Despite the development of new drugs and other therapeutic strategies, cardiovascular disease (CVD) remains still the major cause of morbidity and mortality in the world population. A lot of research, performed mostly in the last three decades, revealed an important correlation between “classical” demographic and biochemical risk factors for CVD,  with endothelial dysfunction associated directly with the nitric oxide deficiency. The discovery of nitric oxide and its recognition as an endothelial-derived relaxing factor was a breakthrough in understanding the pathophysiology and development of cardiovascular system disorders. The nitric oxide synthesis pathway and its regulation and association with cardiovascular risk factors were a common subject for research during the last decades. As nitric oxide synthase, especially its endothelial isoform, which plays a crucial role in the regulation of NO bioavailability, inhibiting its function results in the increase in the cardiovascular risk pattern. Among agents altering the production of nitric oxide, asymmetric dimethylarginine—the competitive inhibitor of NOS—appears to be the most important. In this review paper, we summarize the role of L-arginine-nitric oxide pathway in cardiovascular disorders with the focus on intraplatelet metabolism. Group associated with neuronal transmission, where the NO plays an inhibitory role as a mediator in peripheral nonadrenergic noncholinergic (NANC) neurotransmission  Group playing an inflammatory role, where NO is produced by the inducible isoform of nitric oxide synthase (iNOS)Group related to the cardiovascular systemAfter establishing the real nature of EDRF by Furchgott et al. , 2, whic− which results in the peroxynitrite formation. Peroxynitrite is a potent oxidative compound which promotes posttranslational modifications of proteins (including the eNOS protein) . I. Ineg plthy ones . FurtherLittle is known about the effect of antiplatelet drugs on NO release by thrombocytes. Inhibition of the GPIIb/IIIa receptor (responsible for fibrinogen binding during platelet aggregation) resulted in the enhancement of NO production and reduction of the formation of superoxide anion . Acetylsneg/eNOSpos ratio, may enable the application of the more appropriate, individualized treatment or early implementation of proper prevention. More research on the exact relation between cardiovascular disorders and the amount of nitric oxide synthesized by platelets is necessary to fully determine their clinical importance. Finally, the knowledge about the biochemistry and exact pathways of PDNO actions may serve as a basis for creating new or using already known drugs in new indications.The knowledge regarding the exact pathogenesis of impaired production of platelet-derived nitric oxide may have important clinical implications. Cardiovascular disorders are frequently related to enhanced thrombus formation. What is more, several conditions, despite the proper antiplatelet treatment, are associated with an elevated incidence of cardiovascular events. Identification of the patients with higher risk, for example, by assessment of platelet-derived nitric oxide production impairment or changes in the eNOS


The case of paid family caregiving under the consumer-directed model introduces unique complexities to patient care, especially in the presence of other formal caregiving. The purpose of this study was to address the interface of paid and family caregiving by exploring scenarios where the two types of caregiving overlap or are merged into one role. Participants were 20 formal caregivers and 21 persons with significant disability, recruited with a purposive sampling approach. In-depth, qualitative interviews were conducted with caregivers and patients to triangulate information from different perspectives. Thematic analysis uncovered pathways into formal caregiving that involved a history of family caregiving, transitions from informal family caregiving to formal family caregiving under the consumer-directed model, and challenges that emerged when formal and informal caregivers co-exist in the same environment. Implications for patient and caregiver experiences in care contexts where the boundaries between paid and unpaid care are blurred are discussed.


Animals move in diverse ways, as indicated in part by the wide variety of gaits and modes that have been described for vertebrate locomotion. Much variation in the gaits of limbed animals is associated with changing speed, whereas different modes of snake locomotion are often associated with moving on different surfaces. For several decades different types of snake locomotion have been categorized as one of four major modes: rectilinear, lateral undulation, sidewinding, and concertina. Recent empirical work shows that the scheme of four modes of snake locomotion is overly conservative. For example, during aquatic lateral undulation, the timing between muscle activity and lateral bending changes along the length of the snake, which is unlike terrestrial lateral undulation. The motor pattern used to prevent sagging while bridging gaps also suggests that arboreal lateral undulation on narrow surfaces or with a few discrete points of support has a different motor pattern than terrestrial lateral undulation when the entire length of the snake is supported. In all types of concertina locomotion, the distance from the head to the tail changes substantially as snakes alternately flex and then extend different portions of their body. However, snakes climbing cylinders with concertina exert forces medially to attain a purchase on the branch, whereas tunnels require pushing laterally to form an anchoring region. Furthermore, different motor patterns are used for these two types of concertina movement. Some snakes climb vertical cylinders with helical wrapping completely around the cylinder, whereas all other forms of concertina bend regions of the body alternately to the left and right. Current data support rectilinear locomotion and sidewinding as being distinct modes, whereas lateral undulation and concertina are best used for defining categories of gaits with some unifying similarities. Partly as a result of different motor patterns, I propose recognizing five and four distinct types of lateral undulation and concertina, respectively, resulting in a total of 11 distinct gaits previously recognized as only four. Animals move in diverse ways depending on their body plan, the structure of the environment, and locomotor speed. The diversity of vertebrate locomotion is commonly categorized by defining different gaits or modes of locomotion for terrestrial limbed animals and aquatic and limbless species. At some level, the terms “gait” and “locomotor mode” can be used interchangeably  given thSome definitions of gaits use quantitative criteria and split a continuum of variation into convenient categories. A classic example of this approach for limbed locomotion is partitioning a bivariate plot of the relative duration of foot contact (duty factor) and the phase lag between an ipsilateral pair of limbs . AlthougIn some cases, quantitative variation creates qualitative differences. For example, the continuous variation in both duty factor and the phase lag between limb movements can give rise to a different sequence in the number of feet that simultaneously contact the ground . In otheFor a given species, much of the variation in the gaits of limbed animals is associated with different speeds of locomotion, and many species of fish also have a regular progression of different modes of swimming as speed increases. Although some variation in the gaits of snakes is associated with variation in speed, the shape and mechanical properties of surfaces are dominant factors influencing the use of different modes of locomotion .For several decades workers have identified four major modes of snake locomotion: rectilinear, lateral undulation, sidewinding, and concertina locomotion . In contPrior to the mid-1980s, quantitative kinematic data for the locomotion of snakes were sparse, and motor patterns had not been determined experimentally. The only information on the energetics of snake locomotion was a preliminary study that was never published in its entirety . FurtherSince the mid-1980s, electromyography has been used to determine the muscular mechanisms of all four of the previously recognized snake locomotor modes . The eneCompared to many other groups of amniotic vertebrates, vast areas of skin along the snake’s body are vitally important for transmitting locomotor forces . Snakes Although the mid-dorsal skin of snakes attaches firmly to the vertebrae, the skin along the belly and lateral to the ribs can move substantially relative to the skeleton, and several muscles attach to the skin in this region. Unlike limbless lizards, snakes have costocutaneous inferior (CCI) and superior (CCS) muscles that connect the ventral and ventro-lateral skin to the ribs . Hence, Of the several additional axial muscles of snakes, the three largest expaxial muscles commonly comprise more than half of the total cross-sectional area of the axial muscles  and fromRectilinear locomotion uses different anatomical structures for propulsion than all other modes of snake locomotion. The ventral and ventro-lateral skin of snakes during rectilinear locomotion periodically shortens and lengthens while this portion of the skin oscillates longitudinally relative to the underlying skeleton . AlthougElectromyographic experiments  support Bipes) are another group of limbless squamate reptiles, and in tunnels they can propel themselves forwards and backwards by moving their skin  and generalized shape trout;  and aquaThe following quantitative differences occur between the aquatic and terrestrial lateral undulation of snakes. In swimming snakes both the amplitude and wavelength of the waves of bending increase regularly from anterior to posterior , and theHydrophis platurus , are equally adept at swimming forward and backward using lateral undulations (Acrochordus granulatus (Acrochordidae) swimming backward . File snakes and true sea snakes are phylogenetically very distant (A. granulatus), the paddle-shaped tail, emphasizes the importance of the entire height of the snake for pushing against water to provide propulsion, whereas nearly all locomotion of snakes on solid surfaces uses only a fraction of the entire surface area to push against the environment.Some species of sea snake, such as ulations . I have  distant , which sChrysopelea can modulate the sharpness of the keel  forward aquatic lateral undulation , (2) bacAt first glance sidewinding seems radically different from terrestrial lateral undulation, partly because it allows movement on flat smooth uncluttered surfaces upon which terrestrial lateral undulation is difficult or impossible. Movements of sidewinding differ from terrestrial lateral undulation by the following traits: (1) some parts of the snake have static contact with the ground, (2) all points along the length of the snake follow distinctly different but nearly parallel paths, (3) regions of static contact create disconnected tracks that are parallel to each other and oblique to the overall direction of travel , and (4)Sidewinding and terrestrial lateral undulation have the following major similarities . First, Two features of the axial motor pattern of sidewinding differ from terrestrial lateral undulation . First, Concertina locomotion may be performed on flat, smooth horizontal surfaces, within the confines of tunnels and on cylindrical surfaces such as branches . Snakes Python reticulatus, total lengths = 179–197 cm) on a flat surface in the laboratory  flat-surface concertina , (2) tunBoiga irregularis) provide several additional insights regarding the plasticity of axial motor patterns and the diversity of locomotor modes  AxiRecent findings, especially those arising from electromyographic studies, make a compelling case for recognizing far more distinct modes of snake locomotion than the traditional scheme of four . The terms rectilinear and sidewinding still retain their original utility as they each refer to a unique mode. By contrast and analogous to symmetric and asymmetric limbed gaits, the terms lateral undulation and concertina now seem most useful as categories of locomotion within each of which many distinct types of locomotion occur. I recognize the following five types of lateral undulation: (1) terrestrial lateral undulation, (2) forward aquatic lateral undulation, (3) backward aquatic lateral undulation, (4) lateral undulation with a ventrolateral keel, and (5) arboreal lateral undulation. Four types of concertina locomotion are: (1) flat-surface concertina, (2) tunnel concertina, (3) arboreal concertina with alternate bends, and (4) arboreal concertina with helical wrapping. Thus, I favor recognizing at least the 11 distinct modes of snake locomotion listed above that would have been traditionally considered as only four modes. If one were to include all behaviors and directions involved in crossing gaps and the variable orientations relative to gravity for movement on solid surfaces, the total number of likely distinct modes would be even greater. One should also remember that considerable quantitative variation occurs within all of the modes depending on the species of snake and the environmental conditions.Clearly, complex systems are most easily understood by starting with the simplest cases, and this is reflected in the progression of knowledge for the locomotion of snakes. However, conclusions regarding the complexity of systems and extent to which behaviors are stereotyped can be very misleading if only the simplest cases are studied. Thus, the continued study of snake locomotion by many workers over many decades nicely illustrates the enhanced understanding of the diversity of form, function, and behavior that can emerge from building levels of complexity, in part by using the diverse behavioral repertoire of animals in nature as the ultimate guide for inquiry.This work was partially supported by a grant from the National Science Foundation to B.C.J [IOS 0843197]. I am especially grateful to S. A. Jayne and S. H. Jayne for paying for the publication costs as well as for more than 50 years of unwavering support for my interests in biology.ICB online.icaa017_Supplementary_DataClick here for additional data file.


We extend a recently proposed computational strategy for the simulation of absorption spectra of semi-rigid molecular systems in condensed phases to the emission spectra of flexible chromophores. As a case study, we have chosen the CPL spectrum of camphor in methanol solution, which shows a well-defined bisignate shape. The first step of our approach is the quantum mechanical computation of reference spectra including vibrational averaging effects and taking bulk solvent effects into account by means of the polarizable continuum model. In the present case, the large amplitude inversion mode is explicitly treated by a numerical approach, whereas the other small-amplitude vibrational modes are taken into account within the harmonic approximation. Next, the snapshots of classical molecular dynamics computations are clusterized and one representative configuration from each cluster is used to compute a reference spectrum. In the present case, different clusters correspond to the two stable conformers of camphor in the S1 excited electronic state and, for each of them, to different numbers of strong solute-solvent hydrogen bonds. Finally, local fluctuation effects within each cluster are taken into account by means of the perturbed matrix model. The overall procedure leads to good agreement with experiment for absorption and emission spectra together with their chiral counterparts, thus allowing to analyze the role of different effects  in tuning the overall experimental spectra. Circularly polarized luminescence (CPL) and electronic circular dichroism (ECD) are complementary techniques giving access to the properties of the excited and ground electronic states, respectively for chiral chromophores or chromophores embedded in chiral environments  and emission (OPE) spectra and of their chiral counterparts ECD and CPL. We employ our recently developed ONIOM/EE-PMM  and Herzberg-Teller (HT) effects. Finally, internal coordinates are used in order to minimize the coupling between normal modes and LAMs, which are properly accounted for and treated separately.a posteriori by means of full QM calculations of vibrational modulation effects by means of models based on the Franck-Condon principle (see sections 2.3). Conversely, as already reported , we accounted for its effects by extracting the most representative conformers characterizing the excited state potential energy surface as a function of the carbonyl out of plane bending . In details, for each frame of each sub-trajectory, the system Hamiltonian is written as the diagonal matrix of the eigenvalues of the reference configuration plus a perturbation matrix representing the difference of the electrostatic potential between the considered frame and the reference value. Diagonalization of this matrix provides a set of eigenvalues (electronic states) representing the instantaneous effects of the embedding environment as provided by the MD trajectories. The operator representing the variation between the perturbing effects exerted by the environment in each frame and the reference, is modeled by exploiting the latest development of the PMM procedure, that is by expanding the perturbing electrostatic potential within the atomic region around each atomic center (atom-based expansion)  effects in electronic spectra using models based on the Franck-Condon principle and a continuum description (PCM) of bulk solvent effects, as described in detail in Barone et al. , Bloino Once computed the vibronic spectra for the reference structure of each conformer, they need to be combined with the outcome of the ONIOM/EE-PMM procedure to obtain the final spectra.At the FC level, a simple shift by the transition energy and scaling by the transition moments for each snapshot leads, after proper averaging, to the final spectrum. Furthermore, on the grounds of previous experience . Normal modes connected with the LAM or methyl rotations were removed. Gaussian distribution functions with HWHM of 900, 550, and 450 cm−1 were used as broadening functions for pure electronic ONIOM/EE-PMM, vibronic PCM, and combined ONIOM/EE-PMM vibronic approaches, respectively. Spatial Distribution Functions plotted as isosurfaces and virtual sites were visualized employing the Caffeine software  contributions.The effectiveness of the interaction between camphor and the embedding solvent was at first assessed by computing the Spatial Distribution Function (SDF) of the methanol molecules around the solute for the ground state simulation. In The partitioning is the first step toward application of the ONIOM/EE-PMM method, with the four clusters providing the different statistical ensembles from which the representative frames to be employed for the ONIOM/EE calculations were extracted. Then, the PMM procedure was applied to account for fluctuations (within each cluster) of the external electric potential tuning the electronic properties of the chromophore.In order to increase the accuracy of the results, all the transition energies were shifted with reference to the values computed in the gas-phase at the Cis(d) B2PLYPD3/jun-cc-pVTZ level, which is significantly more reliable than TD-DFT with hybrid functionals , which requires, inter alia, the challenging reproduction of significantly different ECD and CPL spectra. The computational strategy starts from the collection of transition energies and dipole moments tuned by environmental effects provided by MD simulations. Next, vibrational modulation effects on the different electronic transitions are taken into account by a fully quantum mechanical approach including Franck-Condon and Herzberg-Teller contributions together with bulk solvent effects described by a polarizable continuum model. At variance with previous applications, a large amplitude motion has been explicitly considered by means of a discrete-variational approach. Specific chromophore-environment interactions and their fluctuations are described by a recently proposed hybrid procedure, which combines a variational approach (ONIOM/EE), with the PMM perturbative approach. In this way, it becomes possible to obtain accurate results without the need to perform explicit computations for a statistically significant number of solute-solvent configurations. For each stationary point of this flexible system  we partitioned the overall simulations into four subsets (clusters) related to the presence or not of strong solute-solvent hydrogen bonds. Although the flexibility of the system increases the number of explicit QM computations with respect to semi-rigid chromophores, the proposed ONIOM/EE-PMM approach strongly reduces the computational effort with respect to a standard QM/MM computation. The good agreement between all the computational results and their experimental counterparts, gives confidence about the robustness and reliability of the overall procedure and permits the analysis of the role of different contributions  in tuning the overall spectra.The original contributions presented in the study are included in the article/All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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. The reviewer LE declared a past co-authorship with one of the authors VB to the handling editor.


A 43-year-old female shiatsu therapist complained of sudden snapping of the metacarpophalangeal joints (MCPjs) of both ring fingers during a specific hand posture. The extensor tendon of the ring finger was dislocated ulnarly when the MCPj of the ring finger was flexed and deviated ulnarly and the MCPj of the middle finger was extended. Surgical exploration revealed an attenuated radial sagittal band. We plicated the juncturae tendinum of the extensor digitorum communis between the middle and ring fingers and released the ulnar sagittal band partially to centralise the extensor tendon excursion. Twenty-six months postoperatively, the patient regained full active and passive range of motion of all fingers without extensor tendon dislocation or snapping in either hand during work. Extensor tendon dislocation at the metacarpophalangeal joint (MCPj) of the hand has four etiologies: congenital origin, degenerative, traumatic, or spontaneous sagittal band rupture –3. DegenA 43-year-old female shiatsu therapist with 20 years of experience complained of sudden snapping of the MCPj of the left ring finger (her nondominant hand) and pain in the dorsum of the MCPj. The patient did not have any conditions that would predispose her to sagittal band laxity including prior trauma to the hand. Two weeks later, the snapping and pain occurred in the right ring finger. On physical examination, the extensor tendons at the dorsum of the MCPjs of both ring fingers dislocated with a specific hand posture . On actiFour weeks after the first visit, we performed reconstruction of the extensor tendons of the both ring fingers with wrist blocks. Surgical exploration through a longitudinal curved skin incision at the dorsum of the MCPj of the ring finger revealed a markedly attenuated radial sagittal band and ulnarly dislocated extensor tendons bilaterally . We plicPostoperatively, we applied a bulky hand dressing with a forearm-based volar plaster splint to the MCPj in the extended position in order to prevent inadvertent passive flexion of the MCPj. Active flexion and extension exercises were performed from 1 to 6 weeks postoperatively. Six weeks postoperatively, we removed the splint and allowed all MCPj movements. Six months postoperatively, the patient resumed work as a shiatsu therapist without extensor tendon dislocation and snapping at the MCPjs. All finger movements were performed with no limitations in either hand. Twenty-six months postoperatively, the patient remained pain-free during work without extensor tendon dislocation or snapping in either hand.Dislocation of the extensor tendon usually presents with symptoms of pain and snapping at the MCPj during MCPj flexion. In our case, however, the extensor tendon was dislocated only when the MCPj of the middle finger was extended and the MCPj of the ring finger was flexed with ulnar deviation. In acute injuries, conservative treatment may provide satisfactory results . When noThe sagittal band is the primary stabilizer of the extensor tendon at MCPj, keeping the tendon in position during flexion and extension. Failure of the sagittal band to centralise the tendon, which may be the result of trauma, laxity, or congenital absence, causes dislocation of the extensor tendon . UsuallyContrary to most reports, our case indicated that excessive traction stress by repetitive use of a specific posture may contribute to rupture of the radial component of the sagittal band of the ring finger . This ra


Endotherapy is a recognized, widely available, and minimally invasive treatment method for pancreatic fluid collections (PFCs) formed in the course of acute pancreatitis (AP). The use of endoscopic techniques in the treatment of main pancreatic duct (MPD) disruption due to AP remains unclear. In this article, a comprehensive review of current literature referencing our observations was performed to identify publications on the role of MPD stenting in patients undergoing endoscopic drainage of PFCs resulting from AP. In this paper, we attempt to clarify this most controversial aspect of endotherapy for PFCs based on existing knowledge and our own experience regarding the endoscopic treatment of AP sequelae. Endoscopic retrograde pancreatography should be performed in all patients undergoing endoscopic drainage of walled-off pancreatic necrosis to assess the integrity of the main pancreatic duct and to implement endotherapy if pancreatic duct disruption is detected. Passive transpapillary drainage is an effective method for treating MPD disruption in the course of necrotizing AP and is one of the key components of endoscopic therapy for local pancreatic necrosis. Conversely, in patients with pancreatic pseudocysts, passive transpapillary drainage reduces the effectiveness of endoscopic treatment and should not be used even in cases of MPD disruption during transmural drainage of pancreatic pseudocysts. In conclusion, the use of transpapillary drainage should depend on the type of the PFC. This conclusion is of great clinical importance, as it can help improve the results of pancreatic endotherapy for fluid collections resulting from AP. Acute pancreatitis is associated with high morbidity and mortality, especially if an infection of the necrotic region is present. According to the 2012 revision of the Atlanta Classification of Acute Pancreatitis, depending on the stage of disease and morphological type of acute pancreatitis, four types of fluid collections formed in the pancreatic and peripancreatic regions in the course of acute pancreatitis can be distinguished: acute peripancreatic fluid collection, pancreatic pseudocysts, acute necrotic collection, and walled-off pancreatic necrosis .In the early stage of the interstitial-edematous form of acute pancreatitis, acute peripheral fluid collections may develop, which, after about 4 weeks, develop into pancreatic pseudocysts ,2,3. AcuDuring the first 4 weeks of acute necrotizing pancreatitis, pancreatic fluid collections are referred to as acute necrotic collections, which are poorly demarcated fluid reservoirs containing a large amount of necrotic tissue that form in most patients over these first 4 weeks of illness ,2,3. NeaOver the past decades, major changes have been observed regarding the treatment strategy of pancreatic and peripancreatic fluid collections in the course of acute pancreatitis ,7,8,9. IIn recent decades, minimally invasive techniques for treating the sequelae of acute pancreatitis have dynamically developed ,9. EndotThe disruption of the main pancreatic duct may occur in the course of acute pancreatitis, manifesting as a leakage of contrast into the reservoir during endoscopic retrograde pancreatography ,10,11. PEndoscopic treatment of pancreatic duct disruption consists of endoscopic sphincterotomy and stenting of the main pancreatic duct (passive transpapillary drainage) to ensure physiological outflow of pancreatic juices into the duodenum ,11,12,13Few publications are available in the current literature about passive transpapillary drainage in patients with acute pancreatitis, and the available data are often contradictory. In this paper, a comprehensive review of current literature referencing our observations from pancreatic referral centers was performed to identify publications on the role of pancreatic duct stenting in patients undergoing the endoscopic drainage of pancreatic fluid collections resulting from acute pancreatitis. In this publication, we attempted to clarify this most controversial aspect of endotherapy for pancreatic fluid collections based on existing knowledge of the endoscopic treatment of acute pancreatitis sequelae. Due to the our substantial experience in the field of endotherapy of the consequences of acute pancreatitis, and because few publications were available, this review article is, to a large extent, based on our own observations derived from data available in the current literature. Consequently, we tried to avoid conclusions drawn from the publications and rather speculate on the mechanisms and requirements for future study in the context of a randomized series.Endotherapy for post-inflammatory pancreatic and peripancreatic fluid collections A–L is a A 2018 publication presented the results of the endoscopic treatment of 226 patients with walled-off pancreatic necrosis . DisruptThere is no clearly defined timing for passive endoscopic transpapillary drainage. The basis of the treatment is to perform passive transpapillary drainage during ongoing transmural drainage of walled-off pancreatic necrosis—never in reverse. Transpapillary drainage performed before transmural drainage leads to secondary infection of the necrotic collection. Consequently, it worsens the clinical condition of the patient due to the inability to perform complete drainage via the transpapillary route. Consequently, active transmural drainage of pancreatic necrosis with endoscopic necrosectomy should be performed first, and only during ongoing transmural drainage should the endoscopic pancreatic duct stenting be performed.Two other studies presented the results of endoscopic treatment of pancreatic fluid collections, where the vast majority (93–100%) of the study group consisted of patients with pancreatic pseudocysts ,15. BothMoreover, patients with pancreatic pseudocysts and pancreatic duct disruption should undergo transpapillary drainage or transmural drainage of the pseudocyst. Implementing both drainage methods  in patients with pancreatic pseudocysts increases the condition’s duration and worsens the outcomes of endotherapy.In patients undergoing transmural drainage of walled-off pancreatic necrosis, the use of passive transpapillary drainage improves the results of endotherapy. Conversely, in patients undergoing transmural drainage of pancreatic pseudocysts, passive transpapillary drainage worsens the short- and long-term outcomes of endoscopic treatment and increases the duration of endotherapy.The use of passive transpapillary drainage through pancreatic duct stenting should depend on the type of pancreatic fluid collection being treated. Endoscopic retrograde pancreatography should be performed to assess the integrity of the main pancreatic duct and to implement endotherapy in case a disruption of the pancreatic duct is identified for all patients undergoing endoscopic drainage of walled-off pancreatic necrosis, as opposed to patients with pancreatic pseudocysts. The endoscopic treatment of main pancreatic duct disruption constitutes the key component of endotherapy for walled-off pancreatic necrosis. Stenting of the main pancreatic duct in patients with main pancreatic duct disruption in the course of acute necrotizing pancreatitis increases the effectiveness of endotherapy for walled-off pancreatic necrosis, improves the long-term results of endoscopic treatment, and reduces the number of recurrent pancreatic fluid collections. The implication of the hypothesis for clinical practice is the implementation of endoscopic retrograde pancreatography in all patients with pancreatic necrosis to assess the integrity of the pancreatic duct and pancreatic duct stenting if a duct disruption is identified. In patients with pancreatic pseudocysts, stenting of the main pancreatic duct adversely affects the results of endoscopic treatment and prolongs endotherapy.The literature contains few publications regarding passive transpapillary drainage in patients with acute pancreatitis, and the available data are contradictory. Endoscopic treatment of main pancreatic duct disruption in the course of acute necrotizing pancreatitis is one of the key elements of endotherapy for walled-off pancreatic necrosis. Stenting of the main pancreatic duct is an effective method for treating disruption of the pancreatic duct, and it improves the results of endoscopic treatment in patients with walled-off pancreatic necrosis . SimilarPassive transpapillary drainage performed during pancreatic pseudocyst drainage, reduces the effectiveness of endotherapy and prolongs endoscopic treatment. Hookey et al. found no significant differences in the effectiveness of treatment between patients undergoing only endoscopic ultrasound-guided transmural drainage versus the group where main pancreatic duct stenting (combined drainage) was applied in addition to transmural drainage . They alIn the cited papers ,15,16, tDisruption of the main pancreatic duct occurs in most patients with acute pancreatitis. Partial pancreatic duct disruption is more common than complete disruption ,10,17. IIn this paper, we demonstrated the effectiveness of passive transpapillary drainage in patients with walled-off pancreatic necrosis, as opposed to patients with pancreatic pseudocysts, where main pancreatic duct stenting worsens the outcomes of endotherapy. In combination with active wall drainage, passive transpapillary drainage is an effective, minimally invasive treatment method for walled-off pancreatic necrosis. In contrast, in patients with pancreatic pseudocysts, the combination of transmural drainage with passive transpapillary drainage does not offer any therapeutic benefit.As described above, the aim of endoscopic treatment of main pancreatic duct disruptions is to ensure physiological drainage of pancreatic juice into the duodenum, which consequently decreases leakage of pancreatic juice into the lumen of the collection communicating with main pancreatic duct. Similar results should be achieved with the use of somatostatin and its analogues , which reduce the pancreatic exocrine secretions ,20. The Endoscopic treatment of pancreatic duct disruption includes endoscopic sphincterotomy and implantation of a prosthesis into the main pancreatic duct. Passive transpapillary drainage (stenting of the pancreatic duct) decreases the pancreatic ductal pressure and helps to rapidly close the disruption. In the case of pancreatic pseudocysts communicating with the main pancreatic duct, passive transpapillary drainage aims to evacuate serous content from the collections to achieve complete regression of the pseudocysts. Patients with pancreatic pseudocysts and pancreatic duct disruption should undergo transpapillary drainage or transmural drainage of the pseudocysts. Implementing both drainage methods  in patients with pancreatic pseudocysts worsens the outcomes of endotherapy and increases its duration. The case is different in patients with walled-off pancreatic necrosis. The main reason for passive transpapillary drainage during transmural drainage of pancreatic necrosis is not to drain the necrotic content through the stent but to ensure physiological drainage of pancreatic juices into the duodenum. It helps to heal pancreatic duct disruption and decreases leakage of pancreatic juice into the lumen of collections, which consequently also helps to heal the collections. In all patients with walled-off pancreatic necrosis treated at our medical center, we attempted to perform endoscopic retrograde pancreatography to assess the morphology and integrity of the main pancreatic duct and the possible use of endoscopic treatment. In the case of the disruption of the pancreatic duct, endoscopic sphincterotomy was performed and pancreatic endoprosthesis was introduced into the main pancreatic duct, which was then replaced on average at 3, 6, 12, and 24 months or until there was no contrast flow outside the duct. The size and length of the pancreatic stent should be selected individually according to the fluoroscopic image of the main pancreatic duct during endoscopic retrograde pancreatography. The most common stents are straight or one-pigtail, the size of 5 or 7Fr, and the length of 9 or 12 cm. The scheme of passive transpapillary drainage in patients with pancreatic pseudocysts looks similar. The only difference is that larger pancreatic stents  are used more frequently.In our opinion, not every patient during endoscopic treatment of pancreatic fluid collections requires stenting of the main pancreatic duct (endoscopic passive transpapillary drainage). The use of passive transpapillary drainage during endoscopic transmural drainage should depend on the type of pancreatic fluid collection. There is a need to perform endoscopic retrograde pancreatography with pancreatic duct stenting in all patients with pancreatic duct disruption during endotherapy for walled-off pancreatic necrosis which helps to improve the results of endoscopic treatment in patients with acute necrotizing pancreatitis. Conversely, passive transpapillary drainage should not be performed during transmural drainage in patients with pancreatic pseudocysts, even in cases of confirmed main pancreatic disruption as it negatively affects treatment outcomes. We emphasize, however, that further randomized trials are necessary to confirm the conclusions.However, it is our opinion that, relying on the current state of knowledge, passive transpapillary drainage is an effective method for treating main pancreatic duct disruption in the course of acute necrotizing pancreatitis, and it improves the results of endoscopic treatment in patients with walled-off pancreatic necrosis. In patients with pancreatic pseudocysts, passive transpapillary drainage worsens the results of endoscopic treatment and should not be used even in cases of main pancreatic duct disruption.


The use of cardioplegia solutions as a myocardial protection technique is essential during cardiac surgery with cardiopulmonary bypass. The del Nido cardioplegia solution (DNS) has been widely used as a myocardial preservation technique for pediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Its unique pharmacological features have created growing interest for adult cardiac surgery, especially for elderly patients or those with ventricular dysfunction who are more prone to ischemia-reperfusion injury. Ever since its implementation, several retrospective studies have been published to validate the efficacy, safety, and efficiency of DNS in adult patients undergoing coronary revascularization, valve replacement, or combined procedures. Recently, a meta-analysis based on nine retrospective studies was published claiming the noninferiority of DNS compared to other conventional cardioplegia solutions. Few prospective randomized studies have been conducted whose primary outcome was the assessment of DNS clinical efficacy compared to other solutions commonly used in adult patients.The aim of this randomized clinical trial is to assess the benefits of DNS compared to Cardi-Braun blood cardioplegia solution in clinical and biochemical terms regarding myocardial protection during adult cardiac surgery.acute cardiovascular event). The clinical trial will be carried out under conditions of respect for the fundamental rights of the person and the ethical principles that affect biomedical research with human beings, as well as in accordance with international recommendations contained in the Declaration of Helsinki and its subsequent revisions.This is the protocol of a controlled, randomized, single-center clinical trial carried out at the Puerta de Hierro Majadahonda University Hospital in Spain. A total of 474 participants over the age of 18 years undergoing elective cardiac surgery with cardiopulmonary bypass will be assigned to groups by simple randomization to receive either DNS or Cardi-Braun blood cardioplegia solution. The primary outcome will be the differences between groups in myocardial protection in biochemical terms  and clinical terms  2017-005144-14; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2017-005144-14+; ClinicalTrials.gov NCT04094168; https://clinicaltrials.gov/ct2/show/NCT04094168DERR1-10.2196/17826 Myocardial protection during cardiac surgery with cardiopulmonary bypass is essential to avoid detrimental effects of ischemia secondary to aortic cross-clamping. To do so, several strategies have been used throughout the years, such as intermittent aortic occlusion, induced ventricular fibrillation, deep systemic hypothermia, or the administration or cardioplegia solutions.In 1955, Melrose et al were the first to propose the concept of hyperkalemic cardioplegia, using a high-concentration potassium-citrate solution to afford elective reversible cardiac arrest [On the other hand, there has been a tangible change in the features of patients undergoing cardiac surgery for the last two decades. Patients are older and, therefore, have increased comorbidity, and they undergo more complex surgical procedures, which entail longer ischemia times. The quest for a cardioplegia solution providing maximal myocardial protection has never been more important.The del Nido cardioplegia solution (DNS) was first formulated for pediatric cardiac surgery in the early 1990s and has been widely used ever since . It contIts pharmacological properties have contributed to its popularity for elderly patients with depleted myocardial reserve undergoing cardiac surgery ,4. ExperSeveral retrospective studies have assessed the safety and efficacy of DNS in adults undergoing coronary revascularization, valve replacement, combined procedures, and cardiac reinterventions -8.In 2017, a meta-analysis comparing the effects of DNS and conventional cardioplegia solutions in adult cardiac surgery was published . It concRecently, two prospective studies assessing the effects of DNS in adults have been published ,11, yet The aim of this study is to establish the benefits of DNS in clinical and biochemical terms regarding myocardial protection during adult cardiac surgery.The study was planned according to the updated Consolidated Standards of Reporting Trials (CONSORT) statement, the Declaration of Helsinki, and the Guidelines of Good Clinical Practice issued, as required, by Spanish regulatory authorities. This study will be conducted at one center, the Puerta de Hierro Majadahonda University Hospital.This study is designed as a single-center, double-blind, controlled clinical trial. Participants will be randomized into a group receiving del Nido cardioplegia (intervention group) or a group receiving Cardi-Braun cold blood cardioplegia  or extracorporeal membrane oxygenation (ECMO); or preoperative intubationPatients undergoing mitral valve replacement surgery using the Heartport techniqueWithin the control group, blood cardioplegia will be administered by means of a cold induction dose at 4-8 °C and a maintenance dose administered every 20 minutes. It will be dispensed via the anterograde or retrograde approach according to the protocol of the center.Within the intervention group, del Nido cardioplegia will be administered according to the usual practice in a single dose of 1000 cc via the anterograde or retrograde approach according to the protocol of the center. Additional doses (550 mL) will be administered when spontaneous electrical activity appears or, in the case of periods of ischemia, longer than 90 minutes. Common clinical practice will not be modified in the remaining perioperative aspects.acute cardiovascular event and the biochemical variable maximum postoperative troponin value.The main variables of the study will be the composite clinical variable acute cardiovascular event variable will consist of one or several of the following events:The Early perioperative myocardial infarction: occurring during the first 72 hours after surgery and defined according to the criteria of the Task Force of the European Society of Cardiology, the American Heart Association, and the World Heart Federation.Prolonged low cardiac output: defined as the need to maintain support with two or more inotropic and/or other circulatory mechanical assistance devices—intra-aortic balloon counterpulsation (IABC) or extracorporeal membrane oxygenation (ECMO)—beyond the first 24 postoperative hours.Appearance of ventricular arrhythmias: ventricular tachycardia (VT) and ventricular fibrillation (VF) requiring electrical cardioversion in the first 24 postoperative hours.To analyze the effect of cardioplegia on myocardial protection at a biochemical level, the level of troponins will be monitored upon arrival at the ICU and during the first 48 hours. Likewise, the maximum troponin peak will be collected during the first 48 postoperative hours.Other secondary variables of efficacy and safety will be analyzed. Among the intraoperative variables, surgical times , the volume of cardioplegia solution administered and its route of administration, temperature, average blood pressure, and maximum blood glucose values, as well as the need for electrical cardioversion after aortic cross-clamp release, will be monitored.Among the postoperative variables, the occurrence of atrial fibrillation will be registered, as well as the requirement for inotropic and mechanical pharmacological support, time to withdrawal, and the occurrence of clinical complications . The need for ICU readmission, ICU and hospital length of stay, and mortality will also be noted.Subgroup analyses will be carried out in four populations: elderly patients (over 80 years), patients undergoing prolonged cardiopulmonary bypass (longer than 120 minutes), patients with low ventricular ejection fraction (less than 30%), and patients subjected to coronary artery bypass grafting.Follow-up will be carried out from the beginning of the randomization until the participant is discharged. The variables will be collected in the operating room postoperatively; variable collection will occur at a higher frequency within the first 48 hours.The research team will monitor the possible adverse events, including the time of occurrence, duration, intensity, course, and outcome, in order to make an assessment of the causal relationship between the adverse event and the drug.The literature reviewed reflects a need for postoperative inotropic vasoactive support ranging from 35% to 40%. In the sample size calculation, we propose that better myocardial protection will be reflected in a lower need for electrical cardioversion, lower pharmacological inotropic or mechanical support, and a lower incidence of myocardial infarction.For a hypothetical reduction of inotropic support within the first 24 postoperative hours from 38% to 25%, with an α risk of 5%, at a statistical power of 80% (β=.20), by bilateral test with application of the Fleiss correction factor, and estimating losses of 10%, 474 participants distributed into two groups will be necessary.Participants will be assigned to groups by simple randomization of the sample, obtaining a computer sequence by Stata 16 (StataCorp). The computer distribution will assign 234 participants to the intervention group (DNS) and 240 participants to the control group (blood cardioplegia). When patients arrive at the theater, perfusionists will enroll participants.prolonged low cardiac output syndrome—will be created from the following original variables: presence of two or more inotropic agents at 24 hours of admission, mechanical support with IABC, and/or mechanical support with ECMO or other ventricular assistance. The main composite variable—acute cardiovascular event—will be created from the following variables: perioperative myocardial infarction, prolonged low cardiac output syndrome, prolonged vasoplegia, and/or VT or VF episodes in the first 24 hours.A description of the data from each group of the study and the total sample will be carried out. The properties of the original variables will be defined, and the aforementioned composite variables will be created. The main variable—P value by means of the Student-Fisher t test; correction for unequal variances for the quantitative variables, and the association with the odds ratio and the P value, will be obtained with chi-square tests for the categorical variables.The quantitative variables shall be described through the mean (SD), median (IQR), 95% CI, and minimum and maximum values. Qualitative variables shall be presented as relative and absolute frequencies. To ensure the uniformity of the groups, a detailed analysis will be made by evaluating the association using the Pearson correlation coefficient and the The raw effect of each type of cardioplegia on the acute cardiovascular event will be estimated using a logistic regression model.Two populations will be defined through intention-to-treat analysis and by biological efficacy. The first population will include all the initially randomized subjects, including all those who leave the study due to noncompliance. The second population will include all those subjects who complete the study within the same group in which they were randomized. An intermediate safety analysis will be performed when approximately 50% of patients have been randomized.low intervention–level trial, due to the fact that the cardioplegia solutions used are already approved and used in accordance with the terms of the marketing authorization; as well, the solutions are extensively backed up by published scientific evidence on their safety and efficacy .The clinical trial is defined as a The confidentiality of the identity of the volunteers will be respected if the data obtained in this study are published. Subjects’ data included in the study will be treated in accordance with Organic Law 15/1999, December 13, on the Protection of Personal Data.This study has been registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) (No. 2017-005144-14) and at ClinicalTrials.gov (No. NCT04094168). The study protocol has been approved by the Ethics Committee of Puerta de Hierro Majadahonda University Hospital and was approved by the Spanish Medicines and Health Products Agency (AEMPS).This clinical trial will be carried out under conditions of respect for the fundamental rights of the person and the ethical principles that affect biomedical research with human beings, as well as in accordance with international recommendations contained in the Declaration of Helsinki and its subsequent revisions. Likewise, national recommendations will be followed in accordance with the guidelines of the AEMPS.Participants will receive information, both orally and in writing, regarding the manner in which the study will be carried out, the study aims, possible risks that may arise from the study, and the rules that must be observed during the follow-up period. If the patient fulfils the inclusion criteria and agrees to participate in the study, she or he will provide written informed consent; providing consent will not prevent the patient from withdrawing such consent and abandoning the study at any time and for any reason.The datasets used and/or analyzed during the study will be available from the corresponding author upon reasonable request.The inclusion process started in 2018. Data cleaning and analyses are expected to take place in the fall of 2020 and the results are expected in January 2021.This study is expected to expand knowledge of DNS in adult cardiac surgery. DNS is assumed to be beneficial in terms of myocardial protection, and it is expected to corroborate a reduction in VF after declamping the aorta and in the number of defibrillations. Also, it is presumed to result in a reduction in postoperative troponin levels and inotropic support for low cardiac output syndrome. Although it is not the main objective of the study, the trial will provide information regarding the benefits of DNS in high-risk subpopulations, such as elderly patients and those with longer periods of cross-clamping or low ventricular ejection fraction.This study is particularly relevant as it will be the first to analyze the clinical effects of del Nido cardioplegia on the basis of direct myocardial protection parameters. Although the meta-analysis published in 2017 highlighted some clinical benefits in favor of del Nido cardioplegia, there was a fundamental limitation, which is that data collection was based on retrospective studies.Further published prospective studies also failed to focus their primary objectives on the analysis of the possible clinical effects of del Nido cardioplegia. Ad et al analyzed the postoperative troponin peak and the need for electrical cardioversion after aortic cross-clamp release in a population of 89 patients; in addition to its small sample size, this study excluded high-risk patients over 80 years of age, and the data showed short aortic clamp times .Sanetra et al analyzed troponin peak and electrical activity after aortic cross-clamp release in a population of 150 patients undergoing aortic valve replacement. All clinical outcomes detailed in the study were part of the secondary objectives. Likewise, they excluded from their analysis reoperated patients with ejection fractions under 30% or with coronary artery disease susceptible to percutaneous interventionism or surgery .In light of the above studies, carrying out prospective studies based on primary clinical objectives with a larger sample, high-risk patients, and longer cardiopulmonary bypass times continues to be necessary . We beliThis clinical trial has several strengths. The calculated sample size is large and includes elderly patients with a history of ventricular dysfunction. It does not exclude complex procedures that may involve longer cardiopulmonary bypass times.The trial also has some limitations. Although surgical procedures will be performed by different surgeons, the single-center design may generate external validation problems. The exclusion of emergent interventions and of patients with preoperative vasoactive support also limits extrapolation of results to unstable patients.In developing the methodology, we have aimed to reduce bias as much as possible. The compilation of other myocardial protection variables has been fundamental in addressing bias.


Atopic diseases in childhood are a major burden worldwide and there is still a lack of knowledge about treatable causes. In industrialized countries such as Germany, almost every second child is sensitized to at least one common allergen. Recent studies show that although the predisposition to allergies is inherited, the adaptive immune system of neonates and infants follows a developmental trajectory and whether an allergy actually occurs depends also on timing of allergen exposure including diet as well as environmental factors. New recommendations are far from being rigid of allergen avoidance; it is rather moving toward conditions that stand for more biodiversity. The observation that introduction of peanuts or eggs early in life significantly reduced the development of a later allergy will change our recommendations for the introduction of complementary foods. This is consistent with the hygiene hypothesis that early provocation shapes the developing immune system so that it reacts appropriately. Therefore, promoting the development of tolerance is at the heart of sensible allergy prevention - and this begins with the last trimester of pregnancy. In light of this concept, actual recommendations are discussed. Atopic diseases are among the most common chronic health problems affecting children and young people all around the world . Althougasophils . ReencouThe definition of immune tolerance to allergens is establishment of a long-term clinical unresponsiveness to one specific or many allergens , 5. It iSudden resolution of food allergy in infancy and childhood has been reported regularly. This natural induction of tolerance is often associated with reduction of allergen-specific antibody production of the IgE isotype and activity of basophils in addition to enhanced levels of allergen-specific antibodies of the IgG4 isotype and frequencies of regulatory T cells (Tregs) –9. This Numerous recommendations for allergy prevention, as formulated in guidelines in Germany have been subject to considerable fluctuation on the basis of recently published clinical studies . In someDuring infancy and childhood, atopic diseases are the most common chronic diseases . CurrentIn industrial countries, one in four is suffering from allergy symptoms . The corMultiple factors influence the development of neonatal immunity among them maternal IgG and cytokines, as well as antigen exposure and numbers of lymphocyte subpopulations and antigen presenting cells (APCs). A developmental trajectory of changes in cell composition of the blood has been demonstrated during the first seven days of life . Herein,+ T cells (in utero affect differentiation of Th cell and mediate subpopulation characteristic profiles of genomes during immune system development (+ T cells with SEB (Staphylococcus Enterotoxin B) and monocytes or with Candida albicans-matured or Staphylococcus aureus (S. aureus) SEBneg-matured monocytes  - at least under some circumstances - and suboptimal Th1 cytokine production   and B ce T cells . In term T cells . Additioelopment . Therefoonocytes .in utero effects the development of the immature lung and airways with additional impacts on the immune system.In terms of environmental toxicity, there are adverse effects of neonatal and infant exposure. With many developing organ systems toxic exposure of the fetus in the womb has even more serious consequences , 44. ForIn utero, the imprinting could start as early as the second trimester of pregnancy, because at this point the fetus starts to show first signs of immune competence. It is also shown that reinforced microbial contact during pregnancy is more powerful for prevention of allergies than starting at birth or even later  the risk of AD but non-significantly reduced the risk of asthma , 84. KeeFurthermore, early introduction of food is beneficial but avoidance of food allergens early in life can be harmful because children especially with AD can become sensitized to food allergen by skin exposure. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase III found that the prevalence of AD affects between 7% to 8% children (aged six to seven) and young teenager (aged 13 to 14) . Also upvia oral exposure  study of Japanese high-risk infants with AD, development of egg allergy was demonstrated to reduce the risk by 30% compared with a control placebo group when egg powder was introduced early in life . FurtherPeanut allergy has a potential anaphylactic risk and once acquired it is very difficult to outgrow. In the past some experts suggested that the introduction of foods that contain peanuts should be delayed until the three years of age , unfortuThe mechanism behind the increase in food allergies over the past two decades is poorly understood. Therefore, various research focus on the investigation of the hygiene hypothesis, delivery by cesarean section, changes in dietary fat content, Vitamin D deficiency, or insufficiency, darker skin tone . Furtherwww.allergy.org.au) already adjusted the current guidelines accordingly and recommend using commercial infant formula until the age of 12 months if an infant is not or only partially breastfeed. However, since different hydrolyzed formulas exist, the allergenicity, tolerance, efficacy and clinical impact also differ. Therefore, every product should be tested. The effects of the routine use of the different hydrolyzed formulas in larger populations of non-exclusively breastfed infants need further investigation to determine the benefits. Adaptation of food for allergy prevention aims, among other things, at an "optimal" microbiome in the gut. However, if confrontations of the organism with pathogenic bacteria are prevented early in life, the risk of asthma and allergies increases  or which measures are to be omitted  but in the end these measures do not actively induce tolerance Figure 1Bifidobacterium longum (B. longum) which is colonizing the gut by a fast expansion. B. longum is an anaerobic, Gram-positive microorganism, which is considered to be a beneficial commensal  polyunsaturated fatty acids (PUFA), during pregnancy is associated with lower risk of allergy development in infants and children . A FinniTaken together, early exposure to the n-3 PUFAs in pregnancy can be a strategy to induce immune effects that prevent infant and childhood allergic disease. Nevertheless, the available data are not completely consistent. In order to characterize more precisely the immunological and clinical effects and to evaluate their protective effects and persistence, further studies on the increased supply of long chain n-3 PUFA during pregnancy, and infancy are required.Just how to prevent atopic diseases in childhood, is a "billion dollar" question as it may be prevention for a lifetime. On the one hand, during the initial allergen exposure, especially the prevailing environmental conditions have a great influence by modifying the immune responses. Therefore, as a logical consequence, pregnant women and parents of infants are advised to limit risk factors. These include smoking, pollutants, and any unfavorable proinflammatory exposures. On the other hand, it includes a balanced and nutritional diet. To achieve more tolerogenic conditions during pregnancy and early life is at the heart of sensible allergy prevention and there is growing evidence that exposure to allergens is necessary for development of immune tolerance. According to latest studies administering antibiotics too early or the usage of hydrolyzed cow´s milk formula does not prevent allergic disease in high at-risk infants. Similarly, the observation that the early introduction of peanut-containing foods could significantly reduce the development of a later peanut allergy in British children will change recommendations for the introduction of complementary foods. The recommendations on breastfeeding over the first four months, avoiding environmental tobacco smoke, and avoidance of overweight will remain unchanged. Studies from tolerance induction in established allergic disease underline the significance of Treg cells. Optimizing the environment especially during the last trimester of pregnancy and first months of life to favour these regulatory pathways represents a good strategy to prevent allergy development. However, knowledge about induction and functioning of neonatal and pediatric Treg cells are scarce. As many of the approaches would have broader biological impact, improved understanding of early life immune responses combined with determinants of atopic diseases will be of interest. This offers a broader perspective for strategies to prevent allergic disorders such as early administration of probiotics, prebiotics, bacterial lysates, but also polyunsaturated omega-3 oils and nutrients with anti-inflammatory properties.The precise time window of possible successful interventions for allergic protection must still be determined and mechanistically understood. Knowledge of this timeframe and the mechanisms for implementing tolerance to potential allergens could make it possible to guide the immune system in a short, defined time interval with anti-inflammatory nutrients. Thus, a much better understanding of the functioning of the neonatal and pediatric immune system is necessary to improve measures to prevent atopic disease.MB-W, MP, and AA wrote the manuscript. All authors read the manuscript and provided important intellectual input to the manuscript. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. All authors contributed to the article and approved the submitted version.The work was supported by DFG Br 1860/12-1.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.


Spondylosis deformans is a type of spinal claw osteophytosis which can be found on the anterolateral vertebral bodies of any region, and which consists of protrusions of intervertebral disc tissue covered by a bony shell. We report here a case of thoracic spondylosis deformans and multilevel instrumented fusion found during routine dissection of a cadaver. Theories of the etiology of this condition are reviewed in general, and with respect to this specific case and the potential interaction of the presenting comorbidities. The clinical implications of these osteophytes, including musculoskeletal and visceral sequelae, are also discussed. Spondylosis deformans (SD) is a type of spinal osteophytosis of uncertain etiology which contains elements of both an osteophyte and an intervertebral disk (IVD) herniation. These nodules arise from Sharpey's fibers at the rim of the anterolateral vertebral endplates and grow towards the adjacent vertebral body . This boApproval to conduct this research was received from the body donor program that provided our study subject, and exemption from human subjects review was obtained from the Thomas Jefferson University Office of Human Research. This report concerns observations made during a routine dissection of an 84-year-old male during a gross anatomy laboratory course. The cause of death was congestive heart failure and respiratory failure, with no other past medical history available. After removal of the anterior chest wall, the subject's bronchi, pulmonary vessels, and inferior vena cava were transected. The lungs were then removed and the heart reflected superiorly, revealing large osteophytes on the thoracic spine. These were noted to arise from the anterolateral vertebral bodies of T6 to T11 and to bridge the intervening IVDs .The anterior longitudinal ligament was partially degraded where it contacted the osteophytes between T6 and T9 . AlthougThe pathology seen in the spine of our subject is complex and includes disk herniation, osteophytosis, multilevel instability, and both organic and surgical spinal fusion. Interactions among these conditions are very likely, but the lack of available medical history makes the sequence of onset of the various conditions unknown.Although research on SD is very common in the veterinary literature , 4, humaPhysical stress, including obesity, is considered the primary cause of osteophyte formation , 9. BiomFissures in the annulus, a common age-related change in human and canine spines, have been noted to be a precursor to both SD and IVD herniation . AnterioOther common spinal lesions involving both the vertebral bodies and the IVDs can be differentiated from SD by considering the specific lesion location and anatomical features involved. For example, diffuse idiopathic skeletal hyperostosis (DISH) results in a fusion of spinal segments that is similar to the fusion seen with SD; however, DISH always involves ligament ossification . In the The multilevel instrumented fusion seen in the present subject suggests that adjacent segment disease (ASD) was present in addition to the other pathologies previously discussed. Adjacent segment disease refers to pathological changes that arise in the mobile segments next to a spinal fusion. Spinal fusion surgeries are performed in cases of traumatic instability, or when decompression surgery at multiple levels creates this instability. The pathological manifestations of ASD can include degeneration, listhesis, instability, herniation, and osteophyte formation –17. The Our subject represents an unusual case of thoracic SD coupled with multilevel instrumented spinal fusion. The presence of SD in the thoracic spine is inherently contradictory because thoracic disk bulges are rare and represent fewer than 3% of all disk herniations , while t


This waIn the animal experiments of the first stage, three doses  of FSH receptor binding inhibitor (FRBI) were intramuscularly injected into mice, respectively. The authors found FRBI could dose-dependently reduce the ovarian cortex thickness (OCT) and ovarian weights of mice. In the second stage, the authors designed four doses of FRBI in order to verify these outcomes.The results in Figure 1 and Table 1 represented the results of these experiments, and the main results in each article overlapped except the FRBI-4 group. The duplicated results are accurately reported. The authors apologize that some results were repeated without this being explained, and the editorial board agreed with the publication of this corrigendum.


We present the case of an HIV-negative man with asymptomatic penile erythematoviolaceous papules associated with similar slightly verrucous papules in the interdigital space of the right foot. A biopsy of the penile lesion confirmed Kaposi's sarcoma. No other causes of immunosuppression were observed. Penile lesions of KS are rare in HIV-negative individuals but it should also be considered in the differential diagnosis. Careful follow-up is recommended. A middle-aged heterosexual Caucasian man of Italian origin was seen at a dermatology practice with asymptomatic lesions on the penis and without general symptoms. He reported having a regular sexual partner for several years, as well as occasional partners, with whom he reported regularly using condoms. He had been adequately treated for syphilis five years earlier and had no other significant health problems.Physical examination indicated erythematoviolaceous papules on the coronal margin of the glans on the ventral surface of the penis . A genera)Molluscum contagiosumb)Genital wartsc)Kaposi's sarcomad)Pyogenic granulomaIn greater detail, gaps with extravasated erythrocytes, few atypical cells, and several mitoses can be observed . The immKaposi's sarcoma (KS) is a spindle cell neoplasm described in 1872 by Moritz Kaposi. It is a rare disease that is usually observed in men over 60 years of age, especially of Mediterranean and/or Jewish origin. It commonly appears in the lower limbs, in which it remains indolent. Metastases and deaths are rarely reported.The Kaposi's sarcoma-associated herpesvirus is a gammaherpesvirus (HHV-8). Infection is considered necessary, but not sufficient, for the development of this sarcoma. Its transmission through saliva or other body fluids is accompanied by an unpredictable period of latency that is similar in other herpesviruses.Penile lesions of KS are rare in HIV-negative heterosexual individuals, which highlights the relevance of the present case report. Few cases of KS of the penis among patients without HIV infection have been published in the literature.None declared.Mauro Cunha Ramos: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.Fabiana Bazanella de Oliveira: Elaboration and writing of the manuscript; obtaining, analyzing, and interpreting the data; critical review of the literature; critical review of the manuscript.Vicente Sperb Antonello: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature.Ana Leticia Boff: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases.None declared.


Coalition is defined as abnormal bridging between two bones, and the connection can be osseous or nonosseous. Most coalitions in the foot involve the hindfoot. Intermetatarsal coalition is thought to be much rarer than the more common hindfoot coalitions and has only been reported sporadically in the orthopedic literature. We present two patients with nonosseous intermetatarsal coalition presenting with nonspecific dorsolateral foot pain and describe the imaging findings of intermetatarsal coalition with different modalities. We suspect that whilst rarely described, intermetatarsal coalition is quite likely a more common underrecognized entity than a rare entity. This report is aimed at increasing the awareness of coalition in this location, in the radiology community, particularly the nonosseous ones, given that this condition can be debilitating but treatable. Coalition, or abnormal bridging between two bones, has a prevalence of up to 13% in the foot with majority of the foot coalition occurring in the hindfoot . IntermeA 40-year-old otherwise healthy female had an MRI and X-ray performed for one week's history of dorsal foot pain following an increase in activity. The imaging was performed for investigation of possible stress fracture. The initial X-ray showed abnormal articulation between the base of the third and fourth metatarsals with concave scalloping of the medial margin of the fourth metatarsals, best appreciated on oblique projection Figures . No fracMRI Figures  revealedThere is, in addition, a third intermetatarsal bursal-neuroma complex  and low-A 29-year-old female patient underwent radiologic investigation following 3 years' history of dorsolateral forefoot and midfoot pain exacerbated by activity. Initial ultrasound examination revealed dorsal surface metatarsal bony irregularity and adjacent soft tissue oedema and hyperaemia at the region of interest, corresponding to the base of the third and fourth metatarsals . X-ray cMRI revealed nonosseous coalition at the base of the third and fourth metatarsals with localized marrow oedema in the third metatarsal, surrounding periostitis and reactive bony changes including osteophyte lipping across this articulation Figures .A conservative approach was also undertaken, with good results.Coalition is defined as abnormal bridging between two bones . The conCoalition was classically thought to be present in approximately 1% of the population, although more recent studies have suggested prevalence as high as 13%, given the increased accessibility to imaging for detection of the asymptomatic cases .Intermetatarsal coalition is much less well known and only a small number of cases have been reported in the English literature . For theThe common presentations described are nonspecific dorsolateral or forefoot pain corresponding to the site of the coalition. This is similar to how our cases presented. The cause for the pain is thought to be due to the altered weight-bearing mechanics, with reduced mobility and flexibility as a result of the coalition which then results in inefficient weight distribution between the metatarsal heads and hence increased stress on the forefoot . The sitRadiographs are usually the first imaging modality for investigation of foot pain given the availability and relative low cost. Osseous bridging or hypertrophy of the metatarsals can be readily apparent but is frequently not recognized by the reporting radiologists due to the rarity of the condition. One can be alerted to nonosseous coalition by observing osseous deformity along the margins of the coalition . Other fComputed tomography (CT) with thin slices and 3-dimensional reconstruction ability via surface rendering offers a better appreciation of the anatomy depicted on radiographs without the overlapping composite shadowing. Osseous coalition is defined by its osseous continuity between normally separate structures. Nonosseous coalition can be differentiated from normal joints by its irregular opposing margins, subchondral cyst formation, and usually narrowed space  Figure . CT alsoUltrasound, whilst of limited value in the diagnosis of coalition, is useful in localizing the pathology and in assessing for secondary inflammatory changes associated with coalition as a potential cause for pain . Not infMagnetic resonance imaging (MRI) findings are relatively similar to CT with the addition of being able to distinguish between fibrous and cartilaginous coalition and visualization of bone marrow oedema signal. Cartilaginous coalition is T2 hyperintense, and T1 isointense to muscle, whilst fibrous coalition is T2 and T1 iso-hypointense. There are often overlapping imaging features; hence, for simplicity, these can be termed fibrocartilaginous coalition. MRI can also demonstrate bone marrow oedema signal or any stress response associated with the coalition more elegantly, to confirm the coalition being a pain generator.Other potential soft tissue complications of coalition to assess for, apart from interdigital bursal-neuroma complexes as mentioned above, are plantar plate degeneration and metatarsal head oedema from the altered weight-bearing dynamics .Technetium-99m with single-photon-emission tomography (SPECT) may also show increased uptake at the site of coalition if there is active stress or inflammatory response. None of our patients have undergone any functional imaging.The treatments described in the literature for the treatment of symptomatic metatarsal coalition include the conservative or surgical approach. The primary aim of the treatment is to correct the foot deformity for better anatomic alignment and function. In general, surgery is usually reserved for cases recalcitrant to conservative management and usually involves resection or disconnection of the coalition . There iIn conclusion, intermetatarsal coalition is rarely described, but it is almost certainly an underrecognized condition, particularly in the radiology community. This report adds to the literature by presenting two different cases of intermetatarsal coalitions and describing the imaging findings of different imaging modalities. Potential downstream complications of intermetatarsal coalition are also discussed. Prompt diagnosis of coalition for patients presenting with nonspecific metatarsalgia is important as this condition can be debilitating but treatable and when addressed early, progression to degeneration can be halted. Potential future research includes more large-scale radiology studies to determine the prevalence of the isolated, nonsyndromic intermetatarsal coalition.


The World Health Organisation Western Pacific Region countries were declared free of polio in 2000 until a polio outbreak involving 305 cases occurred in Indonesia in 2006. It was not until 2014 that the World Health Organisation South East Asia region was officially declared polio-free again. However, in February 2019, the Global Polio Eradication Initiative announced a new circulating vaccine-derived poliovirus outbreak in the Papua province of Indonesia. To make matter worse, the outbreak responses were tardy and led to transmission among migrating communities to other cities. The pressing regional issues of polio outbreak caused by circulating vaccine-derived poliovirus and use of oral polio vaccine have not been well presented. Our letter highlighted the suboptimal outbreak responses as well as the necessity of cross-border vaccination to curb continued poliovirus transmission. Until recently, there had been no reported cases of polio since 1978 in Brunei . The WorcVDPV remains a menace to the end game of polio eradication as it is one of the main causes of re-emerging polio apart from vaccination refusal. cVDPV originates from the oral polio vaccine. This weakened virus is excreted by the body through feces which could spread easily in a non-sanitary environment. In the early 2000s, in order to avoid the risk of cVDPV posed by the weakened poliovirus transmitted through oral polio vaccine (OPV), inactivated polio vaccine (IPV) was strongly advocated. By June 2018, 39 of 47 African countries had changed from OPV to IPV. In spite of that, sporadic cases of cVDPVs were spotted in countries using OPV with low population immunity . For exaAnother approach to totally eliminate the risk of reemergence of wild poliovirus type-2, is to utilize bivalent OPV that contains Sabin serotypes 1 and 3 strains, instead of trivalent OPV that contains Sabin strains of all three poliovirus serotypes .{RegionaBesides the use of IPV or bivalent OPV, a comprehensive vaccine coverage is essential. Even though in general Brunei and Malaysia had achieved more than 95% immunization rates, approximately 12% of the children living in the affected sites on the coastal region of Sabah were not vaccinated, putting the whole community at risk of losing the vital herd immunity. The situation is heterogenous as across the South China Sea, the immunization rate among 105 million residents in the Philippines stood at 66 and 41% for OPV and IPV, respectively [Cross border cooperation and efforts are needed. The mapping of less accessible border areas e.g. in Papua New Guinea and Timor Leste as well as migrant routes is important. The vaccination should be given by humanitarian groups to stateless children or non-citizens. It is especially important to maintain coverage of polio immunization at over 95% in high-risk areas with seasonal migrant populations. Surveillance of vaccination patterns based on data mining and geo-mapping of migrant and cross-border vaccinations that has proven successful in containing polio in Nigeria could be adopted to optimize the limited vaccine stocks and healthcare resources.The health authorities need to increase the inactivated polio vaccine coverage to prevent further spread of cVDPV. Doctors should always look out for polio-like symptoms of acute flaccid paralysis among children by testing the presence of polio virus or cVDPV in the patients’ stool samples. Other important precautionary measure is to test the presence of polio virus or cVDPV at sewage treatment plants. Application of advanced analytics and disease transmission model to map out and estimate seasonal migrant routes and populations could save time and lives of the vulnerable populations. Despite of inactivated polio vaccine stock-outs and cost of polio vaccination, cross-border vaccination at permanent transit point and surveillance of nomadic populations would still be cost-effective. The existence of inadequately vaccinated groups within neighbouring countries pose a serious threat to reintroduction of the poliovirus.


Software verification has recently made enormous progress due to the development of novel verification methods and the speed-up of supporting technologies like SMT solving. To keep software verification tools up to date with these advances, tool developers keep on integrating newly designed methods into their tools, almost exclusively by re-implementing the method within their own framework. While this allows for a conceptual re-use of methods, it nevertheless requires novel implementations for every new technique.cooperative verification in order to avoid re-implementation and enable usage of novel tools as black-box components in verification. Specifically, cooperation is employed for the core ingredient of software verification which is invariant generation. Finding an adequate loop invariant is key to the success of a verification run. Our framework named CoVEGI allows a master verification tool to delegate the task of invariant generation to one or several specialized helper invariant generators. Their results are then utilized within the verification run of the master verifier, allowing in particular for crosschecking the validity of the invariant. We experimentally evaluate our framework on an instance with two masters and three different invariant generators using a number of benchmarks from SV-COMP 2020. The experiments show that the use of CoVEGI can increase the number of correctly verified tasks without increasing the used resources.In this paper, we employ


Although significant improvements have occurred in fast-growing meat-type broilers, myopathies affecting meat quality especially in the pectoralis major muscle have occurred. Many of the broiler breast muscle myopathies are caused by inflammation leading to the necrosis of existing muscle fibers and resulting in replacement of the muscle fibers with extracellular matrix proteins especially fibrillar collagens, fibrosis. This review explores how the fibrotic deposition and organization of extracellular matrix proteins especially the fibrillar collagens, Types I and III, affects the phenotype of the Wooden Breast myopathy, functional properties of the pectoralis major muscle, and meat quality.The poultry industry has placed significant emphasis on the selection of meat-type broilers for increased body weight, increased meat yield especially the pectoralis major (breast) muscle, decreased time to processing, and improved feed conversion Broilers have been selected for increased growth, carcass weight, pectoralis major (breast) muscle yield, decreased time to reach processing weight, and improved feed conversion . DespiteThe fibrotic process of the replacement of muscle fibers with connective tissue is induced by chronic muscle fiber damage, necrosis, with associated tissue inflammation. In normal muscle, the damage will be repaired without changes in the myofiber structure or fibrosis. However, fibrosis results in muscles with chronic necrosis leading to the excessive deposition of fibrillar collagen as is observed with myopathies like WB. It is not the concentration of fibrillar collagen synthesized during fibrosis, but the organization of the fibrillar collagen will determine the tissue flexibility and the tenderness of the meat. In recent studies, it has been shown that there may be multiple necrotic/fibrotic myopathies associated with the broiler pectoralis major muscle . Many ofThe extracellular matrix is defined as all the secreted molecules extrinsic to the cell composed of collagens, proteoglycans, and non-collagenous glycoproteins. The composition and structure of the extracellular matrix is not random as it is tissue-type and age specific. The matrix is thus dynamically expressed and directly impacts muscle cell proliferation, adhesion, migration, and the repair of damaged muscle fibers. In skeletal muscle there are three layers of connective tissue containing extracellular matrix macromolecules. They are the endomysium, perimysium, and epimysium. The epimysium forms a sheath around the entire muscle, the perimysium encompasses muscle fiber bundles, and the endomysium surrounds individual muscle fibers. The predominant extracellular matrix proteins in these layers are the fibrillar collagens especially Types I and III.The fibrillar collagens are characterized by a single triple-helical domain containing three peptide chains forming an alpha helix. After the triple helical structure is formed, the collagen is secreted into the extracellular matrix space where it is aligned into a quarter stagger array leading to the formation of collagen fibrils that are stabilized by crosslinking between the collagens. Crosslinking of the fibrillar collagens is necessary for both its structural stability and functional properties and is a major determinant of meat textural properties. The covalent hydroxylsylpyridinoline (HP) crosslink is a mature, non-reducible, trivalent crosslink that forms from the condensation of two divalent ketoimine crosslinks . The forThe predisposition to the development of degenerative breast muscle myopathies has its origins in the formation of muscle and its continued growth as well as how selection for fast-growing heavy weights lines has altered the development and growth of the pectoralis major muscle including the extracellular matrix environment. The development and growth of skeletal muscle is a precisely regulated process with specific phases. Embryonic myoblasts are derived from the somites and once they migrate to the areas of muscle formation will further proliferate, align to form multinucleated myotubes, and ultimately muscle fibers. After the myoblasts form multinucleated myotubes they withdraw from the cell cycle. During the formation of skeletal muscle, the muscle fibers will form bundles with the bundles being separated by perimysial connective tissue spacing and the individual muscle fibers by endomysial connective tissue. At the time of hatch, muscle fiber formation is complete .The continued posthatch growth is from the enlargement or hypertrophy of existing muscle fibers. Hypertrophy is solely dependent upon a mesodermally derived stem cells population of adult myoblasts, satellite cells. With myofiber injury, the satellite cells are responsible for the repair and regeneration of the myofiber back to its original state.Having enough perimysial and endomysial connective tissue spacing is necessary for the livability of the avian pectoralis major muscle myofibers . The perThe degeneration or necrosis of the muscle fibers will initiate satellite cell repair mechanisms. Satellite cells are, in general, quiescent and must be activated to reenter the cell cycle to proliferate and differentiate. Satellite cells require the appropriate niche environment for activation. For satellite cell activity to occur, the muscle stem cell niche must contain vascularization within 21 μm of the satellite cells . HoweverThe degeneration of muscle fibers results in inflammation of the pectoralis major muscle tissue leading to an increased deposition of extracellular matrix proteins like collagen and proteoglycans. The extracellular matrix proteins form an architectural network outside the cell which determines, in part, the structural stability of the tissue, stretch, and water-holding capacity. Measures of extracellular matrix protein concentration alone will not determine the functional attributes of the tissue. For example, the primary phenotypic feature of WB is a hard pectoralis major muscle detected by palpation . As showThe process of fibrosis is a self-perpetuating response to muscle necrosis resulting in the progressive overproduction of fibrillar collagens Types I and III in the perimysial and endomysial connective tissue spaces. The phenotypic characteristics of necrotic/fibrotic myopathies is not a direct relationship to the concentration of these collagens. There are numerous factors determining the tissue phenotype resulting from fibrosis. These include, but are not limited to fibril diameter, degree of crosslinking, proteoglycan localization and type, fibril alignment, and morphometric organization of the collagen fibrils.All collagens are composed of three polypeptide chains with the amino acid repeat Glycine-X-Y where X and Y are any amino acid but are frequently proline or lysine. The polypeptide chains will wrap around each other intracellularly to form a right-handed triple helix. At this point, the collagen molecule is exocytosed into the extracellular space where fibril and fiber formation take place. The collagen fiber is the functional form impacting tissue structure, elasticity, and ultimately meat quality. After secretion, the collagen molecules will align in parallel to forming a quarter staggered array which is a necessary step leading to the assembly of collagen fibrils. The collagen fibrils are stabilized by the formation of reversible divalent crosslinks. The alignment of the collagen molecules is not a random process and after alignment there are gap and overlap areas within the quarter staggered array. The length of one overlap zone is 67 nm and this is termed a D banding-period. If the alignment of the collagen molecules is altered, the length of the D-period will be modified affecting collagen fibril function. After collagen fibril formation, the collagen fibrils will come together forming collagen fibers. With maturation, divalent ketoimine crosslinks are replaced with trivalent non-reversible HP crosslinks. The HP crosslink is a critical factor in tissue stiffening. After three collagen triple helices are linked together, additional helices are linked together increasing collagen fibril diameter and crosslinking. The formation of HP crosslinks is a progressive process with age and is likely a major factor in the phenotypic detection of WB by palpation and the reduction in meat quality.Since the WB myopathy is characterized by excessive collagen fibril deposition, it is of importance to understand the ultrastructural intramuscular organization of the fibrillar collagens in fast growing meat-type broiler lines of differing parental lineage. To comprehensively study collagen fibril structure, a series of studies was conducted examining collagen fibril structure in three fast growing commercial broiler lines with distinctly different levels of phenotypically detectable WB . These lTransmission electron microscopy (TEM) analysis was used to further investigate histological differences, measure collagen D-periodicity, and collagen fiber diameter in Lines A, B, and C affected and unaffected WB birds . VellemaMore importantly the TEM study by Since the organization of collagen fibrils is altered by the fibrotic process, it is necessary to determine mechanistically how this organizational change occurs. A primary candidate for altering collagen fibrillar structure is the chondroitin and dermatan sulfate proteoglycan decorin. Decorin plays a critical role in the formation of the quarter stagger array aligning the collagen helices  and subsTo summarize this review provides novel insight into the fibrillar organization of collagen in the broiler pectoralis major muscle and its impact on the phenotypic detection of WB affected birds. Despite Skeletal muscle contains fibrillar collagens Types I and III. The expression of collagen is age dependent. During early development, Type III collagen is the predominant collagen but with increased age there is a shift toward Type I collagen . With inThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.