Medication-related osteonecrosis of the jaws (MR-ONJ) is one of the most relevant side effects of bisphosphonate therapy; it is clinically defined as a non-healing wound in combination with an avascular and necrotic jaw within ongoing bisphosphonate therapy or after completed bisphosphonate therapy. Different theories concerning the development of MR-ONJ have been reported, while the exact pathophysiology is still unknown. Recent studies have increasingly focused on angiogenesis and revascularization concerning MR-ONJ pathophysiology, which seems to be a relevant factor in the development of MR-ONJ and a possible and promising point of action for MR-ONJ prevention and therapy. Therefore, and with respect to the different aspects and specific forms of angiogenesis, the enclosed review summarizes the possible role of angiogenesis and revascularization in the pathophysiology of MR-ONJ. Special focus is given to the strong negative influence of bisphosphonates on progenitor and mature endothelial cells in vitro as well as on microvessel sprouting in vitro and in vivo, which might result in overall reduced wound healing of oral soft and hard tissues, and therefore in an exposed and avascular jaw from a clinical viewpoint. Further, it will be summarized whether and in what way the aspect of angiogenesis might be used for possible MR-ONJ prevention and therapy. Bisphosphonates represent one of the most important and most clinically relevant antiresorptive agents in various fields of medicine and especially oncology. These agents, which chemically resemble pyrophosphate, have revamped the therapy for a plurality of benign and malign bone diseases, such as osteoporosis, chronic osteomyelitis, osteodystrophia deformans, osteoblastic and osteolytic bone metastases of various malignancies, and malign lymphoma, e.g., multiple myeloma ,5,6,7,8.Bisphosphonates’ mode of action is based on different point of actions within the mevalonate pathway, the biochemical pathway of cholesterol synthesis. Overall, toxic ATP analogues and an inhibition of the enzyme farnesylpyrophosphate-synthase lead to an inhibition of isoprenoid geranylgeraniol (GGOH) synthesis and therefore to an absence of second messenger protein prenylation of the RAS superfamily. This biochemical cascade leads to the start of apoptosis in osteoblasts and osteoclasts, ultimately leading to overall inhibited and reduced bone turnover .While various side effects of bisphosphonate therapy have been known since its clinical introduction, bisphosphonate-related osteonecrosis of the jaws (BR-ONJ) was reported as a new and unpredictable side effect in 2003 for the first time, especially after pamidronate and zoledronate therapy, and continues to increase in incidence to date ,12,13,14MR-ONJ is frequently observed after surgical procedures, such as tooth extractions or dental surgery. According to the guidelines of the American Association of Oral and Maxillofacial Surgeons (AAOMS), MR-ONJ is defined as avascular and necrotic bone of the maxilla and/or the mandible for at least eight weeks in combination with an inflammation of the surrounding soft tissues and a non-healing wound during or after bisphosphonate therapy. In addition, radiation in the head and neck region must be excluded in the patient’s history . FurtherConcerning MR-ONJ pathophysiology, different theories have been reported. One of the most popular theories describes overall reduced bone remodeling, which is induced by bisphosphonates’ strong influence on osteogenic cells (osteoblasts and osteoclasts). The resulting complete standstill of bone turnover and bone regeneration potential might consequently result in jaw necrosis after bone irritation, for example after surgical procedures, where fast, sufficient bone regeneration and healing potential are absolutely indispensible. Other popular theories describe an influence on oral soft tissues and inflammatory reactions. In this context, oral soft tissue cells, especially gingival fibroblasts and oral keratinocytes, might be directly damaged by bisphosphonates, potentially resulting in a non-healing wound or uncovered, exposed jaw bone. This process might be additionally triggered and enhanced by local inflammation, most likely caused by high local bisphosphonate concentrations in the jaw bone and the surrounding soft tissues. Interestingly, different bacteria, such as actinomycetes, have been detected in ONJ specimens, which might also have an influence on MR-ONJ development. The potential role of bacterial contamination is discussed extremely controversially in the literature since it is still unclear whether bacterial contamination is the primary reason for MR-ONJ development or simply a subsequent phenomenon of a necrotic jaw ,18,19,20In addition to these theories and hypotheses, the aspects of angiogenesis, revascularization, and microvessel development concerning MR-ONJ pathophysiology have become more popular and are frequently discussed in the current literature. The role of angiogenesis might be very relevant since angiogenesis plays a fundamental key role in wound healing as well as in soft and hard tissue regeneration ; further, reduced angiogenesis could explain both clinical manifestations of MR-ONJ: reduced wound healing of oral soft tissues as well as avascular and necrotic bone in the context of MR-ONJ. Bisphosphonates might contact and influence blood vessel development, and thereby MR-ONJ development, in two different ways: (I) through high circulating bisphosphonate concentrations in the entire circulatory system immediately after intravenous bisphosphonate application and (II) in the region of wound healing  where new blood vessels should sprout into a wound in the presence of high local bisphosphonate concentrations in the bone and the surrounding soft tissues .Since angiogenesis represents a comprehensive, promising, and sufficient approach for MR-ONJ pathophysiology and new MR-ONJ therapies, this manuscript reviews all articles on in vitro and in vivo experiments concerning the topic of bisphosphonates and angiogenesis published by the authors within the time frame of 2010 to 2016. In addition, the most relevant articles concerning the aspect of angiogenesis and MR-ONJ development within the time frame of 2015 to 2016 are summarized.Walter et al. analyzed the influence of different nitrogen-containing  and non-nitrogen-containing bisphosphonates (clodronate) on human umbilical cord vein endothelial cells (HUVEC) concerning their cell viability, proliferation and migration ability as well as their cell morphology in vitro. The findings demonstrated a strong negative influence, particularly for pamidronate and zoledronate, on HUVEC cells in all assays and in the confocal laser scanning microscopy visualization, whereas the impacts of ibandronate and clodronate was less distinct. The effect of non-nitrogen-containing clodronate on HUVEC cells was particularly marginal . Next, ZBased on these in vitro studies, Pabst et al. designed an in vivo study and analyzed the effects of bisphosphonates on angiogenesis and microvessel sprouting in a murine 3D-matrigel assay. Matrigel plugs were subcutaneously implanted under the dorsal skin of bisphosphonate-treated  nude mice and the matrigel plugs were then analyzed by CD31 immunochemistry and microvascular corrosion casting. All bisphosphonates induced a significant decrease of the microvessel density compared to the controls within the matrigel plugs, which was similarly observed for the microvessel area in the matrigel plugs. Overall, pamidronate and zoledronate had the strongest negative influence. Interestingly, ibandronate induced an increase of the mean microvessel size . This stIn further studies, the influence of geranylgeraniol (GGOH) on angiogenesis and microvessel sprouting after bisphosphonate substitution was evaluated. Ziebart et al. analyzed the influence of GGOH on cell viability, proliferation and migration ability as well as the morphological cell architecture of HUVEC cells after bisphosphonate substitution  in vitro. The findings demonstrated that GGOH cell treatment was able to reverse the strong negative effects of the tested bisphosphonates on HUVEC cells and therefore angiogenesis and revascularization in vitro . Based oAlso, further in vitro and in vivo studies analyzed the aspect of angiogenesis in the development of MR-ONJ.Lang et al. investigated the influence of nitrogen-containing zoledronate in different concentrations on the cell proliferation, migration ability, apoptosis rate and protein expression of vascular endothelial cells in vitro. Overall, the results demonstrated that zoledronate can significantly inhibit all the above-mentioned vascular endothelial cell characteristics and induce cell death of vascular endothelial cells and therefore affect MR-ONJ development . In anotIn addition, the impact of zoledronate on human gingival fibroblasts and their regulation of genes associated with angiogenic regulation has been evaluated in vitro. In this study, an increased expression could be observed for RHOB, VEGF, CD55 and BMP2 genes, while CCL2 and IL6 genes were downregulated. The authors concluded that fibroblasts respond to zoledronate treatment by producing a proangiogenic environment shown by the significantly increased VEGF and BMP2 gene expressions . Borke eOverall, the current literature has demonstrated that bisphosphonates, especially the nitrogen-containing agents pamidronate and zoledronate, have a strong negative influence on angiogenesis, revascularization, and microvessel sprouting in vitro and in vivo. In addition, it could be demonstrated that the natural isoprenoid GGOH is able to reverse bisphosphonates’ strong negative influence on angiogenesis and microvessel sprouting in vitro and therefore might represent a promising and sufficient prevention and treatment option for MR-ONJ.In this context, pamidronate and zoledronate are the agents that are most frequently associated with the development of MR-ONJ ,14. ThisSome aspects concerning angiogenesis and revascularization and the development of MR-ONJ have not been evaluated to date. In this context, it should be noted that several relevant forms and manners of angiogenesis and vasculature development exist:(I) “Angiogenesis” in general can be specified as blood vessel creation due to the development of endothelial cell bridges through the division of mature endothelial cells. In contrast, (II) “vasculogenesis” represents the formation of completely new blood vessels by endothelial progenitor cells (EPCs) which have been released from the bone marrow. (III) “Intussusceptive angiogenesis”, which is also designated as “splitting angiogenesis”, is the creation of new blood vessels by the splitting of pre-existing vessels along their longitudinal axis. This longitudinal splitting has its origin in the development of pillars  and enabWith respect to new MR-ONJ prevention and therapies and the role of angiogenesis, recent studies have demonstrated that the isoprenoid GGOH can reverse the strong negative influence of especially the nitrogen-containing bisphosphonates in vitro. In vivo studies on this topic are still missing. In this context, the mode of GGOH application  is often discussed in the literature ,21,22,24Nonetheless, there is also literature available that does not underpin the importance of angiogenesis and revascularization concerning MR-ONJ development. Wehrhan et al. investigated angiogenesis and vascularization in human MR-ONJ soft-tissue specimens after zoledronate therapy and reported that vascularization and mature capillary density were unchanged. However, this study also demonstrated that vessel remodeling and microvessel formation were negatively influenced in the soft-tissue MR-ONJ specimens analyzed ,35,36.However, there are some aspects and findings that fortify the particular importance of angiogenesis and revascularization in MR-ONJ development . It has To conclude, the current literature deals with multiple studies demonstrating the strong influence of bisphosphonates in vitro and in vivo, giving evidence that angiogenesis and revascularization might be important aspects in MR-ONJ pathophysiology, not that they play an exclusive role—but at least an important role within the generally accepted theory of a multifactorial genesis. In addition, it could be demonstrated that GGOH is able to reverse bisphosphonates’ strong influence on angiogenesis and revascularization. Further studies in this research field should focus on (I) the influence of bisphosphonates on special types of angiogenesis, such as intussusceptive angiogenesis; and (II) whether GGOH might be able to reverse bisphosphonates’ negative influence on angiogenesis and revascularization in vivo.As a limitation, this overview primarily summarizes the previous preclinical in vitro and in vivo studies of the presenting authors.


Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement , the identification of monoamines in the diseases processes  and the prospect of the involvement of monoaminergic mechanisms . In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from  Monoaminergic systems are important cellular targets in a variety of neuropsychiatric and neurological conditions. Improved knowledge of these systems, in terms of function and molecular organization, has confirmed their roles in the efficacy of older medications. Medicinal chemistry has detected some newer compounds that affect identified molecular targets and additional monoaminergic targets are still being investigated. Although monoaminergic systems have a pivotal role in the effect of many existing medicines, there is a need for further developments, as additional targets have been identified that could be as interesting as monoamines , serotonin (5-HT), noradrenaline (NA) and histamine are involved in virtually all cerebral functions and modification of their activity has been identified in most, if not all, neuropsychiatric and neurological diseases. Some of these diseases, including schizophrenia, depression and Parkinson's disease (PD) benefit from monoaminergic-based treatments, but there is still scope for therapeutic improvement. In spite of clear monoaminergic disturbances in other devastating diseases, including Alzheimer's disease, addiction and epilepsy, no approved monoamine-based treatments are yet available. The discovery of the most pertinent drugs in numerous psychiatric diseases was serendipitous while the causal implication of monoaminergic systems in several diseases is still unclear. In this context, the identification of drug targets as well as more detailed neuropharmacological analysis should allow for the improvement of existing drugs.The complexity of the organization of monoaminergic systems in the brain limits the likelihood of drugs acting on a single target to correct a disease selectively, although recent examples suggest that this strategy might be worth continuing  and the substantia nigra pars compacta (SNc), noradrenergic neurons, arising from locus coeruleus (LC), serotonergic neurons, originating from median and dorsal raphe nuclei  are a family of flavin adenine dinucleotide (FAD)-containing enzymes that catalyze the oxidative deamination of primary, secondary or tertiary amines. They produce hydrogen peroxide, ammonia and the corresponding aldehyde. There are two isoforms of MAO present in mammals: MAO-A and MAO-B, which share approximately 70% sequence identity and are encoded by separate genes located on the X chromosome  can also metabolize DA and NA     , or indirectly modify the activity of monoaminergic neurons, thereby altering neurobiological networks beyond their specific distribution.The main selectivity regarding these systems, although limited to some extent, is conferred by the receptors; two families for DA . Thus, adrenergic cells express the αThe last point to consider when dealing with neuropharmacology of monoaminergic systems is that, either by acting on non-selective enzymes such as MAO, or by selectively targeting one receptor, the biological responses likely involve all systems due to their interaction throughout the brain  receptor subtype was a common target of all antipsychotic drugs , which may be considered as the birth of biological psychiatry. Schizophrenia is a complex neuropsychiatric disorder with high prevalence . On the other hand, these compounds are not efficacious against the negative symptoms which may even aggravate  receptor antagonist properties, or to chronic central D2 receptor blockade. Notably the extrapyramidal side-effects (EPS) include parkinsonism, akathisia, dystonia and tardive dyskinesia  vs. D2 receptor subtypes   might unmask a deleterious involvement of other circuits. For instance, while the 5-HT2C receptor blockade has not been shown to be primarily involved in the antipsychotic drug action, its blockade might be necessary to limit the occurrence of EPS induced by typical neuroleptics , came out in 1975  The blockade of SERT at the level of 5-HT cell bodies enhances somatodendritic 5-HT extracellular levels , such as moclobemide . In 193The hypothalamus is a key structure involved in food intake regulation and energy balance. It receives monoaminergic terminals from several different sources and the roles of the monoamines appear to be different: 5-HT and histamine participate as a satiety factors; DA acts as the main signaling molecule in a reward system, and NA tends to enhance energy expenditure. Animal studies have shown that phenyl-tertiary-butylamine, phentermine, and fenfluramine cause the release of amines from the nerve terminals as well as inhibiting their uptake. While d-amphetamine has higher affinities for DAT and NET than SERT, fenfluramine has a higher affinity for SERT  display a lower affinity at HPD is a neurological condition characterized by motor impairments including bradykinesia, tremor and rigidity  and reach the striatum before conversion to DA by AADC. The first trials started in 1961 and L-DOPA still represents the main pharmacological treatment of PD   and the psychostimulant drugs amphetamine and cocaine, were recognized before the existence and significance of the DA reward system in the brain was known. Studies of drug addiction received an increased impetus when the primary physiological target in the brain was thought to be determined, namely the DA neurons from the VTA innervating the nucleus accumbens. All drugs of abuse share similar neurobiological property, since they increase DA release in the nucleus accumbens that parallels the reinforcing properties of the drugs , whereas 5-HT2C receptor agonists inhibited the impulse-dependent release of DA. In parallel, behavioral data have shown that 5-HT2C receptor agonists and 5-HT2A receptor antagonists were capable of dampening the reinforcing properties, the craving and relapse, produced by drugs of abuse, in particular cocaine  in the brain are found in AD patients . Propranolol was proposed for the treatment of aggression or agitation  is a homodimer glycoprotein with enzymatic function that binds leukocytes through its semicarbazide sensitive amine oxidase (SSAO) activity inducing inflammation (Smith et al., In spite of the different cellular localization of both MAO isoforms as well as SSAO/VAP-1, and their different substrate specificities, a cross-talk between these oxidases occurs. It has been described that MAO modulates the behavior of SSAO/VAP-1 (Fitzgerald and Tipton, Dynamic communication between cells of the neurovascular unit is required for normal brain functioning. The neurovascular unit consists of all major cellular components of the brain including neurons, astrocytes, brain endothelium, pericytes, vascular smooth muscle cells, microglia, and perivascular macrophages. In a situation of hemorrhagic stroke, an alteration of the homeostasis between all components of the neurovascular unit occurs, and the role of amine oxidases, especially the SSAO/VAP-1 activity is increased, contributing through its catalytic activity to the oxidative stress and inflammation (Hernandez-Guillamon et al., Despite the progress made on the influence of monoamines in the three above-mentioned diseases, no monoamine-based treatments are available at present. In most cases, one emerging strategy would be the use of SSRI or MAO-Is, two approaches that are altering monoaminergic transmission throughout the brain rather than a specific monoaminergic drug targeting the injured tissue. In fact, there are two interconnecting issues: one addressing the regional origin of the disease, and the other addressing the functional consequences away from the dysfunctional site. Assuming that the benefit of antidepressant drugs like SSRI or MAO-I is related to the ultimate reorganization of neurobiological networks, their possible benefit could be related to actions away from the injured sites.2, D3, 5-HT2B/2C, 5-HT1A, 5-HT2A, H3, or α2 receptors. All these targets, apart the 5-HT2A receptor, exert widespread influences in the brain and alter multiple brain functions simultaneously. Thus, compounds affecting monoaminergic transmission have numerous consequences for the brain and its neurobiological networks. While researchers are aware that the symptomatic treatment of a disease results from multiple actions on the brain function, the linkages enabling a favorable reorganization of brain function after monoamine-based treatments are still not fully understood.Monoaminergic drugs affect different processes in the brain that control the tone of neurotransmission or/and tissue excitability, and therefore should be studied as future targets for novel therapeutic approaches, not only for depression, but also for schizophrenia, addiction, obesity, PD, epilepsy, AD and stroke. This analysis acknowledges the Neuroscience based Nomenclature proposed by the IUPHAR which is based on the pharmacological profiles of psychotropic drugs rather than the clinical indication (Zohar et al., The search for effective targets in the treatment of brain diseases was facilitated by the serendipitous discoveries of compounds that were efficacious in schizophrenia, depression and obesity. Several new compounds have been developed that retain the original pharmacological targets involved in those therapeutic benefits combined with actions on new targets, identified from subsequent research, whilst aiming to minimize undesirable “off-target” actions. Knowledge of the monoaminergic mechanisms underlying drug efficacy led to the development of drugs with more specific mechanisms of action; lorcaserin, agomelatine, and vortioxetine are interesting achievements in this context. The identification of pathophysiological causes to tailor appropriate therapeutic approaches has been less successful. It has shown some success with PD but not with addiction to drug of abuse. Nonetheless, the failure to improve on current antiparkinsonian therapies confirms that the efficacy of these treatments is not simply related to a compensation of the loss of striatal DA. To some extent, the remarkable clinical success of L-DOPA was serendipitous. It is difficult to implement new monoaminergic treatment strategies in the clinic unless they depend on those currently accepted. This is exemplified by the third group of diseases where the progress regarding the involvement of monoamines in these diseases has not yet resulted in new monoamine-based treatments.Current attempts to address the full spectrum of action of existing drugs can be improved. It is to be hoped that novel approaches, such as connectomics with polyomic research addressing brain functions, neurobiological networks, monoaminergic systems and their mutual interactions, might offer new perspectives and enhance the current state-of-the-art biological research in these psychiatric and neurological disorders.All authors contributed to the conception and interpretation of the work and to its critical revision. All authors have approved the final version and may be held accountable for the integrity of this review of current literature.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.


Postherpetic neuralgia (PHN) is an unpredictable complication of varicella zoster virus- (VZV-) induced herpes zoster (HZ) which often occurs in elderly and immunocompromised persons and which can induce psychosocial dysfunction and can negatively impact on quality of life. Preventive options for PHN include vaccination of high-risk persons against HZ, early use of antiviral agents, and robust management of pain during the early stage of acute herpes zoster. If it does occur, PHN may persist for months or even years after resolution of the HZ mucocutaneous eruptions, and treatment is often only partially effective. Classical trigeminal neuralgia is a severe orofacial neuropathic pain condition characterized by unilateral, brief but recurrent, lancinating paroxysmal pain confined to the distribution of one or more of the branches of the trigeminal nerve. It may be idiopathic or causally associated with vascular compression of the trigeminal nerve root. The anticonvulsive agents, carbamazepine or oxcarbazepine, constitute the first-line treatment. Microvascular decompression or ablative procedures should be considered when pharmacotherapy is ineffective or intolerable. The aim of this short review is briefly to discuss the etiopathogenesis, clinical features, and treatment of PHN and classical trigeminal neuralgia. Herpes zoster (HZ) is an acute, localized self-limiting infection caused by the varicella zoster virus (VZV), a neurotropic alpha-herpes virus, most frequently affecting elderly or immunocompromised persons. Reactivation of latent VZ acquired during previous episodes of VZV infection (chickenpox) and which have persisted in a latent form within the dorsal root ganglia neural cells results in viral replication followed by spread of the virus down the sensory nerve to the skin/mucosa. The reactivated VZV can then cause unilateral vesicular eruptions with acute, stabbing radiating pain, confined to a dermatome –6. TypicThe mucocutaneous damage is thought to be the consequence of the direct cytopathic effect of VZV on epithelial cells , 4, 8, 9The vesicular mucocutaneous eruptions of HZ are usually preceded by two or three days of localized pain, and the acute neuritis that accompanies the eruptions may sometimes leave the legacy of postherpetic neuralgia (PHN). PHN is thus a complication of HZ and is characterized by symptoms of neuropathic pain including intense burning sensation, allodynia, and/or hyperalgesia that may continue long after resolution of the mucocutaneous eruption , 2. PHN About 10 to 15% of persons with HZ will develop PHN. This is uncommon under the age of 40 years, but in HZ-affected persons older than 60 years, it occurs in more than 50% .Available evidence-based information about the efficacy of different treatment modalities for PHN is sparse , so treaPHN is that pain which in some cases persists in the dermatome affected by mucocutaneous HZ after resolution of the vesiculopapular rash. In most cases, PHN resolves spontaneously over weeks or months from the resolution of the rash, but sometimes, the pain may persist longer. It has been reported that rarely PHN may have its onset months or even years after the initial episode of HZ has resolved .Postherpetic neuralgic pain is characterized by allodynia and hyperalgesia in response to nonnoxious mechanical and thermal stimuli and by spontaneous pain variably described as burning, sharp, shooting, or electric shock-like . Within Reactivation and subsequent replication of latent VZ viruses (VZVs) in neural cells of the dorsal root ganglia induce both direct cytopathic damage to central and peripheral neurons, and VZV-mediated inflammatory tissue damage will exaggerate the neuralgic pain , 6. The These biopathological events during the acute stage of HZ can in time cause both peripheral and central sensitisation characterized by downregulation of central pain inhibitory pathways, alterations in expression of genes encoding neuropeptides, and expansion of receptive fields. This results in hyperexcitability of dorsal horn neurons with the capacity to fire spontaneously. These sensory functional alterations within the neurons account for the allodynia, hyperalgesia, burning, and electric shock-like sensations characteristic of postherpetic neuralgic pain , 6, 11. There is no effective and predictable treatment for PHN , 7. VaccA single dose of live attenuated VZV vaccine will boost virus-specific cell-mediated immunity, and in those who develop HZ despite the vaccination, it will reduce the incidence of PHN . NonsterIn established PHN, a multimodal approach is usually necessary for a good clinical outcome. This includes a combination of topical and systemic medications, relaxation, psychological intervention, and social support. Topical medications used include anaesthetic agents, capsaicin, and various anti-inflammatory preparations ; systemiIt appears that drug-combination therapy is more effective and better tolerated than the use of a single drug in reducing the intensity of PHN pain , 16, andTrigeminal neuralgia (tic douloureux) is an orofacial pain disorder characterized by unilateral, recurrent paroxysms of lancinating pain confined to the somatosensory distribution of the trigeminal nerve. The second and third divisions of the trigeminal nerve are more frequently affected than the first division. Typically, an attack of pain is elicited by innocuous tactile stimuli to trigger points somewhere in the distribution of the trigeminal nerve –19. ActiAt the onset of a paroxysm of trigeminal neuralgia, the pain reaches peak intensity immediately and lasts a few seconds to one or two minutes, and the lancinating pain is sometimes accompanied by involuntary spasms of the facial muscles (tic douloureux) , 24. OccThe clinical course of trigeminal neuralgia is characterized by a progressive increase in frequency, duration, and severity of attacks, gradual diminution of response to medication, and sometimes the development of constant dull pain between attacks. However, there may be spontaneous remissions of six months or more , 22.Classical  trigeminal neuralgia is either idiopathic or is associated with vascular compression of the root of the trigeminal nerve close to its point of entry into the pons (the “root entry zone”), by an aberrant arterial or venous loop , 26, 28 Trigeminal neuralgia can also be symptomatic if it is associated with some other cause such as multiple sclerosis or nonvascular space-occupying lesions in the brain , 31 Fig. SymptomClassical trigeminal neuralgia can be either idiopathic or caused by vascular compression of the proximal portion of the trigeminal root at the level of the brain stem. The compression causes some ischaemic and mechanical damage with microstructural changes to the trigeminal neurons and with the appearance of focal zones of demyelination .Physiologically, after a sharp response to a brief stimulus, the membranes of sensory nerves rapidly return to a resting state; where patches of demyelination have exposed neuronal membranes, where there are sites of structural anomalies or aberrantly myelinated axonal clusters, the threshold of excitability may not only be lowered but these sites may also act as autonomous pacemakers with the capacity to generate an attack or barrage of impulses in response to brief stimuli . A proloAs a minority of cases of classical trigeminal neuralgia are not caused by vascular compression and appear to be idiopathic, it is possible that disordered physiological, anatomical, genetic, toxic, or degenerative factors may precipitate the generation of abnormal discharges by the Gasserian ganglion, the trigeminal nerve root, or the trigeminal nucleus, causing the neuralgic pain , 35. Altβ touch sensation conducting fibres to pain conducting C-fibres may occur, explaining how tactile stimulation of trigger points in persons with trigeminal neuralgia may generate trigeminal neuralgic pain [In zones of trigeminal nerve compression and demyelination, the high-frequency discharge of impulses in the affected neurons may cross-excite neighbouring electrically silent axons, with impulse amplification and the generation of an intense, explosive discharge causing sudden lancinating pain. Furthermore, in zones of trigeminal nerve demyelination, extra-synaptic transmission of electrical impulses from Agic pain . In thisgic pain .v 1.9 channels may mediate the generation of persistent sodium currents at subthreshold voltage, promoting depolarisation and reducing the threshold of the current required to trigger an action potential, resulting in a state of hyperexcitability of sensory neurons [In those cases of trigeminal neuralgia not associated with vascular compression, genetic alterations causing dysfunctional activity of Na neurons .Classical trigeminal neuralgia may be either idiopathic or induced by vascular compression of the trigeminal root. Demyelination probably plays an essential role in the hyperexcitability and abnormally high-frequency repetitive neuronal firing in trigeminal neuralgia, but demyelination per se is probably not sufficient to cause trigeminal neuralgia .It appears that the onset of classical trigeminal neuralgia without evident vascular compression of the root of the trigeminal nerve occurs at a significantly earlier age than does idiopathic trigeminal neuralgia , and regardless of treatment modality, recurrence is more frequent for those cases of trigeminal neuralgia that were not originally caused by vascular compression than for those that were .In the treatment of classical trigeminal neuralgia, the anticonvulsants carbamazepine and oxcarbazepine are equally effective and are the drugs of choice , 31, 32.Microvascular decompression for classical trigeminal neuralgia is a major surgical procedure in which the compressing blood vessels are separated from the trigeminal nerve root in the posterior fossa. Alternatively, sensory fibres of the trigeminal nerve can be ablated, either peripherally or centrally, though pain relief is then at the cost of varying degrees of sensory loss . About 9Another surgical modality in the treatment of idiopathic classical trigeminal neuralgia is the “nerve combing” method. This involves the longitudinal splitting of the trigeminal root into several fascicles from the entrance to the pons. The speculative biological rationale for pain relief achieved by “nerve combing” is the assumption that the surgical trauma to the trigeminal root somehow affects the dysregulated neural circuits in the brainstem, abolishing their abnormal activity –40.(i) Contact of blood vessels with the root of the trigeminal nerve is normal, inevitably with some hydrostatic pressure on the nerve, but only if there is vascular pressure on the nerve sufficient to cause neuronal damage, can this become an aetiological factor. In classical trigeminal neuralgia, neuronal microstructural alterations including demyelination can occur independently of any vascular pressure, and it is not clear whether or not there is any correlation between the degree of severity of the neuronal microstructural damage caused by the vascular compression and the idiopathic microstructural alterations unrelated to the vascular compression on the one hand and the severity and duration of the trigeminal neuralgic pain on the other hand , 37, 41.(ii) One of the criteria for the diagnosis of classical trigeminal neuralgia is an absence of any common sensory abnormality in the distribution of the trigeminal nerve. However, in classical trigeminal neuralgia, sometimes routine examination reveals unrelated sensory neurological deviations in the distribution of the trigeminal nerve . It can Both postherpetic neuralgia and trigeminal neuralgia are painful, debilitating conditions which are often treatment-resistant, causing psychosocial dysfunction and reduced quality of life. A better understanding of the pathogenesis of these incapacitating chronic pain conditions is needed for the development of more effective treatment strategies.


In a Perspective, Jacqueline Deeen discusses challenges in balancing the individual and population risks and benefits for CYD-TDV (Dengvaxia), the first available dengue vaccine. In tropical Asia and Latin America, dengue is a significant public health threat. Several characteristics of the disease contribute to this high sense of priority, including its geographic spread, lack of specific treatment other than supportive therapy, and the burden it imposes on clinics and hospitals. In hyperendemic areas with circulation of the four dengue serotypes, recurrent dengue infections are common. Primary infection is generally asymptomatic or manifests as self-limiting dengue fever, whereas there is an increased risk of severe dengue during secondary infection . The mosWide-scale dengue vaccination would represent a major advance in the control of the disease, but dengue vaccine development has been slow and difficult . VaccineThe CYD-TDV vaccine consists of four chimeric viruses made by replacing the premembrane and envelope structural genes of the attenuated yellow fever 17D vaccine strain with the corresponding genes from each of the four dengue serotypes . CYD-TDVPLOS Medicine, which used the assumption that CYD-TDV vaccination immunologically primes seronegative recipients, causing their first natural dengue infection to have higher severity, like that seen with secondary infection in unvaccinated persons [The World Health Organization convened a Strategic Advisory Group of Experts (SAGE) who reviewed the evidence and recommended that countries consider introduction of the vaccine only in settings with high endemicity, defined by a seroprevalence of at least 70% in the target age group . The exp persons . The mat persons ,12.The WHO recommendations have split the dengue community into those that support ,14 and cEarlier this year, the Philippines launched a pilot project to vaccinate nine-year-old children in public schools in three regions of the country . Brazil The current debate surrounding CYD-TDV use highlights the urgent need for a better dengue vaccine. Of the dengue vaccine candidates, two are furthest along in clinical development . The Tak


Woroniecki and colleagues’ article on left ventricular hypertrophy (LVH) in pediatric hypertension (HTN) reviewed current definitions, clinically relevant methods of LVM measurements, and normalization methods as well as its epidemiology, management, and reversibility in children with HTN .Since the publication in 1977 of the First American Task Force for the diagnosis, evaluation and treatment of high blood pressure (BP) in children and adolescents, updated in 1987, 1996, and more comprehensively in 2004 (as Fourth Report), the importance of HTN-related organ damage; in this context, LVH has been widely stressed. Likewise, the latest European Society of HTN guidelines for the management of HTN in children and adolescents published in 2016 has highlighted the assessment of subclinical organ damage as an intermediate stage in the continuum of vascular disease, targeting predominantly LVH (Woroniecki and colleagues’ article  exposed These aspects complicate the resolution of a definition of LVH for prehypertensive patients.Unquestionably, the search for a definition of LVH in the context of the issues raised in this commentary is complex with potentially multiple answers. To date, no outcome-based solution has been identified. Nevertheless, there is a reasonable expectation that some results will be forthcoming from the American Heart Association’s SHIP-AHOY study, intended to evaluate BP thresholds, ambulatory BP, and metabolic phenotype that predicts hypertensive target organ damage. While SHIP-AHOY will definitely inform future guidelines, currently, after extensive review of 15,000 manuscripts; the new Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents  recommenIn our opinion, the appraisal of HTN-induced LVH must also include early diastolic alterations as regional mitral Ea, Aa, and the E/Ea ratio by Tissue Doppler Imaging that precede the onset of LVH . Those tThe PESESCAD-HTA study found diastolic abnormalities even in prehypertensive adolescents without LVH, which underlines the relevance of targeting diastolic alterations on individuals prone to be hypertensive in the short term .In short, the issue of LVH in pediatric populations remains challenging. The solution will require large multinational studies to find a more reliable and matching approach to determine the cardiac organ damage that HTN entails in children and adolescents.The author confirms being the sole contributor of this work and 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.


Photo-responsive multifunctional nanomaterials are receiving considerable attention for biological applications because of their unique properties. The functionalization of the surface of carbon nanotubes (CNTs) and graphene, among other carbon based nanomaterials, with molecular switches that exhibit reversible transformations between two or more isomers in response to different kind of external stimuli, such as electromagnetic radiation, temperature and pH, has allowed the control of the optical and electrical properties of the nanomaterial. Light-controlled molecular switches, such as azobenzene and spiropyran, have attracted a lot of attention for nanomaterial's functionalization because of the remote modulation of their physicochemical properties using light stimulus. The enhanced properties of the hybrid materials obtained from the coupling of carbon based nanomaterials with light-responsive switches has enabled the fabrication of smart devices for various biological applications, including drug delivery, bioimaging and nanobiosensors. In this review, we highlight the properties of photo-responsive carbon nanomaterials obtained by the conjugation of CNTs and graphene with azobenzenes and spiropyrans molecules to investigate biological systems, devising possible future directions in the field. Carbon nanomaterials, such as carbon nanotubes (CNTs) and graphene, present unique physicochemical properties and have been studied as platforms for the development of a wide variety of biological applications, including sensing and drug delivery  isomer is exposed to UV light, it converts to the cis (or Z) metastable form  and it shows a planar conformation and a delocalized π electron system , by coupling the channel itself with a synthesized cysteine-selective iodoacetate moiety attached with a SP unit  ion is an essential micronutrient for the body growth, however it can cause neurodegenerative diseases at high level, therefore its rapid detection in biological fluids is particularly important. Li et al. (−) increasing the GO's capability to adsorb liphophilic compounds on its surface  precise time-scale responsiveness to the external stimuli, (ii) the required solubility properties in the desired media and (iii) the specific functional groups for the conjugation to nanomaterials. Moreover, the possibility to chemically functionalize the surface of carbon nanomaterial, by using covalent and noncovalent approaches, allows the preparation of photo-switchable hybrid materials with well-defined and tunable physical and chemical properties, making those materials very promising scaffolds for biological applications. The successful applications of these systems in drug delivery, bioimaging and biosensors, which have been shown 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.


Coastal habitats provide important benefits to people, including habitat for species targeted by fisheries and opportunities for tourism and recreation. Yet, such human activities also can imperil these habitats and undermine the ecosystem services they provide to people. Cumulative risk assessment provides an analytical framework for synthesizing the influence of multiple stressors across habitats and decision-support for balancing human uses and ecosystem health. To explore cumulative risk to habitats in the U.S. Northeast and Mid-Atlantic Ocean Planning regions, we apply the open-source InVEST Habitat Risk Assessment model to 13 habitats and 31 stressors in an exposure-consequence framework. In doing so, we advance the science priorities of EBM and both regional planning bodies by synthesizing the wealth of available data to improve our understanding of human uses and how they affect marine resources. We find that risk to ecosystems is greatest first, along the coast, where a large number of stressors occur in close proximity and secondly, along the continental shelf, where fewer, higher consequence activities occur. Habitats at greatest risk include soft and hard-bottom nearshore areas, tidal flats, soft-bottom shelf habitat, and rocky intertidal zones—with the degree of risk varying spatially. Across all habitats, our results indicate that rising sea surface temperatures, commercial fishing, and shipping consistently and disproportionally contribute to risk. Further, our findings suggest that management in the nearshore will require simultaneously addressing the temporal and spatial overlap as well as intensity of multiple human activities and that management in the offshore requires more targeted efforts to reduce exposure from specific threats. We offer a transparent, generalizable approach to evaluating cumulative risk to multiple habitats and illustrate the spatially heterogeneous nature of impacts along the eastern Atlantic coast and the importance of spatial scale in estimating such impacts. These results offer a valuable decision-support tool by helping to constrain the decision space, focus attention on habitats and locations at the greatest risk, and highlight effect management strategies. Coastal and marine ecosystems sustain and enhance human well-being by providing important services such as protection from storms and erosion, habitat for economically important fish and shellfish species, high quality food resources, and opportunities for recreation, tourism, and inspiration –3. For eTo address this challenge, managers, scientists, governments, and various stakeholder groups have called for ecosystem-based management (EBM) to understand multiple human uses, determine how these uses affect marine resources, and holistically manage marine and coastal species and habitats to secure the services they provide to people ,13–17. EOne important application of EBM is ocean planning, a process of assessing and allocating human activities to achieve multiple objectives in marine areas. Globally, more than three dozen countries are involved in, or have completed, some form of marine spatial planning ,27. For A key tension that EBM and ocean planning processes must address is that human activities in the ocean and coastal zone, while they enhance human well-being in the short term, may simultaneously compromise the functioning of ecosystems that underpin this well-being in the long-term. Risk assessment, which is based on components of exposure  and consequence (or ‘severity’ or ‘sensitivity’) offers a comprehensive and quantitative methodology to assess the combined influence of multiple human activities and natural stressors on the ecosystem. Risk assessment provides managers with needed decision-support for ocean planning by helping to prioritize management areas and effective management strategies. It has become a fundamental component of EBM –43 and hThis analysis is the first to assess habitat risk from a diverse set of human activities and natural stressors across the entirety of the U.S. Northeast and Mid-Atlantic planning areas in the National Ocean Policy, incorporating the extensive human use and ecosystem mapping efforts conducted as part of the recent regional planning processes. We build on previous examples of risk assessment in this region that were focused on climate stressors , social We explore the risk of habitat degradation from human activities along the Atlantic coast of the United States, focusing on two regions of ocean governance: The Northeast region that stretches from Maine to Connecticut, and the Mid-Atlantic region that continues from New York to Virginia. These regions are the first two areas along the coast of the United States to establish Regional Planning Bodies (RPBs) under the U.S. National Ocean Policy. These areas critically rely on adjacent marine habitats for livelihoods and well-being: in 2013, economic activity connected to the ocean in these states represented 935 thousand jobs and $63 billion in GDP . SuccessIn this paper, we advance the science priorities of the Northeast and Mid-Atlantic regions by synthesizing the wealth of human use data available on regional portals and then assessing the impact these uses have on marine ecosystems. The Northeast Ocean Plan details an array of science priorities, including a priority to advance EBM and to improve our understanding of human uses and how these uses affect marine resources. The Mid-Atlantic plan echoes these priorities, and emphasizes cataloguing and synthesizing human uses through the Human Use Data Synthesis project . MoreoveTo assess the influence of multiple human activities on coastal and marine ecosystems, we apply the InVEST Habitat Risk Assessment (HRA) model. The HRA model is a quantitative approach to evaluating the cumulative influence of stressors associated with human activities on habitats ,51 and iExposure is the degree to which a habitat encounters a stressor and consequence is the habitat-specific result of that exposure. Both exposure and consequence are made up of multiple criteria that can be defined by the user. In this analysis, exposure criteria include spatial data of the footprint (i.e. extent) and intensity of the stressor as well as non-spatial information about the frequency of occurrence and scale of effect of the impact , which jk is the exposure score specific to habitat j, from stressor k; Cjk is consequence score, eijk is the exposure rating criterion i, specific to habitat j and stressor k; cijk is the consequence rating. When the data were available  l is the Euclidean distance from the origin in an exposure-consequence plot. We map this habitat-stressor specific risk score where the habitat and stressor overlap in space  the lowest intensity and the upper quartile the highest intensity, with the middle quartiles composing moderate intensity. This spatially-explicit intensity score is included as an exposure criterion in the risk equation . See theThe highest levels of risk are concentrated along the coastline and along the continental shelf, though all areas throughout the Northeast and Mid-Atlantic region experience some degree of risk . IndicatThe risk assessment approach provides spatially explicit information that highlights variation in in risk at multiple scales. While greater risk in the nearshore may be an intuitive result, our results show that nearshore risk is generally lower and less concentrated in the Mid-Atlantic than in the Northeast. Within the Mid-Atlantic, high risk areas are concentrated in northern New Jersey and at the mouths of the Delaware and Chesapeake Bays, while the rest of the Mid-Atlantic coastline is at lower risk. The Northeast coastline contains greater area at the highest risk levels, with risk concentrated along the coastlines of Massachusetts, New Hampshire, and Maine . The higEcosystem risk maps, which incorporate habitat locations as well as the exposure and consequence of each stressor on each habitat, go beyond simple un-weighted overlays of human activities and identify different areas . While oPatterns of risk further vary between habitats and across regions. The RPBs did not formally delineate boundaries between the Northeast and Mid-Atlantic planning areas, choosing to have some overlap in the waters off of New York. For the purposes of quantitative comparison between regions, we bisect the two planning areas with a line running from New York Harbor to the continental shelf near Hudson Canyon. This delineation is consistent with other research efforts supported by the RPBs under the National Ocean Policy .Across regions, risk is highest for rocky intertidal, hard-bottom shelf, tidal flats, and soft and hard-bottom nearshore habitat. Higher median scores for these habitats indicate a greater area at high risk. Between regions, habitats are generally at greater risk in the Northeast than in the Mid-Atlantic. Risk is higher in the Northeast for tidal flat, seagrass, marsh, algal, soft-bottom nearshore habitat, soft-bottom shelf habitat, shallow and deep pelagic, and bathyal shelf habitats. Habitat risk is higher in the Mid-Atlantic only for rocky intertidal, hard-bottom shelf, hard-bottom nearshore, and beach habitat . These iTidal flats are one of the most at-risk habitats and this risk varies spatially. There are over 550sq. km of tidal flats in the Northeast and an additional 190sq. km in the Mid-Atlantic. Variation in risk is evident in the Northeast along the coastline of Connecticut, Rhode Island, and New Hampshire, where risk to tidal flats is predominantly in the upper quartile , 75% of risk is explained by eight human activities: warming sea surface temperatures, four kinds of commercial fishing, shipping, recreational fishing, and wildlife viewing . SpecifiRisk can be further deconstructed to determine how habitat types are variably affected by the exposure and consequence of stressors . Of the This analysis is, to our knowledge, the first to assess the cumulative risk to habitats across the entirety of the Northeast and Mid-Atlantic Ocean Planning regions. In doing so, we advance the science priorities of EBM and both regional planning bodies by synthesizing the wealth of available data to improve our understanding of human uses and how they affect marine resources. In this analysis, we identify areas of high ecosystem risk across the regions, investigate which habitats are at the greatest risk and where, and determine the primary causes of risk across habitats and locations, illustrating the effect of spatial scale on risk evaluations. We find that risk to ecosystems is greatest 1) along the coast, where a large number of stressors occur in close proximity and 2) in a relatively narrow outer offshore region, where fewer, higher consequence activities occur. Habitats at greatest risk include soft and hard-bottom nearshore areas, tidal flats, soft-bottom shelf habitat, and rocky intertidal zones—with the degree of risk varying spatially. Across all habitats, our results indicate that rising sea surface temperatures, commercial fishing, and shipping consistently and disproportionally contribute to risk. These results offer a valuable decision-support tool by helping to constrain the decision space, focus attention on habitats and locations at the greatest risk, and highlight effect management strategies.As the Northeast and Mid-Atlantic regional planning bodies begin implementing their ocean management plans, ecosystem risk maps can help constrain the decision space. These planning regions cover nearly a quarter of a million square kilometers and decision-makers within them are tasked with managing a multitude of activities, habitats, and interests. Specific agencies like the Bureau of Ocean Energy Management (BOEM), for example, could use risk maps in conjunction with spatially-explicit wind energy values to explore trade-offs between the two as they site new lease areas. As an example, we plot the levelized cost per unit of energy  are primarily the result of exposure rather than consequence; management that focuses on addressing total spatial extent, frequency, or intensity of these activities will better alleviate the effects of these activities than efforts to reduce the consequence of these activities. Identifying the root causes of risk is essential for helping agencies, from BOEM to NOAA to the RPBs, select effective management strategies.In addition to providing management tools and insight, HRA is an integral step in connecting the multitude of stressors to changes in ecosystem services. In New Hampshire’s Great Bay, NOAA’s Office for Coastal Management and others , relatedThis approach is, of course, imperfect. Four issues merit further discussion. First, HRA’s additive approach does not capture positive or negative dynamics between stressors or across time. In some cases, our additive approach to assessing risk will underrepresent risk by missing interactions between stressors that might be synergistic or over-represent those that might cancel one another out ,66. FurtDespite these limitations, we believe our habitat risk assessment approach Click here for additional data file.


Electronic health  interventions may improve the quality of care by providing timely, accessible information about one patient or an entire population. Electronic patient care information forms the nucleus of computerized health information systems. However, interoperability among systems depends on the adoption of information standards. Additionally, investing in technology systems requires cost-effectiveness studies to ensure the sustainability of processes for stakeholders.The objective of this study was to assess cost-effectiveness of the use of electronically available inpatient data systems, health information exchange, or standards to support interoperability among systems.An overview of systematic reviews was conducted, assessing the MEDLINE, Cochrane Library, LILACS, and IEEE Library databases to identify relevant studies published through February 2016. The search was supplemented by citations from the selected papers. The primary outcome sought the cost-effectiveness, and the secondary outcome was the impact on quality of care. Independent reviewers selected studies, and disagreement was resolved by consensus. The quality of the included studies was evaluated using a measurement tool to assess systematic reviews (AMSTAR).The primary search identified 286 papers, and two papers were manually included. A total of 211 were systematic reviews. From the 20 studies that were selected after screening the title and abstract, 14 were deemed ineligible, and six met the inclusion criteria. The interventions did not show a measurable effect on cost-effectiveness. Despite the limited number of studies, the heterogeneity of electronic systems reported, and the types of intervention in hospital routines, it was possible to identify some preliminary benefits in quality of care. Hospital information systems, along with information sharing, had the potential to improve clinical practice by reducing staff errors or incidents, improving automated harm detection, monitoring infections more effectively, and enhancing the continuity of care during physician handoffs.This review identified some benefits in the quality of care but did not provide evidence that the implementation of eHealth interventions had a measurable impact on cost-effectiveness in hospital settings. However, further evidence is needed to infer the impact of standards adoption or interoperability in cost benefits of health care; this in turn requires further research. Information technology (IT) applied to health care, or electronic health  , ostensiImprovements in health and economic indicators are relevant metrics to justify IT investments. Indeed, planning and investing in IT is necessary for the efficient use of information that not only advances health care but also holds financial, social, cultural, and ethical benefits. Comparative cost-effectiveness studies guide agencies and institutions in choosing the best option for desired clinical outcomes and costs, which is the key to ensuring the sustainability of government health systems and their welfare programs ,4.This review analyzes systematic reviews addressing the cost benefit and effectiveness of electronic medical records (EMR), standards adoption, or interoperability to discuss the benefits, drawbacks, and lessons learned from the implementation of actions related to eHealth and serves as a reference for government representatives and stakeholders. The assessment of the involvement of government and private health institutions in the implementation and maintenance of eHealth interventions that were tested and valuated worldwide is also of interest. The study was directed by 2 questions: What evidence exists regarding the impact of computerizing applications, standards, health information exchange, or interoperability to support the quality of care or patient outcomes in hospital settings? What critical cost-benefit evidence is published to provide a clear understanding of the value of eHealth implementations?The terms used here to describe eHealth technologies are available in It is also important to emphasize that interoperability is usually divided into (1) syntactic interoperability: the capability of two or more systems to communicate and exchange data through specified data formats and communication protocols, and (2) semantic interoperability: the ability for data shared by systems to be understood at the level of fully defined domain concepts .Worldwide coordinated efforts resulted in the development of standards to define an EHR as one or more repositories of actionable information by computers. The European Committee for Standardization (CEN), health level seven (HL7), International Organization for Standardization (ISO), and openEHR Foundation are nonprofit organizations dedicated to providing frameworks and standards. Terminologies, EHR specifications, and information models are proposed by these international standards organizations that support the exchange, integration, interoperability, and retrieval of electronic health information .To better represent the meaning of standards in the primary selected systematic reviews, we adopted the generic definition for the term as: “A document adopted by consensus by a recognized entity, that provides rules, guidelines and/or features for common use, in order to obtain an optimal level of performance in a given context…” .Economic analysis supports health care policy and organizational decision making. However, it encounters some difficulties with eHealth systems, which are as follows: constantly changing technology, inconsistent study design to manage inadequate sample sizes, the inappropriateness of conventional techniques of economic evaluation, and the problem of placing value on health and nonhealth outcomes . ConsequThis review of systematic reviews has been conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement  and the On February 22, 2016, electronic searches were conducted on the MEDLINE, Cochrane Library, LILACS, and IEEE Library databases. To identify the EHR concept, standards for interoperability, and health information and its cost benefits, the search strategy was: AND (“Interoperability” OR “Standard of Information”)) AND The search was limited by language of publication , studies in humans, type of study , and year of publication (since 2005). Two systematic reviews that satisfied the criteria were identified manually. To better define certain eHealth technology descriptions, additional sources of evidence were considered.The inclusion criteria were as follows:Primary impact: EMR, standards, or interoperability on cost-benefit, orSecondary impact: EMR, standards, or interoperability on quality of care , andReal-life reviews about interventions in in-hospital settings.Studies in primary or secondary care scenarios, studies without the primary or secondary impact of eHealth actions, and duplications were excluded. Titles and abstracts of retrieved papers were independently screened and evaluated by 2 investigators (ZSNR and TAM). Abstracts providing insufficient information were retrieved for independent, full-text evaluation by 2 investigators to determine study eligibility. Disagreements were resolved by consensus. Additional publications were identified using the reference lists of selected manuscripts.ZSNR prepared electronic data with paper contents abstracted using StArt software (Systematic Review System) to organize the analysis . The datSubgroup 1: eHealth systems implementation without health information exchangeSubgroup 2: eHealth systems with health information exchange functionalitiesThe methodological quality assessment was based on the AMSTAR (a measurement tool to assess systematic reviews) checklist .A total of 288 papers were identified during the initial research phase, which decreased to 273 after removing 15 duplicates. After applying our criteria, only six systematic reviews were included in the final analysis and data-abstraction phase. The review process is represented in The primary cause for excluding the 20 studies was mixed or outpatient settings for eHealth interventions . The Pan American Health Organization (PAHO) conducted a review of the implementation and effective use of standards to achieve interoperability in Latin American and Caribbean countries but without direct or indirect outcomes analysis . MultimeEvidence of the cost-effectiveness of eHealth interventions that met the criteria was identified. Only one systematic review of the six performed a meta-analysis . The quaAmong the included systematic reviews, only one was classified as showing an effect on eHealth implementation without electronic health information exchange (Subgroup 1), and the other five were ranked as showing effects of systems implementation with incorporated health information exchange among other electronic data sources (Subgroup 2).Considering eHealth systems implementation without health information exchange, the review of Thompson et al  reportedThe selected review stated a mix of electronic interventions: EHR, EMR, computerized decision support systems (CDSS), computerized provider order-entry (CPOE) and surveillance systems used by physicians, nurses, allied health professionals, and managers of health services evaluating evidence from pre-and postsystems implementation. The analysis synthesized 46 publications about systems for diagnosis, treatment, and clinical monitoring. The study included a meta-analysis extracted from 26 publications to evaluate the effects of different types of systems regarding health IT in the inpatient of intensive care unit (ICU) setting on mortality, length of stay (LOS), and cost.2 of 59%.Not enough evidence showed that electronic interventions can improve quality and safety of health care. The goals for secondary outcomes were the effects of health IT in the inpatient and ICU on mortality or LOS. The quality of included studies and interventions varied significantly, which was highlighted as the major limitation. Despite this, the surveillance systems had a pooled odd ratio (OR) of 0.85 (95% CI 0.76-0.94) with moderate heterogeneity, ICosts were unable to be evaluated quantitatively because the primary studies presented mixed and inconclusive results, leaving us unable to draw a definitive conclusion about cost-effectiveness. The analysis of costs was more limited than the evidence on quality and efficiency.EHR implementation with health information exchange is a recent worldwide trend in hospital settings. A summary of the results of the systematic reviews included in subgroup 2 is presented in Most of the reviews use ICUs as settings for eHealth intervention analysis. However, the objectives of interventions were quite heterogeneous. Two studies reported the effect of surveillance systems on harm detection  and healAmong reviews focused on improving clinical practice, inconclusive results in direct patient care were reported by Cheung et al . Mapp etNone of the reviews evaluated effects of eHealth interventions on costs.This study found preliminary benefits in the use of electronically available inpatient data systems on the quality of care. Despite the limited number of studies that met the eligibility criteria, the heterogeneity of electronic systems reported, and different interventions on hospital routines, the identification of preliminary secondary benefits on patient mortality was possible . eHealthHowever, no substantial review regarding the impact of electronic interventions on cost-effectiveness was identified. Among the six analyses included, only Thompson et al reported that some preliminary studies have identified decreases in cost, but the heterogeneity and the absence of information of follow-up impaired a proper analysis of cost-effectiveness . ImmediaUnfortunately, no study about interoperability, in the sense of syntactic and semantic meaning, on cost benefit was identified. Importantly, none of the studies in this review properly defined EHR concept as a longitudinal health record with entries by health care practitioners in multiple sites of care or mentioned interoperability applications among electronic systems. However, taking the antecedent step toward full interoperability, an effective information sharing between stakeholders and systems can be attained through the use of standards . StandarThe current results should be interpreted as a whole with the study limitations. Only four major databases were searched and gray literature sources were not evaluated. Additionally, the limitation to English, Spanish, French, Italian, and Portuguese languages prevented the capture of all relevant studies. Furthermore, the quality of included studies was poor, and they varied regarding the type of eHealth interventions, follow-up time, and goals. This systematic review summarized primary and secondary outcomes from different classes of intervention from which to draw results, analysis, and conclusions. Due to the variation in scenarios and lack of numeric goals, a meta-analysis was considered inappropriate.This review identified some benefits on the quality of care but did not provide evidence that the eHealth interventions had a measurable impact on cost-effectiveness, mortality, or LOS in hospital settings. Preliminary evidence indicates that the use of eHealth interventions with information exchange may improve clinical process outcomes. The absence of studies precludes the assessment of impact of interoperability on benefits of health care or cost, and this aspect needs further research. Technological barriers might influence eHealth solutions implementation and data exchange for systems integration or interoperable interfaces. There are also issues with the lack of standardization of most aspects of health information and misuse of terms in the scientific publications. Authors should be explicit when they are using interfacing syntactic interoperability or semantic interoperability to reduce the confusion with different health information exchange possibilities. Further research with long-term follow-up is needed to determine the actual impact of eHealth adoption on health care costs to demonstrate (1) value for money  and (2) the clinical impact of semantic and synthetic interoperability.


Laparoscopic gastrectomy is evolving. With the increasing expertise and experience of oncologic surgeons in the minimally invasive surgery for gastric cancer, the indication for laparoscopic gastrectomy is expanding to advanced cases. Many studies have demonstrated the benefits of minimally invasive surgery, including reduced risk of surgery-related injury, reduced blood loss, less pain, and earlier recovery. In order to establish concrete evidence for the suitability of minimal invasive surgery for gastric cancer, many multicenter RCTs, comparing the short- and long-term outcomes of laparoscopic versus open surgery, are in progress. Advances in laparoscopic gastrectomy are moving toward increasingly minimally invasive approaches that enable the improvement of the quality of life of patients, without compromising on oncologic safety. In spite of a decrease in its incidence, gastric cancer is still the fifth most common malignancy and the third leading cause of cancer-related death in the world  according to GLOBOCAN, 2012. Half of the total global incidence occurs in Eastern Asia (mainly in China)  reportedThe technical difficulties of laparoscopic surgery include the limited mobility of the instruments and the absence of tactile sensation. In HALS, however, the surgeon's left hand is inserted into the abdominal cavity through a special pressurized sleeve, approximately 6-7 cm long, which preserves the operator's tactile sensation . IncorpoIn laparoscopy-assisted gastrectomy (LAG), after laparoscopic full mobilization of the stomach, resection of the stomach and anastomosis is performed extracorporeally through a small incision in the epigastrium for the accurate localization of the lesion and secure reconstruction. For the precise localization of the lesion in LAG, the effectiveness of endoscopic clips and laparoscopic ultrasonography has been reported . The useLaparoscopy-assisted total gastrectomy (LATG) is technically demanding in terms of reconstruction and LND such as stations 11d, 4sa, and 10 , 17. TheIn LAG, the surgical process via minilaparotomy is sometimes difficult to perform, especially in patients with obesity . TotallyFor the standardization of laparoscopic gastrectomy, the procedure must achieve reproducibility, safety, and simplicity in terms of not only the LND but also the reconstruction component. Billroth I anastomosis has been known to offer the advantages of greater simplicity of performance, fewer postanastomosis anatomical changes, increased physiological pathways, and lower incidences of adhesion and internal herniation. Consequently, it has been the most commonly performed anastomosis after distal gastrectomy in Korea and Japan . During Recently, delta-shaped anastomosis, one of the well-established intracorporeal gastroduodenostomy methods, is popularly performed; however, it still demands delicate and precise laparoscopic techniques of the operators and assistants. The technique proceeds in the following way. First, the duodenal bulb is transected using an endoscopic linear stapler at a 90° angle from the usual line. The stomach is then divided in the customary fashion. Small entry holes are created along the edge of the stomach and the duodenum. The posterior walls of both the stomach and the duodenum are approximated using a 45 mm linear stapler. Then, the staple line is meticulously inspected for any defects to ascertain the color of the anastomosis, after which the common entry hole is closed with one or two linear staplers . The mosThe Roux-en-Y method is known to be favorable to postoperative quality of life (QOL) with lower incidence of bile reflux and anastomotic leakage , 11. HowOwing to the difficulty of achieving a secure purse-string suture and the technical challenge of performing an esophagojejunostomy in a narrow and deep surgical field, LATG or laparoscopic total gastrectomy (LTG) is performed relatively less often compared with LADG.Esophagojejunostomy using a circular stapler is the most famous technique in the open surgery. For extracorporeal approaches in LATG, a 4 to 6 cm-sized epigastric incision is made to access the esophagogastric junction. Many reports pertaining to the extracorporeal method describe the procedures in simple terms, such as “the insertion of an anvil with the purse-string suture.” However, the procedure is often very difficult because the purse-string device is too bulky to handle in a small minilaparotomy space, and suturing through a small incision in the deep and narrow operative field is an exacting process , 32. HowThe handling of the linear stapler is easier in LTG field because linear staplers are thinner and have superior mobility of the tip compared to circular staplers. Moreover, surgeons can perform the linear-stapled anastomosis regardless of the esophageal diameter and can achieve a larger anastomosis than in the case of circular-stapled anastomosis. In addition, linear-stapled anastomosis helps the surgeon reduce the torsion of the jejunal limb, which is a severe complication of circular-stapled anastomosis.For the overlap method , a smallThere are two differences between the overlap method and FEEA: the peristaltic direction of the esophagojejunostomy and the methods of closing the common entry hole. Esophagojejunostomy in FEEA is performed in the antiperistaltic direction; therefore, the jejunal limb needs to be lifted further up in FEEA than in the overlap method. In addition, the closure of the common entry hole in FEEA is performed using a linear stapler, whereas the closure is performed using an intracorporeal suture in the overlap method. Thus, since a larger working space is needed in FEEA than in the overlap method, the dissection around the crura of the diaphragm has to be performed in FEEA, which can increase the risk of a diaphragmatic hernia. In contrast, advanced suturing skills are needed in the overlap method, and intracorporeal suturing frequently results in prolonged operative time .PPG was first introduced for the treatment of peptic ulcer, and since then, it has been used as a surgical treatment for EGC to preserve function and maintain a better QOL , 44. AccVPG was designed to decrease postgastrectomy symptoms caused by injury to the vagus nerve. It preserves not only the celiac branches of the posterior vagal trunk that innervate the small intestine but also the hepatic branches of the anterior vagal trunk that innervate the liver and biliary tract . HoweverIn laparoscopic PG (LPG), the type of reconstruction may be the most important issue. Esophagogastrostomy has served as the most simple reconstruction method, though most patients end up suffering from postoperative reflux esophagitis and/or anastomotic stricture. Antireflux procedures including fundoplication, gastric tube formation, pyloroplasty, and esophagopexy with crural repair have been attempted in order to reduce the incidence of anastomotic stricture and reflux esophagitis. However, the results of these efforts have been far from satisfactory –50, and Reduced port or single-port laparoscopic surgery was developed to reduce scars and surgical stress, and indeed, single-port laparoscopic surgery through the umbilicus does not leave any visible scar. A vertical 2.5 cm-sized transumbilical incision is made, and a commercial single-port device is placed in the umbilical incision. An additional assistant trocar is not needed. Then, a flexible scope is used to secure a clear view of the operative field. For effective dissection, curved instruments are used when operating in the lesser curvature side and the suprapancreatic area. Regarding suprapancreatic LND, the neck and body of the pancreas are sometimes overly protruded, which makes it difficult to dissect the lymph nodes behind the pancreas using a straight instrument from the umbilicus. SIDG is not yet generalized because of the continuing need for more advanced techniques and scarring evidences of oncological safety. In addition, although previous reports of SIDG showed comparable morbidity and an absence of open conversion, the risk of unexpected intraoperative accidents in pure, single-port surgery cannot be ignored. A large-scale study is necessary to confirm the safety and oncologic outcomes of SIDG.Robotic systems for surgery were implemented in early 2000 to overcome the drawbacks of laparoscopic surgery. The features of the robotic systems, such as 3-D vision, the elimination of physiologic tremor, and the articulated arms, assist the surgeon by facilitating manipulation in the surgical field . An artip = 0.012), the Korean laparoscopic gastrointestinal surgery study (KLASS) group performed a phase 3 multicenter RCT (KLASS-01) to establish even stronger evidence, and their morbidity and mortality data was recently reported , but most of the high cost will not be a big problem in the future due to depreciation and maintenance costs. Rather than simply calculating the cost per operation, we should study the indications that require robotic gastrectomy, apply robotic surgery where necessary, and reduce the social burden by reducing complications.Recently, the Korean Robot Gastrectomy Study Group reported the results of a multicenter prospective, clinical trial comparing robotic gastrectomy with laparoscopic gastrectomy in EGC . Patientp = 0.721; 5-year disease-free survival: 98.8% versus 97.6% in LADG versus ODG, p = 0.514) [Regarding oncological safety, our group reported the long-term safety of LADG for EGC . Tumor r= 0.514) .There have been several studies on the oncologic outcomes of laparoscopic gastrectomy with extended lymphadenectomy for advanced gastric cancer (AGC). The findings of these studies suggested that the 3-year overall survival (75.3%) and disease-free survival (69.0%) for laparoscopic surgery were comparable to those of published studies on conventional open surgery –76.Two multicenter RCTs, the KLASS-01 study and the Japanese Clinical Oncology Group (JCOG) 0912 trials, are currently ongoing on large-scale studies and seek to elucidate the oncological outcomes of laparoscopic gastrectomy for EGC. The KLASS-01 trial is the first multicenter RCT to compare laparoscopic surgery with open surgery in patients with clinical stage I gastric cancer. Overall survival is the primary endpoint, and the secondary endpoints include morbidity and mortality, disease-free survival, quality of life, inflammatory responses, and cost effectiveness. A total of 1416 patients  were enrolled from 2006 to 2010, and the final results will be reported in the near future . The JCOThe long-term results of laparoscopic surgery for AGC remain controversial because of the paucity of reliable studies. While D2 LND is the standard for AGC treatment in open, laparoscopic, and robotic surgeries, it is very challenging to perform. Even in East Asia, where there are many more cases and experiences of gastric cancer than in Western countries, only a few qualified surgeons are capable of performing a complete D2 LND using a laparoscopic approach. Significant improvements in laparoscopic surgical instruments and techniques have been progressing for decades . This acThree multicenter trials, the KLASS-02, the Japanese Laparoscopic Surgery Study Group (JLSSG) 0901, and the CLASS -01, are current large-scale studies seeking to elucidate the oncological outcomes of laparoscopic gastrectomy for AGC. The KLASS-02 trial is a phase III study evaluating the efficacy of LDG with D2 LND for AGC. The primary endpoint is 3-year disease-free survival, and the estimated population size is 1050. The JLSSG 0901 trial is a phase II/III study comparing LADG and ODG in patients with clinical T2 to T4aM0 gastric cancer. After the recruitment of 180 patients, the rate of major complications will be analyzed. The study will continue the recruitment until 500 patients are enrolled unless there is early termination due to a high complication rate . Lastly,Laparoscopic gastrectomy has many merits over open gastrectomy, such as less pain, shorter postoperative hospital stays, earlier recovery, and superior cosmetic outcomes. In several meta-analyses, the superiority of laparoscopic gastrectomy in terms of postoperative recovery was shown , 87. In Function-preserving surgery was introduced to improve the QOL of patients. Recently, the nutritional and functional benefits of LAPPG were compared to those of LADG . It was In proximal EGC, the application of PG has been limited until now. In a systematic meta-analysis comparing TG with PG, PG with esophagogastrostomy showed a higher incidence of reflux esophagitis and anastomotic stenosis . HoweverLaparoscopic gastrectomy has advanced to look for minimally invasive approaches as well as to maintain the oncologic safety. In accordance with the evolution of surgical instrumentation and increased laparoscopic surgical experience, its indication has been extended to advanced cases. Recent studies show that the oncologic outcomes of laparoscopic gastrectomy for EGC are comparable to those of open gastrectomy. The demonstration of a similarly optimal result regarding the safety of laparoscopic gastrectomy in AGC is awaited. The results of several ongoing multicenter RCTs are expected to establish concrete evidence of the widespread suitability of laparoscopic gastrectomy in the treatment of gastric cancer.


Conus snails and allies have been extensively studied, revealing an amazing chemical diversity of small, highly constrained neuropeptides, whose characterization led to significant pharmacological developments. Conversely, salivary glands, the other main secretory structures of molluscan foregut, have been neglected despite their shared occurrence in the two lineages including predatory members: Gastropoda and Cephalopoda. Over the last few years, the interest for the chemistry of salivary mixtures increased based on their potential biomedical applications. Recent investigation with -omics technologies are complementing the classical biochemical descriptions, that date back to the 1950s, highlighting the high level of diversification of salivary secretions in predatory mollusks, and suggesting they can be regarded as a pharmaceutical cornucopia. As with other animal venoms, some of the salivary toxins are reported to target, for example, sodium and/or potassium ion channels or receptors and transporters for neurotransmitters such as, glutamate, serotonin, neurotensin, and noradrenaline, thus manipulating the neuromuscular system of the preys. Other bioactive components possess anticoagulant, anesthetic and hypotensive activities. Here, we overview available knowledge on the salivary glands of key predatory molluscan taxa, gastropods, and cephalopods, summarizing their anatomical, physiological and biochemical complexity in order to facilitate future comparative studies on main evolutionary trends and functional convergence in the acquisition of successful predatory strategies.Many marine mollusks attain or increase their predatory efficiency using complex chemical secretions, which are often produced and delivered through specialized anatomical structures of the foregut. The secretions produced in venom glands of  Placiphorella velata uses its head flap and precephalic tentacles to capture small invertebrates  Neogastropoda (with about 40 families), (ii) Tonnoidea, (iii) Naticoidea, and (iv) Ficoidea. Fossil record suggests that predation evolved almost simultaneously in late Cretaceous, in the framework of the major reorganization of marine communities known as the Mesozoic marine revolution Vermeij, .Nautilus a scavenger. They emerged as predators since their major diversification event in middle-upper Paleozoic  gland, a non-paired organ lying below the salivary papilla and arranged into several lobes, is well-developed in octopods and Nautilus and cuttlefishes they are enclosed in the musculature , while in octopuses they lay at both sides of the buccal mass . These axons end close to the basal membranes of the tubular cells, with a synaptic cleft (20 nm) and apparently no synaptic membrane specializations. These nerve endings contain a mixed population of vesicles , where catecholamines are found. Noradrenaline and 5-HT are considered to be transported along axons toward the glands from cell bodies in the superior buccal lobe. In analogy, and due to significant quantities of octopamine and tyramine found in the superior buccal lobe  plus other compounds that are now in pre-clinical trials. Despite the discovery of alpha-conotoxins in the salivary secretion of Conus pulicarius  reticulata, revealing a remarkable complexity of the salivary secretion. Neurotoxins, echotoxins, and several enzymes were detected, as well as putative inhibitors of hemostasis such as, TFPI-like protease inhibitors, the novel VWFA1 domain-containing proteins and ENPP-5  and sialic acid, dipeptidase, and hyaluronidase, that probably facilitate the delivery of the viscous secretions of the posterior salivary gland and may be involved in external pre-digestion  were recognized in the late nineteenth century by Lo Bianco . Toxicita et al. . Reportea et al. .Eledone aldrovandi and Eledone moschata, OctTK-1 and OctTK-2 from O. vulgaris  in The remarkably higher complexity of the physiological regulation of salivary secretion in Cephalopoda compared to Gastropoda further confirms a major commitment toward predation since the early evolutionary history of the former group. In gastropods, the basic physiology of salivary secretion appears in agreement with a plesiomorphic condition of microphagous feeding.If we consider the bioactive compounds secreted in the salivary glands of both groups, it should be noted that cephalopods evolved characteristic enzymes and neuropeptides belonging to families that are shared with many other venomous taxa, including snakes and spiders  with respect to their evolutionary origin that dates back to the late Cambrian and had to cope with a In spite of the differences of salivary glands of gastropods and cephalopods we simplified in this review, a common feature emerged: the presence of multiple glands corresponding to an extremely rich chemical assemblage. This trait may have facilitated the specialization and differentiation of different cellular districts to achieve the final composition of the saliva. Several bioactive salivary components with cytolytic, hypotensive and, above all, neuroactive activity are excellent candidates for biotechnological development, due to millions years of natural selection that have contributed to their specificity, a key factor in the evolutionary success of these predatory mollusks.GP and MM developed the concept of the manuscript, searched the literature and wrote a draft. MM further developed the early draft. GP elaborated the figure.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CM-S and handling Editor declared their shared affiliation, and the handling Editor states that the process met the standards of a fair and objective review.