Blood Pressure (HOME BP), a digital intervention to promote hypertension self-management. It illustrates how a Person-Based Approach can be integrated with theory- and evidence-based approaches. The Person-Based Approach to intervention development emphasises the use of qualitative research to ensure that the intervention is acceptable, persuasive, engaging and easy to implement.Our intervention planning process comprised two parallel, integrated work streams, which combined theory-, evidence- and person-based elements. The first work stream involved collating evidence from a mixed methods feasibility study, a systematic review and a synthesis of qualitative research. This evidence was analysed to identify likely barriers and facilitators to uptake and implementation as well as design features that should be incorporated in the HOME BP intervention. The second work stream used three complementary approaches to theoretical modelling: developing brief guiding principles for intervention design, causal modelling to map behaviour change techniques in the intervention onto the Behaviour Change Wheel and Normalisation Process Theory frameworks, and developing a logic model.The different elements of our integrated approach to intervention planning yielded important, complementary insights into how to design the intervention to maximise acceptability and ease of implementation by both patients and health professionals. From the primary and secondary evidence, we identified key barriers to overcome  and effective intervention ingredients . Our guiding principles highlighted unique design features that could address these issues (such as online reassurance and procedures for managing concerns). Causal modelling ensured that all relevant behavioural determinants had been addressed, and provided a complete description of the intervention. Our logic model linked the hypothesised mechanisms of action of our intervention to existing psychological theory.Our integrated approach to intervention development, combining theory-, evidence- and person-based approaches, increased the clarity, comprehensiveness and confidence of our theoretical modelling and enabled us to ground our intervention in an in-depth understanding of the barriers and facilitators most relevant to this specific intervention and user population.The online version of this article (doi:10.1186/s13012-017-0553-4) contains supplementary material, which is available to authorized users. Elevated blood pressure (BP) is currently the highest risk factor for global disease burden, accounting for 7% of global disability-adjusted life years (DALYs)  due to tDigital health interventions offer an opportunity to address the increasing health burden in a potentially cost-effective way , by provThe TASMINH2 trial  providedThe intervention planning and development for the HOME BP study was conducted using a theory-, evidence- and person-based approach –28. The This paper provides an illustration of how the Person-Based Approach can be integrated with theory- and evidence-based approaches to intervention planning and development, by outlining the intervention planning process we undertook for HOME BP. HOME BP is a digital intervention integrating patient and healthcare professional intervention components to deliver the anti-hypertensive medication titration procedure and behavioural support for patients undertaking self-management of hypertension. The HOME BP intervention is currently being evaluated in a randomised controlled trial . In thisIn the following sections, we describe the methods and results for each of the six elements of the intervention planning process in HOME BP see Fig. . Work stThese two streams of work, and also the intervention development and evaluation, were carried out iteratively and in parallel, with the different aspects contributing to one another. The intervention planning documents were therefore updated throughout the intervention development process to incorporate and synthesise evidence and qualitative development work as it emerged. Monthly intervention planning and development meetings were conducted, where input on intervention content and proposed procedures was sought from a variety of sources including experts in hypertension, primary care clinicians, PPI representatives and organisations (Blood Pressure UK) and experts in behavioural science; this expert input was also incorporated into a detailed record of the decision-making process throughout the development of HOME BP.Each of the following sections briefly describes the method used for each element of intervention planning, together with the output from that method and selected examples of how these outputs fed into the intervention development. The methods for collating evidence are not novel and so are described only briefly below , and briefly describe relevant aspects of users and their context . Next, wIn the development of HOME BP, we began to formulate the guiding principles in the first stages of planning, drawing on prior experiences of the TASMINH, TASMINH2 and TASMIN-SR trials of patient self-monitoring of blood pressure and medication titration , 45, 46,The objective of the HOME BP intervention, in terms of outcomes, is to provide cost-effective (hence mainly automated) support to patients with hypertension to improve control of their blood pressure through behaviour change and optimum anti-hypertensive medication titration. In terms of behaviours, this required support for patients to self-monitor their blood pressure and for patients and health professionals to increase their medication if it was not well-controlled. At an early stage of intervention planning, we decided to reduce the emphasis in the intervention on patients also undertaking healthy behaviour change (which was encouraged but not required in HOME BP), as our evidence suggested that most UK primary patients were not motivated to undertake sufficient behaviour change to influence blood pressure  and we wTo use behaviour change theory to code the HOME BP intervention content and map it onto the evidence derived from work stream 1.Our planning process was initially data-driven, in the sense that it was based on the evidence identified in the first work stream. The behavioural analysis tables recorded the four key patient target behaviours  as well as the subsidiary behaviours necessary to enact the key target behaviours. For example, in order to achieve adherence to a new medication, patients must accept the recommended change without a face-to-face GP consultation, collect the new prescription and medication, and then begin the new medication regime. The healthcare professional (HCP) intervention planning tables included three key target behaviours: engaging with the intervention, enacting medication titration procedures and behavioural support provision. The corresponding intervention component designed to elicit the target behaviour was also recorded.To undertake the behavioural analysis, we coded the intervention content using the Behaviour Change Wheel (BCW)  and NormThe HOME BP intervention planning tables consisted of 11 pages and included both the patient and health professional intervention components. The full HOME BP planning tables are presented in Additional file Our theoretical analysis of the determinants of blood pressure self-monitoring, using the BCW, suggested that HOME BP was targeting various behavioural sources, specifically physical and social opportunity, reflective motivation and psychological capability. Our theoretical analysis of the intervention components designed to promote self-monitoring identified that HOME BP employed five different intervention functions from the COM-B model    and coulThis paper has described how we combined evidence-, theory- and person-based approaches to the development of a complex intervention to support patient self-management of hypertension. The importance of basing interventions on existing evidence—synthesised by means of systematic reviews—has been acknowledged for some time . It is nEach of the six elements of our integrated approach see Fig.  contribuAlthough each of the elements of our integrated theory-, evidence- and person-based approach to intervention planning can make an important contribution, the most appropriate way to undertake each element is likely to differ widely depending on the particular context of each intervention. Although we have taken all of the steps outlined above in the planning and development of HOME BP, it may or may not be necessary to undertake primary qualitative or mixed methods research at the start, depending on the quality and relevance of the existing evidence base—although it will always be important to use primary mixed methods research to evaluate and refine intervention elements initially developed on the basis of evidence and theory , 34. MetOur integrated approach to intervention development, combining theory-, evidence- and person-based approaches, increased the clarity, comprehensiveness and confidence of our theoretical modelling and enabled us to ground our intervention in an in-depth understanding of the barriers and facilitators most relevant to this specific intervention and user population.


Secondary tumours of the hyoid bone and thyroid cartilage are extremely rare. In this paper, we present a case of the hyoid bone and thyroid cartilage metastases in a patient treated for sigmoid colon adenocarcinoma.Four years after sigmoid colon adenocarcinoma was diagnosed and treated with surgery and chemotherapy, the patient developed bone metastases in the left sacroiliac joint and right proximal humerus. Although the patient did not complain of any related symptoms, in a bone scintigraphy the accumulation of Technetium-99m was incidentally detected in the two sites of the anterior neck. On ultrasound examination there were two hyperechoic and heterogeneous masses with calcifications placed in front of the hyoid bone and thyroid cartilage. Computerized tomography demonstrated massive hyoid bone and thyroid cartilage destruction.In patients with progressive sigmoid colon adenocarcinoma, destruction of the hyoid bone and thyroid cartilage could be suspected for metastases. Secondary tumours of the hyoid bone and thyroid cartilage are extremely rare. Primary malignancies that frequently metastasize to the hyoid bone and/or the thyroid cartilage arise from the adjacent tissues, e.g. the larynx, the vallecula and pyriform sinus . Only a A 63-year-old male patient was admitted to the hospital due to repeated episodes of abdominal pain and rectal bleeding. Initial workup included colonoscopy, which revealed an ulcerated mass in the sigmoid colon. Results of the biopsy were consistent with an adenocarcinoma. Serum levels of carcinoembryonic antigen (CEA) (89 ng/mL) and cancer antigen 19-9 (CA 19-9) (326.7 U/mL) were elevated. Contrast-enhanced computerized tomography (CT)  of the abdomen and pelvis showed presence of mesenteric lymphadenopathies and hypodense lesions in liver segments III, IV and V. The lesions in the liver were highly suggestive for metastases. According to the tumour board recommendation, a left hemicolectomy with regional lymph node removal was performed and the diagnosis of an invasive adenocarcinoma was confirmed . The treatment was continued with four cycles of bevacizumab plus oxaliplatin-based chemotherapy, after which the patient underwent hepatic segmentectomy. Three months later, the chemotherapy was modified to FOLFOX regimen  due to a CT-verified recurrence of the liver metastases. After a follow-up of 3 years, the chemotherapy regimen was changed to FOLFIRI . Due to slow, continuous progression of the liver metastases, the chemotherapy protocol was changed to FOLFOX and XELOX  regimen. In this period, genetic analysis revealed a mutation of Gly12Asp in 12 codon of K-Ras gene.After the administration of the last chemotherapy cycle, the patient started to complain of severe pain in the left gluteal region and right arm. The significant elevation of serum levels of CEA (60 ng/mL) and CA 19-9 (255.5 U/mL) were detected. Osteolytic lesions within the left half of the sacrum and adjacent part of the iliac bone observed during CT examination indicated the presence of skeletal metastases and the patient underwent a bone scintigraphy. In addition to the increased accumulation of Technetium-99m in the left iliac bone, sacrum and the right proximal humerus, the radiopharmaceutical also accumulated at two sites in the anterior neck . PhysicaAn informed consent was obtained from the patient.Gastrointestinal adenocarcinoma is among the most common malignancies worldwide and one of the most common causes of cancer-related death. Although it commonly spreads to the regional lymph nodes, liver and lungs, it may also metastasize to unusual sites, such as paranasal sinuses and cryptorchid testis . Its metIn the patient described in this case, the hyoid bone and thyroid cartilage lesions were detected simultaneously with osteolytic lesions in other skeletal sites. In the context of differential diagnosis we have considered diseases that may cause osteolytic lesions in the hyoid bone . However, considering the status of primary malignant metastatic disease and elevated serum levels of tumour markers, the lesions in the hyoid bone and thyroid cartilage were highly suggestive of metastatic involvement by adenocarcinoma. This diagnosis was supported by the fact that unusual skeletal metastases of gastrointestinal adenocarcinoma more frequently occur in patients with disseminated disease than in patients without liver and/or lung involvement ,8. MoreoAlthough hyoid bone and thyroid cartilage involvement by sigmoid colon adenocarcinoma was highly suggestive, a biopsy was considered. However, the appropriateness of this procedure was brought into question. At the time of the bone metastases diagnosis, the patient had already developed multiple metastases to the liver and other skeletal sites. Severe pain due to the skeletal metastases contributed negatively to the patient’s general condition (low PS). Having in mind that K-Ras mutation is a predictive factor of survival in patients with colorectal cancer, this also contributed to the poor prognosis of the patient . In patiMetastases of the colorectal adenocarcinoma in this case probably involved the hyoid bone haematogenously. The spread along the branches of the superior laryngeal artery was previously suggested as the most likely pathway . Given tIn summary, destruction of the hyoid bone and thyroid cartilage should be suspected for metastases in patients with progressive sigmoid colon adenocarcinoma. We suggest bone scintigraphy accompanied by CT examination in order to detect silent bone metastases.


This case report describes a 33-year-old female currently undergoing breast cancer treatment following the AC-T-T (doxorubicin hydrochloride (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol) and trastuzumab (Herceptin)) treatment regimen. Her chief complaint at the time of the emergency visit at the dental office was that she had an episode of profuse spontaneous bleeding located at the palatal gingiva in the maxilla between the left central and lateral incisor. To our knowledge, this is a novel finding related to the medications she is utilizing and should be further investigated. Periodontal diseases and conditions, in part, may have different etiological origins and manifestations. The more common types are plaque-induced gingivitis and chronic periodontitis, both caused by interactions between the bacterial biofilm on teeth and the host immune response ,2. GingiThis case report describes a 33-year-old female currently undergoing breast cancer treatment following the AC-T-T (doxorubicin hydrochloride (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol) and trastuzumab (Herceptin)) treatment regimen at the University of Texas MD Anderson Cancer Center in Houston, Texas, USA. She reported an episode with profuse spontaneous bleeding located at the palatal gingiva in the maxilla between the left central and lateral incisor. The patient had no other known medical or oral conditions except for breast cancer, which was treated with 12 weekly infusions of paclitaxel and trastuzumab (T-T) every three weeks prior to her scheduled mastectomy. Her last infusion of T-T was six days prior to the incidence of the intraoral bleeding. The patient reported spontaneous bleeding from her mouth as she was getting dressed in the morning, which occurred before brushing her teeth or receiving any oral stimulus that may cause gingival bleeding, and became very concerned as the bleeding was profuse and difficult to control. A complete clinical oral examination was performed by a periodontist within an hour of the bleeding incident. The probing depths of teeth adjacent to the bleeding site were within normal limits, ranging from 2 to 3 mm, and no visible plaque was detected. A periapical intraoral radiograph from the anterior maxillary area revealed no signs of bone loss or other signs of pathology . The patAcute spontaneous and profuse hemorrhage from the gingiva is a rare and often dramatic clinical occurrence that is disturbing for the patient. While likely not life threatening, it may be difficult for the patient to prevent and control it and it may cause an already stressful cancer life situation to further escalate. To our knowledge there are currently no cases in the literature reporting adverse reactions related to the oral cavity associated with trastuzumab except for reports of mucosal inflammation of the body as a whole recorded among the extensive potential adverse effects of this essential drug . Paclita


At present there is no effective treatment of pathologies associated with the death of neurons and glial cells which take place as a result of physical trauma or ischemic lesions of the nervous system. Thus, researchers have high hopes for a treatment based on the use of stem cells (SC), which are potentially able to replace dead cells and synthesize neurotrophic factors and other molecules that stimulate neuroregeneration. We are often faced with ethical issues when selecting a source of SC. In addition to precluding these, human umbilical cord blood (hUCB) presents a number of advantages when compared with other sources of SC. In this review, we consider the key characteristics of hUCB, the results of various studies focused on the treatment of neurodegenerative diseases , ischemic (stroke) and traumatic injuries of the nervous system and the molecular mechanisms of hUCB-derived mononuclear and stem cells. Until the middle of the last century, it was believed that neural regeneration was impossible. In this regard, neurodegenerative diseases , ischemic (stroke) and traumatic injuries of the nervous system were considered incurable and only symptomatic treatment was offered. Even today, there is no effective treatment of the above-mentioned diseases. However, scientists and clinicians have high expectations for a treatment based on the use of stem cells (SC), which can potentially replace dead cells and synthesize both neurotrophic factors and molecules that stimulate neuroregeneration. Nowadays, stem cell therapy is seen as a promising method for the treatment of neurological diseases. Unfortunately adverse effects and ethical issues have forced researchers to seek non-fetal sources of SC.+ and CD105+ cells (SC markers), which are an indication of high regenerative potential  is widely used as a rich and ethically acceptable source of SC with high regenerative potential. hUCB is easily accessible, can be obtained without risk to the donor and is rarely contaminated with infectious agents, such as cytomegalovirus or Epstein–Barr virus , mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and unrestricted somatic stem cells (USSCs) are the most frequently used to stimulate neuroregeneration  due to the immaturity of the neonatal immune system . It should be noted that MSCs isolated from different sources have common characteristics: typical morphology; growth pattern in culture; ability to differentiate under the influence of specific stimulants into osteogenic, adipogenic, and chondrogenic precursors; support of hematopoiesis in vitro into neural cells  are actively used as therapeutic agents in the treatment of various human neurodegenerative diseases  and Tie-2 (one of the angiopoietin receptors) is characteristic of EPCs. Cultured EPCs differentiate into network forming endothelial cells. Their transplantation induces neovascularization in mouse models of stroke  cells, T lymphocytes and dendritic cells. There are two different subpopulations of mononuclear hUCB cells: adherent and floating. The researchers observed more glial antigens expressed in the adherent population and more neuronal antigens in the floating population  play an important role in suppressing the immune response, in the tolerance to own antigens, and prevention of autoimmune diseases. Given the strong anti-inflammatory activity of Tregs, it is believed that these cells exert a significant neuroprotective effect after stroke through the release of IL10  of hUCB are being established that in the long term would allow to conduct autologous transplantations in which there are no immune complications. In addition, hUCB cells have many properties which allow them to overcome the hurdles of neuroregeneration, which determines some success in the treatment of neurological diseases. Some of these achievements will be discussed below.The method of hUCB cells delivery is of great importance to the clinician. Direct delivery is desirable in that hUCB cells are administered at the site of interest. However, damage from the injection has to be minimal and/or mitigated  can promote functional recovery after SCI through several mechanisms. It has been shown that hUCB cells secrete anti-inflammatory cytokines and growth factors. In particular, it has been proven that systemic injections of hUCB as a treatment for SCI improves the restoration of hind limb function by stimulating the synthesis of IL10, glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF)  approved a clinical trial using hUCB cells for treatment of SCI Table . In a phIn China, a phase I/II trial, which started in September 2011 and concluded in January 2014 , investigated the safety and efficacy of oral lithium, intraspinal hUCB-MC transplant, and their combination in the treatment of acute and subacute spinal cord injury. Additional clinical studies have been suggested the success of which would determine the further development of therapy using hUCB-MCs.+ activated microglia and GFAP+ activated astrocytes occurs in the same way  peptide plays a key role in the pathogenesis of AD Selkoe, . Aβ-peptIt has also been verified that retro-orbital injections of hUCB-MCs exert positive clinical effects in APP/PS1 mice, improving spatial memory, reducing anxiety and nonspecific excitability and increasing the efficiency of exploratory behavior . This study evaluated the safety and the tolerability of NEUROSTEM®-AD (hUCB MSCs) and assessed the maximum tolerated dose (MTD). Apparently, the researchers were able to determine the optimal dose of hUCB MSCs and the best method of their transplantation to patients. Consequently, this team of researchers started a new clinical trial in February 2014 to investigate the safety, dose limiting toxicity (DLT), and explore the efficacy of three repeated intraventricular administrations of NEUROSTEM® vs. placebo via an Ommaya reservoir at 4 week intervals in patients with AD . In March 2012 in China, a phase I/II trial began, which is currently ongoing, but not recruiting new participants . The aim of this study is to determine the safety, tolerability and the efficacy of hUCB MSCs after intravenous injection (8 infusions once every 2 weeks in the first month of each quarter) in patients with AD. Another Chinese trial, which started in May 2016, will evaluate the safety and efficacy of hUCB MSCs in patients with AD after 8 intravenous infusions once every 2 weeks, vs. placebo  . It is hoped that the clinical investigations described above will make it possible to either find an effective variant of cell therapy using hUCB cells in patients with AD or reveal a direction for further studies.ALS belongs to the group of neurodegenerative diseases with progressive loss of brain and spinal cord motor neurons. Results indicating that repeated intravenous administration of hUCB-MCs in mouse models of ALS protect primarily motor neurons against inflammatory processes at the onset of symptoms supports the use of hUCB in the treatment of this pathology  is currently ongoing. These researchers believe that intrathecal injection of hUCB MSCs can secrete trophic factors maintaining motor neuron function. They have designed a phase I/II clinical trial to check the feasibility of this approach in humans. In August 2014 a Korean pilot study of a combination therapy of allogeneic hUCB and granulocyte-colony stimulating factor (GCSF) for patients with brain injury or neurodegenerative disorder  began, but recruitment status and results are unknown .in vitro. Moreover, the transplantation of hUCB MSCs in mouse models of PD has led to behavioral recovery in most animals. These findings support the potential use of hUCB MSCs in the development of viable therapeutic strategies for the treatment of PD  enhances the migration of transplanted hUCB USSCs. This factor is secreted by apoptotic neurons in the ischemia site, while necrotic neurons, in contrast, do not secrete HGF and are not able to trigger the migration of USSCs  and CD45+/B220+ cells (B cells). hUCB-MC-based therapy also reduces the concentration of pro-inflammatory cytokines in the tissue   cell based treatment changes the molecular and cellular processes initiated by cerebral ischemia. Transplantation of hUCB-MCs decreases stroke-induced infiltration of CD45Many cell-based clinical studies for stroke are underway using hUCB cells. Most of them are in phase I, aiming to demonstrate the safety and feasibility of hUCB cell transplantation. The first clinical study on the use of hUCB cells for the treatment of stroke was submitted for registration with FDA to begin in September 2012 in USA . The purpose of this study was to determine the safety and efficacy of autologous hUCB-derived stem cell injections in children with perinatal arterial ischemic stroke. However, this study was witdrawn prior to enrollment. A month later, in October 2012, the FDA approved clinical study using hUCB cells to treat stroke in China . This study was designed to assess the safety and possible efficacy of hUCB-MC treatment of chronic ischemic stroke. The study is still recruiting participants and is scheduled to transplant 10–40 million viable hUCB-MCs into brain tissue adjacent to the infracted site.+ stem cells (in the first study) and the allogeneic hUCB therapy to treat stroke in patients of all age groups (in the second study). In 2015, three clinical trials on the use of hUCB cells were registered and approved, two of them in USA and one in Taiwan. The purpose of the Taiwanese phase I/II clinical trial is to determine if hUCB intravenous infusion for perinatal arterial ischemic stroke is safe; if late functional outcome is improved; if hUCB treatment improves physiologic response in the child's SSEP & EEG and finally describe the effect of hUCB infusion in altering anatomic findings on MRI . The two USA clinical trials using hUCB cells by intravenous injection in acute ischemic stroke patients  have similar goals but different approaches to the dose and type of the transplanted hUCB cells  and also to the time of their injection in the acute phase of stroke . More recently, in January 2017, a phase II clinical trial was approved . The primary objective of this study is to determine the efficacy of a single intravenous infusion of unrelated donor hUCB in improving functional outcomes in patients with ischemic stroke. The large number of clinical trials started in recent years is clear evidence not only of the high interest in hUCB as a source of stem and progenitor cells for the treatment of stroke, but also the success of the preclinical studies.In 2013, two phase I clinical trials on the use of allogeneic hUCB therapy for patients with stroke started almost simultaneously in Taiwan and Korea . The results of these clinical trials are not yet known, but they are of great interest in connection with the inter-cerebral implantation of allogenic CD34Cell therapy using hUCB is a promising strategy for treatment of peripheral nerve injury (PNI). Nevertheless, currently limited experimental data is available on using hUCB cells for PNI treatment. Wang et al. reported that tissue engineered nerves from hUCB-MSCs-derived Schwann-like cells can effectively repair large defects of the sciatic nerve  with adenoviral vector expressing GDNF (hUCB-MCs+Ad5GDNF) improves the motor function and results in a better preservation of tissues at the injury site. This included increasing the number of intact myelinated fibers, compared to transplantation of native hUCB-MCs  is an excellent source of stem and progenitor cells able to exert a neuroprotective effect in neurodegenerative processes. A considerable number of studies have been devoted to the investigation of hUCB cell transplantation in the treatment of traumatic and ischemic injuries of the spinal cord, as well as neurodegenerative diseases. These studies have proven that the accumulated experience has good prospects to be translated into clinical practice. Thus, international clinical trials on the effectiveness of hUCB cells for the treatment of these diseases and injuries are currently being conducted. They will determine the further development of therapies using hUCB cells. It is possible that genetic modification of hUCB cells with therapeutic genes will potentiate their neuroprotective/neuroregenerative activity.LG-collection of data on the characteristics of cells derived from umbilical cord blood, compilation these data. YM-collection of data on the transplantation umbilical cord blood-derived cells into the area of spinal cord injury, compilation these data. SA-collection of data on the transplantation umbilical cord blood-derived cells in neurodegeneration deseases, drawing Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Platychelys oberndorferi, a Late Jurassic early stem pleurodire, and find remarkable convergent morphological and functional similarities with modern cryptodires. Partial vertical neck retraction in this taxon is interpreted to have enabled fast forward projection of the head during underwater prey capture and offers a likely explanation to the functional origin of neck retraction in modern cryptodires. Complete head withdrawal for protection may therefore have resulted from an exaptation in that group.Modern turtles are composed of two monophyletic groups, notably diagnosed by divergent neck retraction mechanisms. Pleurodires (side-necked turtles) bend their neck sideways and protect their head under the anterior margin of the carapace. Cryptodires (hidden-necked turtles) withdraw their neck and head in the vertical plane between the shoulder girdles. These two mechanisms of neck retraction appeared independently in the two lineages and are usually assumed to have evolved for protective reasons. Here we describe the neck of  For supposed protective reasons, turtles developed complex double-bend neck mechanisms allowing neck and head retraction within the shell2Platychelys oberndorferi Wagner, 1853P. oberndorferi was able to bend the neck in the vertical plane and partially withdraw the neck within the shell. Therefore, the typical cryptodiran neck retraction mechanism actually first evolved in Late Jurassic stem pleurodires and was only subsequently developed in cryptodires by convergence. Incidentally, Xinjiangchelys qiguensis, a Late Jurassic stem cryptodire from China4P. oberndorferi was an ambush predator practising ram (the body or the head moves toward the prey) or suction (the prey is sucked into the mouth) feeding, strongly reminding the behavior of the extant matamata (Chelus fimbriatus) and snapping turtles (Chelydra serpentina and Macrochelys temminckii). Since head and neck retraction was only partial in P. oberndorferi, we suggest that vertical neck retraction primarily evolved in this taxon to enable fast forward projection of the head and improve capture of darting prey. These results have important implications for the origin of neck retraction mechanisms in modern cryptodires.The two mechanisms of neck retraction known in modern turtles evolved independently in the two lineages after the Late Jurassic from a supposed ancestral condition, called lateral head tucking, that did not allow full head retraction5678Systematic paleontology.TESTUDINES Batsch, 1788et al.PAN-PLEURODIRA Joyce PLATYCHELYIDAE Bräm, 1965Platychelys oberndorferi. Wagner, 1853Type material. A nearly complete carapace10Type horizon and locality. Kelheim, Bavaria, Germany. Solnhofen Limestone Formation, Tithonian, Late Jurassic.Referred specimens. See hypodigm of Cadena and JoyceThe following cervical vertebrae are described considering the long axis of the centrum as horizontal, although this differs from the neutral position of these elements in the neck, which is defined as the position allowing the maximum overlap of the articular facets of the zygapophysesThe centrum of the sixth cervical vertebra is longer than wide, flattened dorsoventrally, and rectangular in ventral view . The ven1718The centrum of the eighth cervical vertebra is short and trapezoidal in ventral view )6{ {7{ {8) (see WilliamsP. oberndorferi is clearly different from Americhelydia (chelonioids + chelydrids + kinosternoids), in which cervicals 5 to 8 (c5–c8) are usually procoelous. Like P. oberndorferi, testudinoids commonly have a biconvex eighth cervical, but these taxa usually have a procoelous sixth cervical and a biconcave seventh cervical. Finally, trionychians share with P. oberndorferi opisthocoelous articulations between the sixth and seventh and the seventh and eighth cervicals, but they lack the biconcave sixth cervical observed in P. oberndorferi.Although similarities between the cervical vertebrae of P. oberndorferi may otherwise have a typical chelid cervical formula: (2((3((4((5))6))7((8), which would have suggested that this formula was plesiomorphic in pan-pleurodiresP. oberndorferi. In pleurodires, the usually well-developed transverse process is located about midway along the centrum, which contrasts with the reduced, anteriorly positioned transverse process seen in P. oberndorferi and modern cryptodires.Ginglymoidy is unknown in crown-group pleurodires, but it was proposed that Notoemys oxfordiensis P. oberndorferi: neural arch strongly oblique relative to centrum; strongly developed and widely spaced postzygapophyses extending at 90° from the neural arch; and convex posterior central articulation. Cervical vertebrae 1 to 4 are known in Notoemys laticentralis Cattoi and Freiberg, 1961192021P. oberndorferi) and widely spaced zygapophyses. This morphology is congruent with that of the sixth cervical vertebra of P. oberndorferi. Therefore, we can expect the cervical morphology (and possibly the neck retraction) exhibited by Notoemys laticentralis and Platychelys oberndorferi to be general for platychelyids.Little is known about the morphology of cervical vertebrae in other platychelyids. A single, incomplete eighth cervical vertebra is associated with the holotype of Proterochersis robusta from the Late Triassic of Germany was long considered the oldest and most basal pan-pleurodiran turtle, but this taxon was recently reinterpreted as a basal stem turtle72324Platychelys oberndorferi was adapted toward flexion in the vertical plane like modern cryptodires is somewhat counter-intuitive. However, many characteristics of platychelyid turtles agree with their placement as stem pleurodires , in some derived baenids, and in sinemydids and macrobaenids along the stem of crown-group cryptodires7et al.P. oberndorferi has been repeatedly scored as having formed cervical articulations without impact on its phylogenetic position. As a matter of fact, with Proterochersis robusta no longer being considered a stem pleurodire, formed cervical articulations were considered to be primitive for pan-pleurodires as a whole7Most stem turtles as well as numerous early stem cryptodires  lack formed cervical articulations. Formed cervical centra actually appeared independently several times within Testudinata during the Cretaceous, notably in some stem turtles  resulted in 1,128 trees of 860 steps . The strict consensus of these 1,128 trees is strictly identical to the one resulting from the analysis of the original matrixP. oberndorferi has no effect on the phylogenetic position of either this species, platychelyids, or pan-pleurodires. This strongly supports the idea that the cervical morphology of P. oberndorferi is convergent with that of crown-group cryptodires.Ginglymoidy was first scored in a global phylogenetic analysis of turtles by Sterli and Fuente93334Platychelys oberndorferi as well. The anterior central articulation of the first thoracic vertebra is already oriented ventrally in many cryptodires, which means that the initial reorientation of the neural passage at the base of the neck occurs between the first thoracic and the eighth cervical vertebrae. In P. oberndorferi, the anterior articulation of the first thoracic vertebra is oriented anteriorly and the neural canal is reoriented downward within the eighth cervical (60° angle). The articulation of the eighth cervical of specimen NMB So.596 with the first thoracic vertebra of the associated shell clearly shows the downward orientation of the base of the neck in P. oberndorferi. In cryptodires in which the base of the neck bends downward, the neck usually levels out around the fifth and sixth vertebrae. The reorientation of the neural passage can occur within  and/or between  the vertebrae. The emargination between pre- and/or postzygapophyses is usually deeper in the second case. In the sixth cervical vertebrae of P. oberndorferi, the anterior part of the neural canal is bent dorsally, the anterior articulation is oriented anterodorsally, and the neural arch is deeply emarginated between the prezygapophyses. From the above, it follows that the neutral position of the posterior part of the neck in P. oberndorferi is similar to the one observed in cryptodires: the base of the neck bends markedly downward before levelling out anteriorly.In modern cryptodires, the base of the neck bends strongly downward between the first thoracic vertebra and the eighth cervical vertebra. This morphology results in a strong ventral bending of the postzygapophyses of the eighth cervical vertebra that is characteristic of cryptodiresThe articular contacts between the postzygapophyses of the eighth cervical and prezygapophyses of the first thoracic vertebrae are sub-horizontal and moderately elongated. Movements in the vertical plane are favored, but they are relatively limited in extent. Minor horizontal movements were also probably possible. In contrast, the prezygapophyseal articular surfaces of the eighth cervical vertebra are convex and much more developed. The articular surfaces are greatly elongated and probably allowed for a great angular movement in the vertical plane. Additionally, movements between the seventh and eighth cervical vertebrae were limited to the vertical plane by the ginglymoid central articulation. The central articulation between the sixth and seventh cervical vertebrae is also ginglymoid, similarly limiting movement to the vertical plane. The postzygapophyseal articulations of the sixth cervical are reduced and oriented mostly laterally, which is congruent with a limitation of the movements to the vertical plane. Given the small surface of the postzygapophyseal articulations on the sixth cervical, the degree of movement between the sixth and seventh cervical vertebrae was probably reduced. The anterior central articulation of the sixth cervical vertebra is a dorsoventrally flattened, deep oval cavity. This articular surface is oriented anterodorsally relative to the long axis of the centrum, forming an angle of about 35°. This indicates a major reorientation of the neural passage between the fifth and sixth cervical vertebrae. This is also apparent in the deep emargination of the neural arch between the prezygapophyses of the sixth cervical. The prezygapophyseal articular surface of the sixth cervical is elongated and moderately convex. This suggests a relatively important degree of movement, although the latter was restricted to the vertical plane as indicated by the vertical orientation of the prezygapophyses.P. oberndorferi with complete confidence. However, these elements clearly indicate a trend toward the restriction of movement to the vertical plane in the posterior part of the neck and the possibility for the neck to be withdrawn in the vertical plane. Biomechanical reconstructions (P. oberndorferi (see Methods). The greatly developed convex prezygapophyseal articular surfaces of the sixth cervical indicate a high degree of angular movement between the fifth and sixth cervical vertebrae, corresponding to a first kink in the cervical series. A second kink is formed by the strong ventral reorientation of the neural canal within the eighth cervical  and the extensive development of the prezygapophyses of the eighth cervical suggesting an important degree of movement between the seventh and eighth cervical vertebrae. Based on the shape of the vertebrae, the degree of movement along articular joints, the available space between the carapace and plastron, and the comparison with modern turtles, multiple retraction scenarios were tested  and alligator snapping turtle (Macrochelys temminckii) was noted by many workers510151637Platychelys oberndorferi is also characterized by the presence of a wide costovertebral tunnel , large hyoids, a relatively wide skull with orbits placed close to the snout tip, and powerful limbs with strong claws. This strongly suggests that P. oberndorferi had a life style very similar to that of the extant matamata and alligator snapping turtleChelus fimbriatus and Chelydra serpentinaChelydra serpentina), the suction force only compensates for the bow wave and the position of the prey is not affected by the fast approaching head and opening mouthMacrochelys temminckii) has not yet been studied in detail, but observations suggest that the feeding pattern in this species is quite comparable to that of Chelydra serpentina4041Chelus fimbriatus), as well as other chelids and some trionychids, are able to generate an enormous suction force thanks to a highly derived cranio-mandibular morphology, an extremely developed hyoid apparatus and musculature, and a greatly distensible oesophagus44Most modern aquatic turtles capture prey or food item by rapidly extending the neck and projecting the head forward while the rest of the body usually remains stationary. The forward thrust of the head is particularly fast in some species, notably P. oberndorferi evolved primarily to enable and control fast forward projection of the head, hence improving capture of darting prey  was ancestral to all crown group turtlesPlatychelys oberndorferi suggests that a mechanism of neck retraction very similar to what is known in modern cryptodires can evolve for reasons that have apparently nothing to do with protection, but rather with improving prey capture abilities in the aquatic medium. This case offers a likely explanation to the origin of complex vertical neck retraction mechanism of cryptodires. Neck retraction could have evolved gradually as a way to enable fast forward thrust of the head during prey capture under water. Partial neck retraction would already provide an advantage, as demonstrated by the very specialized ecological niche occupied by P. oberndorferi. Once a primary mechanism of vertical neck retraction was in place, it would be easier to obtain complete head withdrawal for protection via natural selection.We therefore suggest that vertical neck retraction may have evolved in cryptodires primarily in order to enable fast forward projection of the head during underwater feeding, and that protection of the head by complete withdrawal within the shell in the vertical plane is actually an exaptationPlatychelys oberndorferi are briefly discussed and figured in the attached NMB So.596 (formerly sor.67.9) consists of a relatively complete shell and articulated pelvic girdle from the Late Jurassic of Solothurn . The specimen is housed at the Naturhistorisches Museum in Basel (Switzerland) at least since 1862, as it is first mentioned in the annual report of this institution for that year. This specimen was studied and illustrated by several authors545517181956Specimen NMB So.596 comes from one of the former quarries that were exploited in the vicinity of Solothurn , one of the richest known locality in Europe for Late Jurassic turtles536545859Platychelys oberndorferi within Testudines, we have updated the last available global matrix of discrete characters for fossil and extant turtlesP. oberndorferi were changed as follows (previous scorings in parentheses): Cervical vertebra G: 1 (?); Cervical articulation I: 0 (–); Cervical articulation J: 1 (–); Cervical articulation K: 0 (–); Cervical articulation L: 1 (–); Cervical vertebra I: 1 (?); Cervical vertebra K: 0 (?); Caudal B: 1 (?). The analysis was run with TNT v.1.5-betaIn order to test the potential impact of the new information presented herein on the phylogenetic position of Platychelys oberndorferi and our interpretation of the degree of movement at their joints. A detailed comparison with modern cryptodires, notably Macrochelys temminckii, was carried out as part of this work. The shell morphology and notably the available space between the carapace and plastron have been directly reconstructed from the marginally deformed shell associated with the cervical vertebrae described herein (NMB So.596), ensuring that the proportions are as close as possible to reality. The morphology of the anterior part of the neck (unknown in P. oberndorferi) has been derived from that of the closely related platychelyid Notoemys laticentralisPlatychelys oberndorferi held in private hand37The reconstructions provided in The updated data matrix is available as How to cite this article: Anquetin, J. et al. A Jurassic stem pleurodire sheds light on the functional origin of neck retraction in turtles. Sci. Rep.7, 42376; doi: 10.1038/srep42376 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


AbstractBackground.The paraesophageal hiatus hernias (PHH) are relatively uncommon, but an increased incidence has been reported and they now account for 5–10% of all hiatus hernias. The surgical treatment is recommended for all the patients with this pathology because of high risk of complications: obstruction, incarceration, strangulation or perforation. The use of prostheses is recommended in the process of repairing the giant PHH because the main problem of this operation is the high rate of recurrence. Case presentation.The patient is a 44-year-old male with a large and symptomatic paraesophageal hernia. Diagnosis was confirmed by instrumental examination. An elective laparoscopic repair was carried out by using polypropylene bifacial anti adhesive synthetic mesh . The postoperative period passed without severe complications. Conclusions.The laparoscopic approach as a therapeutic option can be successfully used in the repair of paraesophageal hernia. A selective use based on clinical experience was recommended, as the technique appeared to be safe, and in case of large hiatus hernia with hiatal defect, greater than 5 cm, the application of synthetic material to minimize the recurrence rate was recommended.  It is estimated that 10-15% of the general population have hiatus hernias, of which more than 90% are sliding hiatus hernias (Type I) [2]. Characteristic clinical signs of PHH include chest pain, postprandial distress . Symptoms of gastroesophageal reflux are not typical for hernias of type II. In as many as 20% of the patients, the clinical presentation of a massive and incarcerated PHH may be urgent or emergent. Therefore, in the absence of restrictive operative risk, all the symptomatic patients should undergo elective repair to prevent life-threatening complications, such as obstruction, strangulation, perforation and bleeding. In paraesophageal hiatus hernias (PHH) Type II, the gastroesophageal junction remains in its normal anatomic position, but the fornix of the stomach herniates into the thorax anterior to the esophagus and within a hernia sac of peritoneum. Approximately 50% of the patients with PHH are asymptomatic or complain of only minor symptoms . Untreated hiatal hernia with gastroesophageal reflux disease is an important causal factor, which defines a specific group of patients at risk to develop Barrett esophagus and esophageal adenocarcinoma [5]. The laparoscopic repair follows the same surgical principles adopted in the traditional operation. Prostheses are recommended in the repair of giant hiatus hernia with hiatal defect greater than 5 cm. Repair with synthetic mesh has the potential of reducing the recurrence rate . The experience of our department began in 2003, by which time we had accumulated more than 9 years of standing, performing laparoscopic repair for gastroesophageal reflux due to Type I hiatus hernias (120 cases). The laparoscopic solution for paraesophageal hernias was applied to 12 patients, 4 of them with mesh repair. The surgical treatment of PHH is currently the only effective therapy. The traditional repair of PHH can be done by left thoracotomy or laparotomy. The minimally invasive laparoscopic approach has been the gold standard in the treatment of hiatus hernias over the past decade . Frantzides et al. showed the results of a prospective randomized trial comparing the simple closure with polytex onlay reinforcement for paraesophageal hernia repair, in cases with a hiatus wider than 8 cm. Recurrences were significantly reduced after mesh placement , without any long-term sequel, after a 40-month follow-up period [10]. The main problem with the use of mesh in the hiatus is the risk of local complications . Nonetheless, the incidence of mesh-related complications in the hiatus is currently less than 2%, although no reports on long-term outcome (>10 years) are available [11]. There are different types of prostheses used in the repair of hernias: polypropylene, polytetrafluoroethylene (PTFE), SIS , polyglycolic acid/ trimethylene carbonate mesh, biomesh  .All our patients with hiatus hernias were symptomatic, and surgical intervention was clearly indicated to relieve the symptoms and to prevent the development of potentially serious complications. In this case report, the patient was symptomatic with impact on the quality of life. The use of prostheses is recommended in the repair of giant hiatus hernia with hiatal defect greater than 5 cm. The information currently available shows that the use of a mesh for hiatal repair is safe and prevents recurrence [13]. This may be advantageous in avoiding complications such as erosion and infection by minimizing foreign body presence. Synthetic meshes can provoke a foreign body response that results in the encapsulation and can cause long-term infection and extrusion of the implant. The acellular dermal matrix leaves the structural architecture intact and provides scaffolding for tissue growth with continued reinforcement. The absorbable mesh is accepted by the body without an immunological or foreign body response [14]. In 2008, GORE introduced BIO-A tissue reinforcement, an absorbable mesh that acts as a scaffold for cells to lay down new matrix material as it is absorbed . Some authors consider that the use of prostheses is unreasonable because of local complications and high rate of recurrence .Several studies have shown that laparoscopic hiatal hernia repair is associated with high recurrence rates of up to 42% as a result of the difficulty in the closure of the hiatal gap and demonstrated advantages of open techniques vs. minimally invasive approach [However, starting with 2010, the surgical mesh was applied in 7 cases of laparoscopic hiatus hernia repair in our department, 4 of them being patients with paraesophageal hernias. Polypropylene bifacial anti adhesive synthetic mesh (Surgimesh XB) was used in all cases with good results, without severe complications. In the presented case report of giant paraesophageal hernia, the use of bifacial silicon-coated mesh led to good results confirmed by the clinical and instrumental examination. The laparoscopic approach as a therapeutic option can be successfully used in the repair of giant paraesophageal hernia. A selective use based on clinical experience is recommended, as the technique appears to be safe, and in case of large hiatus hernia with hiatal defect greater than 5 cm, the application of synthetic material to minimize recurrence rate is recommended. The surgical mesh with anti adhesive properties should be used in order to minimize the eventual complications.None


Under a warming climate, amplification of the water cycle and changes in precipitation patterns over land are expected to occur, subsequently impacting the terrestrial water balance. On global scales, such changes in terrestrial water storage (TWS) will be reflected in the water contained in the ocean and can manifest as global sea level variations. Naturally occurring climate-driven TWS variability can temporarily obscure the long-term trend in sea level rise, in addition to modulating the impacts of sea level rise through natural periodic undulation in regional and global sea level. The internal variability of the global water cycle, therefore, confounds both the detection and attribution of sea level rise. Here, we use a suite of observations to quantify and map the contribution of TWS variability to sea level variability on decadal timescales. In particular, we find that decadal sea level variability centered in the Pacific Ocean is closely tied to low frequency variability of TWS in key areas across the globe. The unambiguous identification and clean separation of this component of variability is the missing step in uncovering the anthropogenic trend in sea level and understanding the potential for low-frequency modulation of future TWS impacts including flooding and drought. On global scales, such changes in terrestrial water storage (TWS) will be reflected in the water contained in the ocean and will manifest as variability in global sea level7, establishing a direct link between observations of the global water cycle and sea level. Understanding this link should enable us to separate the long-term trend in sea level from natural variability about this trend. However, achieving this separation has been elusive thus far, and remains a key barrier to improving our understanding of past and present sea level, and subsequently projections of future sea level rise. Specifically, naturally occurring climate-driven TWS variability can temporarily obscure the long-term trend in sea level rise, in addition to modulating the impacts of sea level rise through natural periodic undulation in regional and global sea level11. Furthermore, with the potential for naturally occurring TWS patterns to change under a warming climate, improving the understanding and representation of this variability in the past and present will aid in future identification of any possible shifts.As the climate continues to warm, there is an expectation for increased variability in the water cycle and associated shifts in precipitation patterns over land, subsequently impacting terrestrial water balance12. As has been demonstrated, reductions of TWS are mirrored by a similar increase of water in the ocean (and vice versa), with the El Nino-Southern Oscillation (ENSO) shown to play a dramatic role in this water exchange on interannual timescales13. Analogously, sea surface salinity from in situ and space-borne sensors monitor the oceanic component of the global water cycle. On longer timescales, however, the utility of satellite observations is more limited. The GRACE satellites extend back to only 2002, with the associated satellite record of TWS only recently surpassing a decade in length. While the satellite altimeter record began in 1993, questions remain regarding the ability to separate decadal-scale variability from a now 23-year record , although with a different window size. As a test of the stationarity of the spatial pattern, the dominant EOF was computed over the time-periods from 1900 to 1950 and from 1950 to 2000. The resulting EOF patterns exhibited strong agreement with the EOF discussed in this paper computed over the full time period. To find corresponding patterns in TWS, precipitation and SSS, ten-year trend patterns were similarly computed from each dataset. The EOF PC time series in Fig. To estimate the dominant decadal trend pattern in the sea level, linear trends over ten-year windows were computed at every location across the globe from the sea level reconstruction spanning from 1900 through 2014. Incrementing by one year at a time, this resulted in 104 ten-year trend maps. An empirical orthogonal function (EOF) decomposition of these trend maps was then performed to determine the dominant ten-year trend pattern in the sea level reconstruction, similar to the analysis done in Hamlington


Inhibitory interneurons participate in all neuronal circuits in the mammalian brain, including the circadian clock system, and are indispensable for their effective function. Although the clock neurons have different molecular and electrical properties, their main function is the generation of circadian oscillations. Here we review the circadian plasticity of GABAergic interneurons in several areas of the mammalian brain, suprachiasmatic nucleus, neocortex, hippocampus, olfactory bulb, cerebellum, striatum, and in the retina. Under day/night conditions the pacemaker is entrained by light or other cyclic environmental cues  and produces oscillations with 24 h period. Circadian information generated by the pacemaker is delivered to other brain regions and to peripheral clocks located in various internal organs. The pacemaker neurons of the SCN exhibit circadian rhythm in electric activity and expression of clock genes which together with their proteins constitute the molecular mechanism of the clock. This mechanism is based on several transcriptional/translational feedback loops, negative and positive [Many aspects of mammalian behavior and physiology show circadian rhythmicity. The circadian rhythms, with a period about a day , are associated with some neurological/psychiatric disorders. These disorders display the loss of circadian rhythms and dysfunction of excitatory/inhibitory balance affecting cognitive performance  and inclThe investigations of circadian plasticity related to GABAergic interneurons have been focused on expression/concentration of GABA and on colocalized neuropeptides and GABA receptors, as well as on the number of GABAergic synapses and electrophysiological changes of neurons.Mammalian SCN located in the anterior part of hypothalamus has been shown to play a role of an oscillator responsible for controlling circadian rhythms in other parts of the brain. SCN is divided into two different regions: dorsal and ventral, containing distinct subpopulations of interneurons. Almost all interneurons in both regions of the SCN are GABAergic –58 and pThe SCN neurons generate self-sustained rhythmic activity with approximately 24 h period and their cyclic neuronal firing is driven by rhythmic gene expression –69. It hThe diurnal oscillations of the interneuron conductance were measured in rat SCN slices and the conductance recorded at the beginning of the subjective day was 40% higher than at the beginning of the subjective night . ElectroIn turn changes in the degree of synaptic depression were measured by paired-pulse depression (PPD) of synaptic contacts between the SCN interneurons. Short-term synaptic plasticity evoked in this way displayed a clear diurnal rhythmicity . MoreoveGABA participates in the regulation of amplitude , 73 and Circadian rhythmicity of GABA content and GAD activity were detected in the rat SCN under LD and DD conditions, suggesting an endogenous nature of the fluctuations . In LD cIn rat SCN, VIP and VIP receptor VPCA2 mRNA levels also showed rhythmicity under LD conditions, with a maximum at night and minimum during the day . A similThe calbindin-  expressing neurons of the hamster SCN exhibited the circadian rhythm of CalB level under both LD and DD conditions, with significantly higher expression during the night and the subjective night .The analysis of synaptic contacts between CalB-immunoreactive axons and AVP cells in the hamster SCN showed an increase in the number of synapses during the night when compared with the day. However, there were no changes in the number of synapses formed by CalB-expressing interneurons on other neurons in the SCN like VIP, CCK, and GRP cells under LD and DD conditions .Postsynaptic densities in the rat SCN synapses formed by optic nerve terminals on interneurons showed changes dependent on light conditions and associated with changes in the number of synapses . FurtherResults of studies provide a strong evidence that GABAergic interneurons affected by VIPergic signaling play a significant role in the regulation and synchronization of rhythmicity in the SCN.Inhibitory interneurons of the mammalian retina include amacrine cells and several types of horizontal cells . AmacrinDiurnal changes in GABA concentration and turnover were shown under LD 14:10 in the hamster retina, with a clear minimum in the middle of the day. GAD activity was also lower in the middle of the day. Both rhythms were maintained under DD, indicating circadian origin of GABAergic inhibition .PV expression was studied in amacrine cells of the rat retina under LD conditions. The level of PV exhibited cyclic changes with a minimum during the second half of the day and maximum in the middle of the night. This rhythmicity was retained under DD; however, after three days of DD the amplitude of PV level was reduced . The expThese observations suggest that the plasticity of retinal interneurons not only results from the direct influence of light but also is controlled by the circadian clock.Inhibitory interneurons constitute about 20% of neocortical neurons and show a wide range of diversity in electrical and molecular properties as well as in morphological structure. They have aspiny dendrites, receive soma-targeted excitatory, and inhibitory inputs and form local connections within cortical columns, although some of them project laterally between adjacent columns , 105–107Diurnal rhythms of GABA turnover and GABA A receptor activity were found in the whole cerebral cortex of hamster in LD 14:10 with peaks at night , 110. HoThe circadian rhythm in the number of synapses localized on dendritic spines was demonstrated in layer 4 of the mouse somatosensory cortex (barrel cortex) which receives sensory input correlated with the circadian rhythm of locomotor activity of animals , 114. UnAs it appears from these studies, somatosensory cortex seems to be the only neocortical region that exhibits circadian plasticity of inhibitory interneurons. Future studies of other neocortical areas are clearly required to extend our knowledge concerning the circadian rhythms in the neocortex.Hippocampal GABAergic interneurons are mainly basket and chandelier cells , 118. ThSubnetworks of GABAergic interneurons in the hippocampus may influence excitability of glutamatergic pyramidal cells ; they arThese results suggest that the main inhibitory transmission of hippocampal interneurons during LTP is mediated by GABA A receptors and is controlled by the circadian clock .Two main subpopulations of GABAergic interneurons in olfactory bulb include periglomerular and granular cells , 127. GrVIPergic interneurons were observed in the external plexiform layer, periglomerular layer, and granule cell layer of mouse olfactory bulb, while expression of VIP receptor (VPAC2) was detected in mitral and external tufted cells .Intrinsic circadian rhythms of firing rate and clock gene expression were observed in olfactory bulb in vitro . In miceA recent study of mouse olfactory bulb demonstrated rhythmic VIP release by interneurons of the external plexiform and periglomerular layers, with the maximum in the middle of the night. Hence, VIPergic interneurons in the olfactory bulb seem to be well positioned to provide circadian coordination of cyclic processes and it is highly possible that they play a similar role to that of VIPergic interneurons in the SCN .Studies on GABAergic transmission and its relation to circadian rhythms in the olfactory bulb could probably complete a picture of the postulated “olfactory clock.”Cerebellar cortex contains several types of inhibitory interneurons mainly releasing GABA except for Golgi cells that also coexpress glycine. Golgi cells provide feed backward inhibition to excitatory interneurons, granule cells . Basket Cerebellum contains a circadian food entrainable oscillator that is responsible for the rhythm in food anticipatory activity and is synchronized by the mealtime during scheduled feeding in mammals . It doesInvolvement of inhibitory interneurons in cerebellar oscillator system is unclear. Diurnal changes of GABA turnover rate were demonstrated in hamster cerebellum in LD 14:10 and LD 10:14. Under both light/dark conditions, the maximum of GABA turnover rate was achieved at night . Taking GABAergic interneurons in striatum constitute at least 3-4% of neurons , 144. ThAlthough striatal interneurons are not numerous, there is strong evidence that they play an important role in the regulation of intrastriatal inhibition.Circadian GABA fluctuations were detected in the rat striatum under LD conditions with a peak at the end of the day. This rhythmic pattern did not change in DD and LL (constant light) conditions, suggesting that GABA rhythmicity in this region is light-independent .The influence of GABAergic transmission on the dopaminergic system and vice versa is particularly interesting, because its dysfunction in the striatum seems to be critical for Parkinson's disease and a wide range of mood disorders. It is also associated with drug and alcohol addictions . All the2+/GABA mechanism that plays the role in stabilizing neuronal activity [2+/GABA ratio lead to the weakening of blood-brain barrier and the intracellular accumulation of Ca2+ [2+ via both GABAergic receptors and glial networks [All stages of Parkinson's disease (PD), according to Braak's model , displayactivity . The cha of Ca2+ . The GABnetworks . Patientnetworks  as well networks  and bloonetworks . PD-assonetworks . Howevernetworks .α1 subunit was observed in the dorsal striatum, suggesting an involvement of GABA A receptors in methamphetamine-associated rewarding memory mechanism [α2 subunit of GABA A receptors and GAD protein levels in the nucleus accumbens [The reward system directly involved in drug and alcohol addictions includes the ventral striatum, especially neurons in the core and shell of the nucleus accumbens , 162. Thechanism . On the ccumbens , 170.Generally, alcohol causes a decreased inhibitory and an increased excitatory activity in neuronal networks leading to stronger dopamine output in the ventral striatum . The decAddictions are strongly associated with disruptions of the circadian clock. Drug and alcohol dependence are accompanied by changes in the daily rhythmicity –178 and The disruption in circadian rhythmicity is also correlated with mood disorders , 185 whiSince all disorders associated with the dopaminergic system in the striatum demonstrate a decrease in GABAergic transmission and reveal changes in the circadian rhythmicity, the involvement of inhibitory interneurons in striatum-related pathology seems to be highly probable.Despite the fact that GABAergic interneurons form diverse networks in different regions of the brain controlled by the circadian clock, they generally perform similar and, moreover, crucial role in all circuits. Inhibitory interneurons are involved in the generation of synchronized circadian oscillations and they are responsible for control of the excitation/inhibition balance. Unfortunately, information concerning diurnal or circadian changes of the particular types of inhibitory interneurons located in different brain structures is highly limited. Further studies of cyclic changes focused on individual interneuron classes could significantly contribute to the understanding of circadian clock mechanisms of their control.


Carbon nanoscroll (CNS) is a graphene sheet rolled into a spiral structure with great potential for different applications in nanotechnology. In this paper, an equivalent open shell model is presented to study the vibration behavior of a CNS with arbitrary boundary conditions. The equivalent parameters used for modeling the carbon nanotubes are implemented to simulate the CNS. The interactions between the layers of CNS due to van der Waals forces are included in the model. The uniformly distributed translational and torsional springs along the boundaries are considered to achieve a unified solution for different boundary conditions. To study the vibration characteristics of CNS, total energy including strain energy, kinetic energy, and van der Waals energy are minimized using the Rayleigh-Ritz technique. The first-order shear deformation theory has been utilized to model the shell. Chebyshev polynomials of first kind are used to obtain the eigenvalue matrices. The natural frequencies and corresponding mode shapes of CNS in different boundary conditions are evaluated. The effect of electric field in axial direction on the natural frequencies and mode shapes of CNS is investigated. The results indicate that, as the electric field increases, the natural frequencies decrease. Rolling a monolayer graphene sheet into a spiral multilayer structure forms a roll-like nanostructure called CNS. The open configuration of CNS contains two boundaries along the curved edges and two boundaries along axial direction. Bacon introduced CNSs as a kind of graphite whiskers for the first time in 1960 . In receAlthough CNSs are very similar to multi-wall carbon nanotubes (MWCNT), their open topology indicates specific characteristics distinct from well-known carbon nanotubes (CNTs). The open structure of CNS makes it possible to design new instruments based on its tunable core by controlling relative sliding between layers. Shi et al. studied equilibrium core radius of CNS by balancing elastic bending energy and van der Waals interaction energy and investigated the constitutive behavior of CNS in response to inner and external pressure ,14. A coAlthough the vibration analysis of CNT is widely studied and reported in the literature, there are only limited reports on the vibration of CNSs. Shi et al. investigated CNS as a gigahertz breathing oscillator . Cheng eModal analysis of nanostructures is essential for device applications like sensors and actuators. In this regard, modal analysis of CNT, carbon nanocone, fullerene, graphene, and other carbon-based nanostructures are conducted using different methods. For instance, vibrational analysis of fullerene is studied using MD simulations  and finiBased on concepts of elasticity, the mechanical behavior of nanostructures, especially CNTs, is widely studied and reported in the literature . For insBeside various studies on different shell theories and their applicability and accuracy, some researchers developed equivalent continuum models considering hexagonal lattice structure of CNTs. Ru proposed the effective bending stiffness of a SWCNT . VodenitOne of the challenges in modeling of MWCNTs arises when each of the nested tubes are considered as individual cylinders. Therefore, the van der Waals forces interacting between layers of MWCNT which come from interlayer displacements should be modeled. Ru presented an elastic model for column buckling of a MWCNT by considering intertube van der Waals forces . Saito eThere are numerous studies on the free vibration of SWCNT ,43, DWCNIn the present study, a model for free vibration analysis of CNS with different boundary conditions is proposed. The model enables researchers to understand the vibrational behavior of CNS at different boundary conditions and study the effect of each parameter on natural frequencies. After considering CNS as an equivalent shell, uniformly distributed springs along each boundary are added to simulate the resultant forces in that boundary condition. The equations of motion are derived based on First Order Shear Deformation Theory (FSDT) by considering Kirchhoff-Love assumptions. The solution is obtained using Rayleigh-Ritz technique by selecting Chebyshev orthogonal polynomial of first kind as admissible displacement functions. As an example, the natural frequencies and mode shapes of a few CNSs with different boundary conditions are reported in this study. Additionally, the effect of van der Waals forces on the vibration characteristics of CNS is investigated.This work deals with modeling vibration behavior of a CNS subjected to arbitrary boundary condition using equivalent continuum thin shell theory. Based on the thin shell theories, the equivalent geometrical and mechanical properties of the CNS are required. The second step is determining equations of motion and solving them. Here, the energy expressions of the equivalent shell are obtained using FSDT and vibration characteristics are extracted through Rayleigh-Ritz procedure. In order to use a unified formulation for vibration behavior of CNSs in arbitrary boundary conditions, the energy stored in boundary conditions is modeled with uniformly distributed springs along each boundary.E, Poisson ratio Different equivalent shell models are proposed for analyzing mechanical behavior of carbon-based nanostructures. For instance, in some studies, the distance between layers of graphite is assumed as wall thickness of equivalent shell and isotropic mechanical parameters are used. However, these equivalent models fail to accurately predict the bending rigidity of CNTs . Previouum shell . This ma=0.34 nm . TherefoXYZ). However, the cylindrical coordinate system (z) might be used for determining the energy expressions of the shell. x direction equals infinity and along tangential direction could be determined byThe curvature radius of the shell along This study investigates low frequency vibration of CNS with large aspect ratio. The thickness of equivalent shell is small and any elastic shell theory could be applied to analyze the vibration of CNS. However, in this study, FSDT based on Love’s approximations is used for modeling CNS. Strain at a point on the equivalent shell using FSDT by considering membrane and bending strains could be expressed asGeneralized Hook’s law describes the equation between components of stress and strain at a typical point. Force and moment applied on the equivalent shell model of a CNS could be calculated by integrating components of stress along the thickness of a shell asThe total strain energy stored in the equivalent continuum shell of CNS could be calculated using Equations (5)–(7).The corresponding kinetic energy of the shell can be written asc is the intertube interaction coefficient per unit length between two layers of MWCNT and can be defined as . In order to implement this procedure, dimensions of CNS need to be transformed. The coordinate transformation between dimensions of CNS and mentioned the interval is x direction. The subscribes V and W can be specified similarly. In order to obtain natural frequencies of CNS, the eigenvalue problem presented in Equation (17) should be solved. The corresponding eigenvector of each natural frequency specifies mode shapes of CNS.Substituting admissible functions of CNS into energy expressions and minimizing total Lagrangian energy with respect to unknown coefficients of displacement construct a set of eigenvaluesThe geometrical structure of a CNS can be described by length, inner radius, separation distance, and subtended angle. However, instead of subtended angle, outer radius of cross section can be used for specifying the geometry of a CNS. The inner radius and subtended angle of a CNS in equilibrium condition can be extracted based on the equations of reference . DistancFinding suitable results in the literature for the vibration behavior of CNS is a serious problem. Therefore, comparing the vibration characteristics of CNS with those of MWCNT is a possible solution. To carry out this investigation a stable CNS, eference . Unlike eference . ConvergThe breathing oscillatory motion studied in the literature is the only vibration behavior of the CNS which could be considered in this research. Shi et al. studied the breathing oscillation of the CNS by neglecting the radial displacement . Their oNatural frequencies and corresponding mode shapes of the predefined CNS: Length of a cylinder is one of the most effective parameters in variation of natural frequencies due to change of mode shapes. Increasing the length of CNS decreases the value of natural frequencies and changes the mode shapes by decreasing number of wave along circumferential direction and increasing number of waves along axial direction. For a specific mode shape of CNSs as open noncircular cylinders, the number of waves in two directions depends on the boundary conditions. However, in general, increasing the length of a CNS leads to reduction in natural frequencies and change in mode shapes. For instance, The energy derived from van der Waals (vdW) interactions between layers of a CNS can be controlled by applying electric field . The appIn order to study the effect of vdW energy on the natural frequencies of a CNS, a graphene sheet, 5 nm × 11.8 nm, has been considered. Rolling up this graphene sheet construct a CNS which its geometric parameters are: A shell model based on FSDT is developed to study the vibration of CNSs. Rayleigh-Ritz method is used to determine the vibration characteristics. The unified model presented in this study enables the researchers to investigate the effect of boundary conditions on the vibration of a CNS.The results show that restricting a CNS at two curved edges leads to local deflections along the straight boundaries. However, generally for other boundary conditions waves along the circumferential direction of CNSs can be observed. The vibration of a CNS cantilever as a target drug delivery system is studied thoroughly. Increasing the length of CNS cantilever decreases the natural frequencies and the number of waves in circumferential direction reduces. It should also be noted that as the length of CNS increases, the number of waves along the axial direction also increases. Applying electric field along the axial direction of CNS results in the enhancement of inner reduce and reduction of natural frequency.


An introduction to the Proceedings of the 2016 CCP4 Study Weekend on protein-ligand complex structures. Since the very early days of protein crystallography, small-molecule ligands have routinely accompanied protein molecules; indeed the first structures seen through the eyes of macromolecular crystallography contained heme moieties associated with hemoglobin and myoglobin.The Protein Data Bank accepted the first structure depositions in the early 1970s and the number of unique ligand molecules rose to about 20 000 in the last half a century. Ligand molecules range from simple ions to large and complex cofactors, elaborate drug-like compounds and intricate post-translational modifications. In spite of their crucial role in biochemical processes, ligands have been the stepchildren of protein crystallography until recently. Unfortunately, this also shows in the quality of many of the deposited ligand structures. This discrepancy can be attributed to a somewhat slower pace of development in ligand building and validation tools within protein crystallography software packages compared with their purely macromolecular counterparts.CCP4 software suite was the novel approach to restraint dictionary generation and the release of the program AceDRG. To promote progress further, outside of CCP4, experts of protein-ligand structure determination and exploitation convened to devise best practices for validation, publication and representation of these structures.Over the last few years this gap has closed considerably. Improvements have been made not only as a result of the efforts made by crystallographic software developers but also because of collaborations involving macromolecular and small-molecule crystallographers, computational chemists and the wwPDB. At the same time, the generation of ligand-complex structures in a high-throughput fashion has gained ground in academic settings as well as at central facilities such as synchrotrons. This in turn presented a higher demand for more robust and automated pipelines that are able to handle ligands and also provided a fertile ground for further improvements and collaborations. The most crucial development of recent years within the Following these rapid changes, crystallography of protein–ligand complex structures was chosen as the topic for the CCP4 Study Weekend held in Nottingham 8–10 January 2016. In spite of the deviation from more traditional topics for these meetings, the 2016 Study Weekend attracted a large international audience with a higher than average attendance, especially amongst students.Ilka Müller and Patrick Collins presented different ways of generating samples for ligand studies. Roberto Steiner, Julie Tucker and Garib Murshudov took the audience through the nitty-gritty details of obtaining high-standard restraints dictionaries for refinement. Rob Nicholls, Joana Pereira, Nicholas Pearce and Paul Adams presented new developments to aid ligand placement into electron-density blobs. Paul Emsley wowed the audience with organic small-molecule validation tools, whereas validation of carbohydrate and metal ligands were discussed by Jon Agirre and Heping Zheng. Ben Bax, Gregory Warren and Oliver Smart highlighted the importance of getting the chemistry and hydrogen placement right, and Peter Moody presented experimental ways to do so. Jason Cole and Colin Groom from the Cambridge Crystallographic Data Centre discussed synergies between small-molecule and protein crystallography. In the final session Charlotte Deane and Martin Noble demonstrated ways of generating and exploiting large numbers of protein–ligand complex structures.Beyond providing a forum for software developers in the ligands field to showcase their latest contributions, the meeting also gave an overview to novice students of the ligand-complex structure determination process from sample preparation through to model building and structure exploitation. Advances both in hardware and software pipelines were presented. Strong common themes included the rich legacy available in the Protein Data Bank, interdisciplinary collaborations and the use of complementary techniques. Stephen Burley and Bernhard Rupp gave introductions from two distinct points of view: one focusing on the validation of already existing data, the other outlining future plans for ligand structures in the Protein Data Bank. These proceedings contain topical review and research articles based on presentations at the CCP4 Study Weekend 2016. We hope that the concepts and tools described here will contribute to further improvements in both the tools that generate protein–ligand complex structures and the resulting deposited structures themselves.The scientific organisers are grateful to CCP4 staff and Working Groups for their practical help and advice in the shaping of the 2016 Study Weekend, and the speakers for their outstanding contributions.