Optimal management of the critically ill patient in shock requires rapid identification of its etiology. We describe a successful application of an emergency physician performed bedside ultrasound in a patient presenting with shock and subsequent cardiac arrest. Pulmonary embolus was diagnosed using bedside echocardiogram and confirmed with CTA of the thorax. Further validation and real-time implementation of this low-cost modality could facilitate the decision to implement thrombolytics for unstable patients with massive pulmonary embolism who cannot undergo formal radiographic evaluation. Identifying the possible causes of shock in the critically ill patient in the emergency department (ED) is challenging due to limited information, broad differentials, and the severity of illness demanding rapid intervention. A quick narrowing of one's differential diagnosis using bedside ultrasound may tailor therapy and guide further workup, especially in patients deemed too unstable to undergo computed tomography imaging. In these situations, ultrasound may be invaluable as a low-cost, real-time, noninvasive modality which allows serial bedside examinations, possibly identifying the cause of hypotension or cardiac arrest. We discuss a case of massive pulmonary embolism diagnosed by bedside ultrasound.2 via a nonrebreather mask. His exam was significant for grunting, otherwise clear bilateral breath sounds, rapid but regular heart tones, weak femoral pulses, and symmetric, non-edematous lower extremities.A 53-year-old man was brought in by ambulance with the chief complaint of multiple “fainting” episodes. He was reported by the paramedics to be hypotensive and tachycardic prior to arrival. His past medical history was significant for hypertension, chronic renal insufficiency, and gouty arthritis. On presentation to the emergency department, the patient appeared critically ill with generalized pallor, perioral cyanosis, with a heart rate of 133 beats per minute (bpm), blood pressure of 130/106 mm Hg, and oxygen saturation of 100% on 15 L O2 and confirmation of adequate tube placement. A repeat bedside ultrasound was performed with visualization of an enlarged right ventricle  and inferior vena cava (IVC) Figures . The patentricle , and an entricle , highly entricle , and altThe patient's course was complicated by bilateral pneumothoraces, acute renal failure, and subconjunctival hemorrhage. However, he was ultimately extubated and discharged home with full neurologic recovery, and a repeat CTA chest demonstrated resolution of pulmonary thrombi . A deep This case demonstrates successful application of bedside ultrasound in the diagnosis of massive PE in a patient resulting in PEA arrest. Although thrombolytics were given immediately after confirmation of PE by thoracic CTA, the sonographic evidence of a right sided thrombus  and an eunstable patient or a patient in cardiac arrest who carries a high probability of pulmonary embolism, visualizing these signs could guide further testing or initiation of therapy such as thrombolytic [Hesitancy to initiate a potentially harmful therapy such as thrombolytics is understandable, given the overall poor sensitivity and specificity of ED-performed sonography for PE. Sonographic findings which support the diagnosis of acute PE include direct signs such as free-floating thrombus in the right heart or pulmonary artery or indirect signs such as RV dilation (>1 : 1 RV/LV ratio), RV systolic dysfunction, flattening or bowing of the intraventricular septum into the LV, IVC dilation without inspiratory collapse, or evidence of DVT on compression ultrasound of the lower extremities . DespiteIn this case, the direct visualization of a clot in the IVC and right atrium, with acute RV enlargement coinciding with clot disappearance, strongly suggested a PE contributing to the patient's hemodynamic instability. The presence of clot on echocardiogram or “thrombosis in transit” has been described previously –13, inclVisualization of right heart thrombus may also suggest poor response to anticoagulation alone based on a small case series  and otheThrough visualization of right heart thrombus, RV dilatation, and acute cor pulmonale, use of bedside ultrasound can help guide diagnosis and therapy in pulmonary embolism and add prognostic information. Similarly, the use of bedside ultrasound in the crashing patient with cardiac arrest may help distinguish between asystole, pulseless electrical activity, and pseudopulseless electrical activity, while identifying alternative diagnoses  and guiding emergency procedures . In factLastly, the thrombolytic dosage used in this case  is a smaller but faster bolus than the current FDA and AHA recommendations for pulmonary embolism  . HoweverBedside ultrasound may help differentiate between the etiologies of hypotension in the unstable patient. In cases of acute PE, evidence of right heart thrombus on real-time ultrasound portends a poor prognosis, and these patients may benefit from more aggressive treatment such as thrombectomy or thrombolysis as in this case. The optimal dosing of thrombolytics for acute PE is controversial and is in need of further investigation.


Nodal physiology is disturbed by altered function, localization, and expression of voltage-gated ion channels clustered at nodes and juxtaparanodes, and by disrupted axon–glial interactions at paranodes. This paper reviews recent discoveries in molecular/cellular neuroscience, genetics, immunology, and neurology that highlight the critical roles of nodes of Ranvier in health and disease.Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the excitable nodal axolemma contains a high density of Nav (voltage-gated Na Since the axons between nodes are insulated by myelin sheaths, the action potentials are regenerated only at the nodes allowing rapid and efficient propagation in a saltatory manner.The main function of neurons is to transmit information among various regions of the brain, from the brain to the body, and from the body to the brain. Ideally, information must be transmitted very rapidly over a long distance with minimal energy using the confines available of the nervous system itself. Vertebrates have solved this problem by creating myelinated nerve fibers: structures composed of long neuronal ‘axon’ processes that communicate with targets, and glial cell derived myelin sheaths, multi-lamellar structures that wrap around them. Mostly axons are ensheathed and insulated by serially arranged myelin sheaths along their entire length. These structures are formed through the interaction between neurons and myelin-forming glial cells, Schwann cells in PNS , and oligodendrocytes in CNS . Myelination is initiated by signals from axons to the glial cells  channels, KCNQ2, and KCNQ3, are clustered in higher densities at nodes and the AIS where they modulate axonal excitability. KCNQ2 channels mediate the slow nodal K+ current regulating the excitability of nodal axons , nodes of Ranvier, paranodes, juxtaparanodes, internodes, and terminals A. Specif+ conductance by binding extracellularly at receptor-site 1 of Nav channels preventing monovalent cations from accessing the pore. In severe cases, patients rapidly develop generalized flaccid paralysis that can progress to respiratory failure and even death. Electrophysiological examinations of peripheral nerves of patients with puffer fish poisoning show reduction of compound action potentials in both motor and sensory nerves, and altered nerve excitability properties consistent with tetrodotoxin blockade of Nav channel pores  characterized by acute progressive limb weakness. GBS is divided into two subtypes, an axonal form [AMAN ] and a demyelinating form [AIDP (acute inflammatory demyelinating polyradiculoneuropathy)]  had autoantibodies to gliomedin, NF186, NF155, contactin, or contactin/Caspr complex , an autoimmune disease of the CNS myelin  are detected in patients with Morvan syndrome, a rare complex disease that combines neuromyotonia with multi-organ autonomic disturbance, insomnia, and encephalopathy , skin biopsy showed that Caspr immunostaining was spread from paranodes into both juxtaparanodes and internodes and Kv channels were distributed in patches along the internodal axolemma rather than remaining in juxtaparanodes (Li et al., Trembler-J mice have a point mutation in the peripheral myelin protein 22 gene and are a model for CMT type 1A. The sciatic nerves of these mice often showed binary clusters of Nav channels, heminodes (see Trembler-J heminodes and nodes contain two unusual ion channel subtypes: Nav1.8 and Kv3.1b. Nav1.8 is a tetrodotoxin-resistant Nav channel subtype normally expressed in nociceptive sensory neurons and may have important roles in pain [reviewed in (Eijkelkamp et al., odes see E, and Kvodes see . FurtherDisruption of nodes of Ranvier may also contribute to the pathophysiology of immune-mediated demyelinating neuropathies. In superficial peroneal nerve biopsy from patients with CIDP, paranodal structures were altered, Caspr expression was up-regulated and diffusely localized along the internodal segments (Cifuentes-Diaz et al., Chronic pain may in part result from partial demyelination during chronic injury, which creates aberrant Nav channel clusters that may serve as sites of ectopic sensitivity or spontaneous activity [for review see (Levinson et al., There is also evidence that nodes of Ranvier are disrupted in metabolic diseases. The disruption of paranodal axo-glial junctions was found in sural nerve biopsy specimens from patients with polyneuropathy associated with type 1 diabetes mellitus, a disease caused by the autoimmune destruction of pancreatic islet cells and loss of insulin production (Sima et al., Similar to the PNS, myelinating oligodendrocytes play critical roles during formation and maintenance of CNS nodes of Ranvier. For example, in the Shiverer mutant mouse, characterized by a disrupted myelin basic protein gene and loss of myelin basic protein and compact CNS myelin, axo-glial junctions although still present were irregular in shape, size, and distribution (Rosenbluth, MS is an autoimmune-mediated disease targeting CNS myelin. Disruption of the paranodal architecture and aberrant molecular organization occurs in human MS pathology (Wolswijk and Balesar, In addition to MS, traumatic injuries in the CNS may involve disruption of nodes. In an experimental model for spinal cord compression, exposure of juxtaparanodal Kv1.2 channels with accompanying myelin retraction at the nodes contributed to the induction of conduction block (Ouyang et al., Neuronal damage can also disrupt molecular complexes located on the axolemma at and near nodes causing disturbance of action potential conduction. For example, in chronic idiopathic axonal polyneuropathies, Caspr immunoreactivity at paranodes was irregular, and Nav channels and KCNQ2 channel staining was also increased in internodal regions (Cifuentes-Diaz et al., Nodes of Ranvier are one key structure for proper functioning of mammalian nervous systems. As reviewed here, dysfunction and/or disruption of nodes play significant roles in the development of neurological symptoms. Ion channel functions are disturbed by genetic mutations and by toxins. Autoimmunity against molecules located at and near nodes, myelin defects, and neuronal damage alter the localization and expression of ion channels and disrupt axon–glial interactions. Many important questions still remain to be answered. For example, what is the mechanism of altered expression of ion channel subtypes in the demyelinating lesions? Is it possible to correct the ion channel composition at injured nodes? How do the initial disruption of nodes and paranodal axo-glial apparatus extend to more severe structural damage such as axonal degeneration leading to permanent disability? What is an effective strategy to limit the injury to nodes or to facilitate nodal repair? Research of this nature will continue to uncover the basic mechanisms that underlie the formation, maintenance, disruption, and repair of nodes of Ranvier, and to establish novel therapeutic approaches for currently intractable neurological diseases.


Adult onset GSDII presents with a wide spectrum of clinical features and variable rates of progression. Three main clinical presentations have been observed: a myopathy with limb girdle muscle involvement (LGMD), asymptomatic hyperCKemia (HCK), and respiratory muscle deficiency preceding limb-muscular weakness. Our study used a new MRI technique with quantitative analysis of muscle fat fraction (MFF) to explore different patterns of muscle involvement and to analyze possible correlations with different clinical aspects in 12 patients with late-onset GSDII.12 patients with late-onset GSDII were recruited before starting enzyme replacement therapy and were divided into three cohorts based on clinical presentation . Clinical assessments included the Walton scale, 6MWT, GSGC, FVC% and MRC scores. The muscle MRI protocol was performed using dual-echo, dual-flip-angle spoiled gradient-recalled imaging, which allowed us to accurately quantify and display the muscle fat fraction (MFF). We evaluated the MFF of all respiratory muscles in 12 ambulant patients with late-onset Pompe disease. MRIs included the lower girdle, paraspinal, abdominal, and respiratory muscles. Statistical correlations were performed using the Spearman Rho test.MFF of the lower girdle muscles was correlated with functional muscle measures such as the 6MWT, GSGC, and MRC. In particular we found a positive correlation with ileopsoas and gluteus muscles. Moreover, we found a statistically significant correlation between the degree of diaphragm atrophy and pulmonary dysfunction, especially in the upright position.MFF is a reliable, relatively fast, and sensitive technique for visualizing muscle involvement, and it provides an accurate fat quantification when compared to muscle biopsy findings in different neuromuscular disorders. In the present study, we show that this technique can be used to evaluate the degree of muscle involvement and is correlated with clinical data currently used as functional outcome measures in Pompe disease. Our data suggested that muscle MRI studies may be a useful tool to evaluate muscle impairment even in the early stages of disease.


Neural cell transplantation and gene therapy have attracted considerable interest as promising therapeutic alternatives for patients with Parkinson's disease (PD). Preclinical and open-label studies have suggested that grafted fetal neural tissue or viral vector gene transfer can achieve considerable biochemical and clinical improvements, whereas subsequent double-blind, placebo-controlled protocols have produced rather more modest and variable results. Detailed evaluation of these discordant findings has highlighted several crucial issues such as patient selection criteria, details surrounding transplantation or gene therapy methodologies, as well as the study designs themselves that ought to be carefully considered in the planning phases of future clinical trials. Beyond the provision of symptomatic efficacy and safety data, it also remains to be identified whether the possibilities offered by stem cell and gene therapy technological advances might translate to meaningful neuroprotection and/or disease-modifying effects or alleviate the nonmotor aspects of PD and thus offer additional benefits beyond those achieved through conventional pharmacotherapy or deep brain stimulation (DBS). Current antiparkinsonian oral drug therapies, with the dopamine (DA) precursor levodopa (L-dopa) remaining the most effective, allow remarkable symptomatic control over the cardinal motor features of Parkinson's disease (PD) in the first years after diagnosis, by restoring the characteristic nigrostriatal DA deficit. Unfortunately, the pharmacotherapeutic window shrinks over time, and treatment is complicated by the onset of motor fluctuations (“ON/OFF” phenomena) and L-dopa induced dyskinesias (LIDs), while signs such as balance disorders, gait freezing, autonomic disturbances, dementia, or affective changes, refractory to dopaminergic substitution, appear –3. ContiSince the late 1980s, over 300–400 PD patients worldwide have received transplants of human fetal ventral mesencephalic (VM) tissue, rich in post-mitotic DA neurons. The experience accumulated from open-label studies suggested significant clinical benefits across multiple parameters in patients receiving grafted cells accompanied by a general reduction in pharmacological requirements . Two douRetrospective analysis of clinical trials and further basic science research have sought to explore factors explaining variability in results of cell transplantation open-label series and double-blind trials and determine whether the most successful cases, which had L-dopa withdrawn and exhibited major clinical improvement for several years, could be reproducible. A number of technical parameters regarding tissue procurement and preparation, such as the age and number of donor fetuses, graft dissection procedures, storage length and conditions, tissue dissociation before transplantation (into pieces or crude cell suspensions), or the use of ancillary neuroprotective strategies to increase graft survival , lazaroids), are likely to have an important role –20. It iNevertheless the shortage of embryonic donor tissue, difficulties in standardization of cell material  as well as ethical concerns associated with the procurement of tissue from aborted human fetuses make routine clinical application for this type of cell replacement therapy impractical. Alternative cell sources such as autografts of sympathetic neurons from the adrenal glands or xenograft tissue  have been abandoned because of discouraging clinical and graft survival results and significant side effects –24. Recent progress in the stem cell field has provided impetus to the cell replacement approach. Stem cells of human origin, potentially able to provide an unlimited supply of standardized DA neurons, may be considered as the most promising future source for a cell-based therapy for PD . Cells wThe generation of these cells has highlighted the unresolved issue whether entirely pure DA cell populations will be sufficient, since the nondopaminergic neurons and most probably glial compartments present in the embryonic mesencephalic grafts used so far may be important for the differentiation and function of the grafted DA neurons per se, as well as constituting important cellular factories for creating reparative microenvironment at the host's brain . IrrespeAt the present time fetal VM tissue still remains the best standard against which to test future sources of cells for dopaminergic cell replacement in PD. In this context, a new European multicentre project, called TransEuro, was recently launched to further investigate the optimization of the collection, preparation, and storage of fetal tissue for grafting, the selection of the optimal patient group for grafting, evaluate the cause of GIDs, and confirm the efficacy of the transplant technique.Based on their functional targets  cells), and proposed mechanisms of action, gene therapy approaches can be subdivided into 3 main categories: (a) restoration of DA synthesis capacity (enzyme replacement), (b) basal ganglia circuit modulation, and (c) disease modification/neuroprotection through trophic factors. All of these approaches have identified issues in trial design relevant to future investigations. Enzyme-replacement gene therapy in PD aims to provide an advantage over peripherally administered L-dopa through restoration of a more physiological manner of dopamine receptor stimulation and/or reduction in the side effects that accompany prolonged peripheral L-dopa administration. These approaches rely on the use of 1 or more of the key enzymes, namely, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and GTP-cyclohydrolase-1 (GCH1) to either replace DA directly (Prosavin), enhance DA synthesis from L-dopa (AADC “prodrug”), or supply continuous DOPA delivery . One conBasal ganglia circuit modulation via gene therapy attempts to inhibit abnormal activity in the STN by increasing the expression of glutamic acid decarboxylase (GAD) (responsible for GABA synthesis) using an AAV2 vector encoding GAD injected into the STN mimicking the effects of DBS , and witThe overall goal for GDNF and Neurturin  gene therapy is prevention or slowing of the ongoing degenerative processes, as well as strengthening and supporting the dopaminergic phenotype of endogenous nigrostriatal cells –49. TropThere are thus a range of potential gene therapy techniques that may confer benefits to PD patients under certain specific situations. The choice of the optimal intervention may, therefore, be individually tailored to specific patient groups .Several clinical trials have been criticized for suboptimal patient selection , 52, 53.Published series of PD patients who have received fetal VM transplants indicated that the selection of patients younger than 60 years of age, and having a less severe disease , had better results at 12 months . With lovery early-stage patients may lack the level of degeneration necessary to stimulate trophic factor release needed to support graft survival and outgrowth, although there is only limited animal data to suggest this [There is to some extent a balanced judgement that needs to be made. With respect to any therapy with potential disease-modifying effects (cell replacement therapy or neurotrophic factor gene therapy), it seems more sensible to target the disease in its earlier stages. On the other hand, the use of experimental, invasive, irreversible techniques in a group of people with relatively mild symptoms needs consideration, in view of the small but important risks associated with functional neurosurgery, although importantly these risks tend to be less among younger people with less brain atrophy. It is possible that est this . The degree of response to L-dopa is clearly of relevance for any dopamine replacement based therapy. PD patients with severe tremor that is nonresponsive to dopamine might, in theory, remain with major disability, despite excellent graft survival and function or cell transfection, because of tremor persistence. Exclusion of subjects without any dopaminergic deficits (SWEDDs) needs to be confirmed through routine F-dopa positron emission tomography (PET) or DAT single-photon emission computed tomography (SPECT) imaging at recruitment , 58. OthContinuous DOPA delivery utilizes both vector-derived TH and GCH1 but differs significantly from the Prosavin approach in that it depends on endogenous striatal AADC in the host brain for DA synthesis. This therapy therefore, is likely limited to less-severely impaired patients with sufficient endogenous AADC levels. In contrast, all other gene therapy approaches could be applied to a relatively wide range population provided they exhibit a predominance of DA responsive symptoms. In addition to age, disease severity, L-dopa responsiveness, and comorbidity based inclusion/exclusion criteria, the impact of these therapies on important genetic subgroups of patients with predominantly motor deficits needs to be determined. Preoperative genotyping for common genetic variants  is to be recommended to allow planned subgroup analyses for individuals with Mendelian forms of PD.The primary objective of either cell transplantation or gene transfer paradigms is to demonstrate significant improvement across predetermined clinical parameters in a defined patient group . For mosThe most widely accepted measure of PD severity is the Unified PD Rating Scale (UPDRS-Movement Disorders Society modified version) which can be rated in a practically defined “OFF” condition, that is, after 12 hours since last dose of dopaminergic therapy. Accompanying this scale, quantitative measurements of speed (timed tests) can also add objectivity to the assessment of treatment response over time . HoweverIt has been suggested that time to reach other disease milestones such as the Hoehn and Yahr scale might be more appropriate simple measures from which to objectively judge disease progression , and thiSome functional neurosurgery interventions have chosen a patient oriented scale (PDQ-39) as the primary outcome measure . This as18F-dopa) and the labelling of the dopamine transporter (DAT) using SPECT [Biomarkers that reflect disease state or rate may also serve as surrogate endpoints in clinical trials. At present, there is no biomarker that is sufficiently well accepted to serve as a primary endpoint in a clinical trial of PD cell or gene therapy. The most relevant technologies available are the dopaminergic imaging modalities, including measuring presynaptic AADC activity using PET  may offer the ideal substrate for a transplantation-based protocol in PD. With respect to gene therapy paradigms, the optimal vector, therapeutic protein, and target site remain to be defined, as does, of course the risk of adverse effects associated with both these techniques. The requirements for either cell or gene therapies to become clinically competitive treatments for PD are very high. Relief of motor symptoms can be achieved, to a variable extent, by oral medication supplemented by alternative route drug delivery  or DBS for advanced-stage disease. Cell and gene therapy treatments will, therefore, have to demonstrate an advantage either in terms of neuroprotection/repair, or in terms of clinical efficacy or safety over both currently available medical and surgical alternatives. The absence of implanted hardware and no need for recurrent battery changes, percutaneous tubes and pumps may represent an advantage over these options in terms of patient convenience. Currently, the safety, efficacy, and disease-modifying capacity of cell and gene therapies remain to be unequivocally proven, and the commercial costs and necessary surgical expertise for their successful delivery will inevitably limit their availability in many countries. Far fewer treatment options address the nonmotor aspects of PD, such as dementia, neuropsychiatric symptoms, autonomic failure, and sleep abnormalities, which dominate the clinical, caregiver, and financial burden in advanced stages of the disease , 8. It iThe number of parameters that will conceivably influence the outcome of clinical trials of cell or gene therapies is very high. We are currently at a stage where an “explanatory” approach is required to demonstrate that these interventions can have useful effects in the hands of very experienced teams recruiting highly selected patients. Whether any positive findings can be subsequently reproduced on a “pragmatic” basis with broader patient inclusion criteria, and in anticipation of inevitable technical advances and refinement of surgical parameters will be critical in terms of future widespread adoption of any of these interventions.There is no actual or potential conflict of interests in relation to this paper.


Present-day correlations between leaf physiognomic traits (shape and size) and climate are widely used to estimate paleoclimate using fossil floras. For example, leaf-margin analysis estimates paleotemperature using the modern relation of mean annual temperature (MAT) and the site-proportion of untoothed-leaf species (NT). This uniformitarian approach should provide accurate paleoclimate reconstructions under the core assumption that leaf-trait variation principally results from adaptive environmental convergence, and because variation is thus largely independent of phylogeny it should be constant through geologic time. Although much research acknowledges and investigates possible pitfalls in paleoclimate estimation based on leaf physiognomy, the core assumption has never been explicitly tested in a phylogenetic comparative framework. Combining an extant dataset of 21 leaf traits and temperature with a phylogenetic hypothesis for 569 species-site pairs at 17 sites, we found varying amounts of non-random phylogenetic signal in all traits. Phylogenetic vs. standard regressions generally support prevailing ideas that leaf-traits are adaptively responding to temperature, but wider confidence intervals, and shifts in slope and intercept, indicate an overall reduced ability to predict climate precisely due to the non-random phylogenetic signal. Notably, the modern-day relation of proportion of untoothed taxa with mean annual temperature (NT-MAT), central in paleotemperature inference, was greatly modified and reduced, indicating that the modern correlation primarily results from biogeographic history. Importantly, some tooth traits, such as number of teeth, had similar or steeper slopes after taking phylogeny into account, suggesting that leaf teeth display a pattern of exaptive evolution in higher latitudes. This study shows that the assumption of convergence required for precise, quantitative temperature estimates using present-day leaf traits is not supported by empirical evidence, and thus we have very low confidence in previously published, numerical paleotemperature estimates. However, interpreting qualitative changes in paleotemperature remains warranted, given certain conditions such as stratigraphically closely-spaced samples with floristic continuity. In a seminal 1915 paper, Bailey and Sinnott proposed “a botanical index of Cretaceous and Tertiary climates” Paleobotanists have since continued to make extensive use of Bailey and Sinnott's “index,” eventually developing a quantitative method known as leaf-margin analysis, based on linear regressions of extant proportions of untoothed species (NT) and mean annual temperature (MAT) Nothofagus, and Rosaceae), indicating phylogenetic signal In particular, precise, quantitative paleotemperature estimates from taxon-free approaches operate under a still-untested core assumption that leaf-trait variation principally results from adaptive environmental convergence, and because it is thus largely independent of phylogeny it should be constant through geologic time. If the assumption is valid, then the current uniformitarian applications are warranted, and modern trait-climate relations should estimate past climate in a quantitatively precise manner. However, certain observations cast doubt on the core assumption An additional, more theoretical consideration is that even under an ideal model of adaptive convergence without phylogenetic signal, directional selection is expected to affect the assumption of constancy through time. Given a hypothetically unchanging climate, with constant species composition, directional selection should shift trait values over time; producing an increase in number of teeth over geological time under a constant low MAT for example. Thus, lineage persistence may contribute to some observed changes in leaf-traits through geologic time, unrelated to climate change. Further, given that lineages are expected to have differing rates of evolution, extinction and species radiation, trait-climate relations should vary through deep time, even if adaptive leaf-trait responses were ideal The issues above are important because if present-day trait-climate relations do not have the expected adaptive explanation, or were not constant over evolutionary time, then the core assumption of the current uniformitarian approach would not be valid . In this case, one would require additional information in order to precisely quantify a past trait-climate relation with confidence, such as data regarding phylogenetic placement of difficult-to-identify fossil leaves, or independent, highly accurate and well-correlated climate proxies. We note that several examples of temperature estimates from isotopic data are considered broadly concordant with associated leaf-physiognomy estimates et al. et al.We test the assumption of adaptive convergence of leaf traits with temperature by quantifying phylogenetic signal in a dataset comprising 21 leaf-physiognomic traits and MAT among 569 species-site pairs at 17 sites in the eastern USA and Barro Colorado Island, Republic of Panamá, published by Huff We note that the issues addressed by our analysis are separate from the numerous additional sources of uncertainty in leaf paleothermometry that have been noted, including environmental, taphonomic/preservational, sampling, and scoring biases et al. and Royer et al. dataset pGLS; The Huff We created a phylogenetic hypothesis for the species included in this study by grafting them onto a family-level phylogenetic supertree of the angiosperms K statistic, which compares the observed phylogenetic signal in a trait to the signal expected under a Brownian motion model of evolution K indicate stronger phylogenetic signal (greater similarity of closely related species), with K = 1 expected for traits evolving under a Brownian motion model of evolution P-values) of the K values for each trait was assessed by comparing the variance of independent contrasts for each trait to the expected values under a tip shuffling algorithm P-value provides a test of whether the phylogenetic signal in each trait is greater than the null expectation of no signal, while the K statistic provides an estimate of the magnitude of phylogenetic signal. All measures of K were calculated using the picante R package K with this site removed  regressions between climate and leaf traits were computed using the APE 10-transformed prior to analysis in order to meet model assumptions of normality. For the phylogenetic GLS analyses, branch lengths were first scaled using the optimal value of Pagel's λ parameter Non-phylogenetic generalized least squares (GLS) and phylogenetic GLS . There was also phylogenetic signal in the climatic associations of taxa . Phylogenetic signal in traits and climate associations was not driven by the inclusion of the single tropical site ; when the tropical site was excluded (413 species-site pairs), signal remained significantly non-random for all traits and MAT  also showed the largest decreases in slope versus MAT after taking phylogeny into account , had the least altered regressions after accounting for phylogenetic relationships, in accord with their relatively low phylogenetic signal  reinforces earlier observations that characters of leaf teeth are taxonomically informative The presence of non-random phylogenetic signal in all traits  invalidapGLS regressions indicate that incorporation of phylogenetic information is important for understanding trait-temperature relationships  for all ionships . IncorpopGLS models; Acer rubrum from a Florida population had more leaf teeth when planted in Rhode Island but still had significantly fewer teeth than the Rhode Island population, supporting the presence of both phylogenetic signal and phenotypic plasticity, as well as probable adaptive trait response in the species. Non-tooth related traits, especially Shape factor (a modified area:perimeter ratio), had the least altered correlations, in accord with their relatively low phylogenetic signal  pGLS; Although we expected to find some influence of phylogenetic signal in the leaf traits and their relation to temperature, the most surprising results involved the high signal in presence of leaf teeth (Margin Untoothed). This trait is the basis of leaf-margin analysis (NT-MAT relation) and a key component of all multivariate approaches that estimate paleotemperature The relations between MAT and the traits Feret diameter ratio, Tooth area : blade area, and Average tooth area also had phylogenetic regressions with highly flattened slopes, similar to that of the NT-MAT relation ; Table 1The weak relationship between presence of leaf teeth and temperature after accounting for phylogeny indicates that the prevailing adaptive scenario since 1915 Because our results indicate that historical events unrelated to temperature contributed to the majority of the present-day distribution of toothed lineages, the modern NT-MAT relationship, which is variable at a global scale, now deserves renewed investigation Nothofagus lineages, Ulmaceae, Rosaceae, Vitaceae) radiated at middle and high latitudes under warmer climates than today The cool-temperature selection scenario, suggested here, is also provisionally consistent with the fossil record, in which many characteristically, or commonly, toothed clades  trait-latitude gradients clearly existed at many times and places in the past with varying similarity to the modern day trait-temperature gradients are usually unknown in the past. Thus, although past trait-latitude gradients allow for qualitative climate inference, confidence is very low for quantitative models of past trait-temperature gradients based directly from modern gradients as currently practiced. This point is well-demonstrated by discrepancies between taxonomic and physiognomic paleoclimate estimates, even when derived by the same workers from the same fossil floras Qualitative analyses, i.e., detection of relative warming and cooling, remain justified using physiognomic data from well-understood regional floras that have supporting data on taxonomy, paleogeography, and distribution of traits along independently inferred paleotemperature gradients . In practical terms, these conditions are met for several heavily studied assemblages . However, we reiterate that although physiognomic Despite our results, it may be tempting to continue relying on current, taxon-free leaf physiognomy to generate quantitatively inferred paleotemperature estimates, by using traits that show clear adaptive responses to temperature (i.e. Number of teeth), using traits that display only slightly altered phylogenetic regressions with temperature , using standard leaf-margin analysis as a convenient proxy for the presence of adaptive tooth-trait response, or relying on multivariate approaches Regional differences in the relationship between proportions of toothed species and temperature (NT-MAT), wherein temperature estimates for a given value of NT differ by >5°C, may well be due to differences in phylogenetic history among biogeographic regions pGLS models. These variables should be able to detect relative temperature changes through time, especially over geologically short intervals with floristic continuity, given sufficient evidence that the trait-climate relationships were not greatly altered in the past.In summary, we have demonstrated that there is evidence for an adaptive response to temperature in many leaf traits. However, the presence of non-random phylogenetic signal throughout leaf physiognomic data leads to leaf trait-climate relationships that are driven both by adaptive evolution and phylogenetic history, and the adaptive signal is especially weak for the most widely used variable, presence of teeth. Non-independence of species data due to phylogenetic relatedness results in conventional, non-phylogenetic models of leaf trait-climate relationships underestimating the true uncertainty in estimates of paleotemperature from leaf traits. An approach that should permit reliable qualitative estimation of change in paleoclimate from leaf traits would be to use leaf physiognomic variables that show the strongest evolutionary correlations with climate based on File S1(DOCX)Click here for additional data file.


The open abdomen has become an important approach for critically ill patients who require emergent abdominal surgical interventions. This treatment, originating from the concept of damage control surgery, was first applied in severe traumatic patients. The ultimate goal is to achieve formal abdominal fascial closure by several attempts and adjuvant therapies . Up to the present, open abdomen therapy becomes matured and is multistage-approached in the management of patients with severe trauma. However, its application in patients with intra-abdominal infection still presents great challenges due to critical complications and poor clinical outcomes. This review focuses on the specific use of the open abdomen in such populations and detailedly introduces current concerns and advanced progress about this therapy. The open abdomen (OA) treatment, defined as leaving the fascial edges of abdomen unapproximated intentionally, is one of the greatest surgical advances in the twentieth century . This tr To date, an increasing intra-abdominal pressure (IAP) >15 mmHg with the onset of newly formed organ failure is an indication for a prompt OA procedure –10. The  Nonclosure of abdominal fascia with an open abdomen, followed by a temporary abdominal closure (TAC), has become a major advance in treatment of IAI , 12. ThiA persistent IAH, defined as an IAP over 12 mmHg, is often associated with a poor outcome due to its induced vicious cycle . A direcα, IL-1, IL-6, IL-10, etc.) around infected areas has already occurred, followed by a systemic inflammatory response cascade. These serial responses would cause microvascular dysfunction, massive visceral edema, and IAH, which require a sufficient source control to terminate. A proper OA procedure can provide repeated access to the peritoneal cavity for required debridement of devitalized tissue, peritoneal effluent, and surgical drainage [Specifically in severe IAI, the outbreak of the disease is usually 6–12 h before a surgical intervention, and a considerable accumulation of inflammatory cytokines  IAP is less than 15–20 mmHg when fasciae can be approximated temporarily. (2) No bowel leak is detected, or a low-volume output of bowel fluids is realized. (3) Abdominal wall integrity can be restored based on systematic preoperative evaluation. (4) No wound-healing problems can be anticipated. (5) Infection source is totally eliminated and debridement of peritoneal cavity is sufficient. (6) Nutritional status and pulmonary function are satisfying to tolerate the stress of operation. Once again, as for an infected open abdomen, VAC system is strongly advocated thanks to its best overall clinical outcomes . Compare Besides the advanced progresses in the OA management, the control of OA-associated complications has been further improved. Enteroatmospheric fistula, one of the most challenging issues from infected open abdomen, is almost impossible to be cured without an operation, as proper soft tissues are not available to cover the fragile bowel wall. As a result, prevention remains the most crucial management principle. Whenever possible, biocompatible materials were preferred as the mediators separating exposed viscera from the ambient atmosphere. In addition, routine wound care should be performed by experienced surgeons or enterostomal nursing specialists . Once th The use of enteral nutrition (EN) for patients with an open abdomen remains hesitancy, since EN is always twisted with issues of enteral access, concerns of bowel edema, or dilemma of intestinal motility and function. A recent multi-institutional study demonstrated that EN after an open abdomen was associated with increased fascial closure rates, reduced complications rates, and improved mortality . Besidesα, should be more emphasized in future clinical practice. Since the use of OA therapy in patients with IAI is quite challenging at present, a large amount of clinical studies, with large sample size and randomized control in design, are required for further evaluating its role in this specific area. The major challenge in treatment of an infected open abdomen is to control septic peritonitis and intra-abdominal fluid secretion and to facilitate repeated abdominal exploration, while preserving the peritoneal fascia for delayed primary closure . Before In conclusion, the open abdomen is one of the greatest surgical advances in recent decades and earns enormous popularity in the daily management of critical or infected patients. This multistage surgical treatment brings about huge benefits to such populations by avoiding a series of problems from abdominal closure under extensive tension, facilitating damage-control procedures, reducing the risk of intra-abdominal hypertension, and contributing to the early recognition of intra-abdominal catastrophes. However, the use of open abdomen in patients with intra-abdominal infection also brings on many challenges beyond those that might be expected from the primary illness. The appropriate management relies principally on recovering normal physiology and nutritional status, protecting skin and fascia, and preventing upcoming septic shock or multiple organ failures. With experienced and careful management, those challenges could be finely met and turned to achievements. Any innovative techniques, designed to improve fascial closure rate and clinical outcomes, should be encouraged to apply in an infected open abdomen. It is the responsibility of the clinician to apply management principles judiciously to obtain the most benefits from the open abdomen. Although the open abdomen treatment for intra-abdominal infection does seem to work, prospective randomized controlled trials are warranted to further clarify its role in such specific populations.


A few decades have passed since intensive care unit (ICU) beds have been available for critically ill patients with cancer. Although the initial reports showed dismal prognosis, recent data suggest that an increased number of patients with solid and hematological malignancies benefit from intensive care support, with dramatically decreased mortality rates. Advances in the management of the underlying malignancies and support of organ dysfunctions have led to survival gains in patients with life-threatening complications from the malignancy itself, as well as infectious and toxic adverse effects related to the oncological treatments. In this review, we will appraise the prognostic factors and discuss the overall perspective related to the management of critically ill patients with cancer. The prognostic significance of certain factors has changed over time. For example, neutropenia or autologous bone marrow transplantation (BMT) have less adverse prognostic implications than two decades ago. Similarly, because hematologists and oncologists select patients for ICU admission based on the characteristics of the malignancy, the underlying malignancy rarely influences short-term survival after ICU admission. Since the recent data do not clearly support the benefit of ICU support to unselected critically ill allogeneic BMT recipients, more outcome research is needed in this subgroup. Because of the overall increased survival that has been reported in critically ill patients with cancer, we outline an easy-to-use and evidence-based ICU admission triage criteria that may help avoid depriving life support to patients with cancer who can benefit. Lastly, we propose a research agenda to address unanswered questions. The number of patients living with cancer has been increasing steadily -3. The aCritically ill cancer patients have lower survival rates compared with patients without comorbidities. However, their in-hospital mortality rates are not higher compared with critically ill patients with other comorbidities, such as heart failure, liver cirrhosis, or other serious chronic diseases . Recent This is not a systematic review but a consensus opinion from experts who care for critically ill patients with cancer. We plea for the development and implementation of broader ICU admission policies. Future observational research will be required to assess the validity of our conclusions.Several studies comparing two time periods in subgroups of cancer patients have reported improvement in hospital survival during the past decade ,11,23-28Although there may have been a general improvement in ICU mortality of cancer patients over time, five hypotheses have been proposed to account for the decreased mortality rate in these patients : 1) an oOverall, the medical literature has documented improvement in survival of critically ill patients with cancer. However, most of the studies have evaluated short-term outcomes, such as ICU, hospital, 28-day, and, rarely, 3- or 6-month survival. To our knowledge, no study has used long-term or meaningful outcomes, such as disease-free survival and quality of life after ICU admission.Current studies still report that the need for mechanical ventilation, presence of invasive fungal infection, development of multiorgan failure, and high severity of illness scores are additional prognostic factors for mortality among cancer patients. Although these prognostic factors are important, they often are unreliable and mostly derived from inconsistent results. For example, a British multicenter study of patients with hematologic malignancy admitted to the ICU showed that BMT was a risk factor for increased hospital death . HoweverThere has been an improved understanding of organ dysfunction, mainly as a result of a close collaboration between hematologists/oncologists and intensivists  Table 22. ClinicIn addition to bedridden patients and those with no lifespan expanding therapy (see point 5 following), there are three groups of patients in whom survival rates remain marginally low. These include allogeneic BMT recipients with severe graft-versus-host disease (GVHD) who are unresponsive to immunosuppressive therapy ,61, patiSeveral studies have assessed the outcomes of allogeneic BMT recipients admitted to the ICU during the past three decades . DespitePatients who develop multiple organ failure are at higher risk for death if their ICU admission is delayed. Khassawneh et al. reported only one survivor in patients admitted with three organ dysfunctions . In patiMarginal survival has been reported in severely impaired or bedridden patients ,24,30, aThe use of life-sustaining therapies in most patients with cancer is no longer futile. However, recent data suggest that duration of mechanical ventilation, use of vasopressors, and dialysis are strong predictors of death. For example, marginal survival have been reported in patients who require invasive mechanical ventilation for 3 days or more ,50. StudThere may be "golden hours or days" of resuscitation associated with improved outcome, for the ICU management of critically ill cancer patients. During this time, everything should be done. Subsequently, the continuation or introduction of life-sustaining therapies in patients whose conditions are worsening may not be beneficial. Further observational studies are needed to confirm the optimal time for the "ICU Trial."Early ICU admission offers the opportunity to use noninvasive diagnostic tests  in acute respiratory failure) and noninvasive ventilation (NIV) ,49. ThisUndoubtedly, some of the improvement in the outcome of critically ill cancer patients can be attributed to formal and informal free exchange of ideas between intensivists and hemato-oncologists. The hemato-oncologists are able to appraise outcomes and to update the intensivists about therapeutic options and potentials for cure of the underlying malignancies. Hemato-oncologists may teach the key pathophysiological aspects of malignant diseases as well as specific complications. Also, ICU admission decisions should be undertaken by both parties based on the acute medical disease, as well as the underlying disease prognosis and patients' preferences and values. ICU clinicians may be more knowledgeable and experienced in setting goals of life-sustaining therapies based on the reversibility of single organ dysfunction and on the presence of multiple organ failure. Decisions to withhold or withdraw life-sustaining therapies are best undertaken by both parties. Information given to patients' relatives and shared decision-making should be presented by both parties together.We are not aware of any study designed to assess the impact of early ICU admission. The following four observations suggest that early admission may improve outcome: a) during the past decade, decreased mortality was observed in association with earlier ICU admission ; b) receWhen ICU admission is warranted, patients should be treated with a full code status, or according to an ICU trial. In both situations, patients receive everything they need during the first few ICU days and then have their situation reappraised after 3 to 5 days of full ICU support. This full-code status includes the administration of cancer chemotherapy along with ventilatory support, vasoactive agents, renal replacement therapy, and other life-sustaining therapies. Indeed, patients with tumor lysis syndrome, pulmonary or renal infiltration by the malignancy, sepsis related to obstructive pneumonia, or ureteral compression may require life-sustaining therapies until the cancer chemotherapy becomes effective. Studies have shown the feasibility of administering chemotherapy in the ICU, with acceptable short- and long-term outcomes ,21. TheyMost critically ill cancer patients are admitted to the ICU during the early management period of aggressive malignancies, i.e., during the first course of chemotherapy  are in order.The common characteristic of all the previous statuses of ICU admission is that patients receive full-code management for an unlimited or a limited time period. Other admission policies need to be evaluated before specific recommendations are made. Such policies include early ICU admission, prophylactic ICU admission, palliative ICU admission, ICU admission for non-ICU care, and terminal ICU admission Figure ; Table 3Many unanswered questions deserve future observational and interventional studies Table . As expe1) The first and most intriguing issue is the lack of studies on long-term outcomes in cancer patients who survive their ICU stay. We do not know whether the increase in the number of survival days is only a prolongation of the dying process or if it is an actual increase in survival with good quality of life. Beside ICU and hospital survival, very few studies have addressed survivors' quality of life. For example, in a study of noncancer patients with acute respiratory distress syndrome, survivors lost 18% of their baseline body weight during the ICU stay, experienced severe muscle weakness and fatigue, and had persistent functional disability 1 year after ICU discharge -79. Thes2) In addition to physical outcomes, mental health and quality of life outcomes must be assessed in ICU survivors. At this time, no study has specifically evaluated health-related quality of life and post-ICU burden in critically ill cancer patients who survived the ICU. Nelson et al. investigated self-reported symptom experience of cancer patients at the time that they were receiving intensive care support . Most pa3) Studies in relatives of critically ill cancer patients should be developed to seek specific needs and communication strategies. Also, determinants of ICU and post-ICU burden on relatives of ICU survivors should be evaluated, because relatives of critically ill patients may become actual caregivers.4) In this review, we describe provisional models of ICU admission with various code statuses that have not yet been evaluated. First, criteria for ICU admission need to be described and appraised. Second, new modalities of ICU admission should be evaluated and the balance between their strengths and weaknesses described. Controversial issues, such as palliative or terminal ICU admission, must be discussed at a global level. Indeed, it is possible, yet debatable, that death that occurs in the ICU is perceived as "good" by patients and relatives. However, broadening ICU admission criteria will be obviously associated with increased mortality and associated conflicts , clinici5) One of the most difficult issues in the ICU trial is determining the appropriate time for making end-of-life decisions . Transit6) The ICU benefits for overall long-term and disease-free survival are still unknown. We can hypothesize that patients with cancer who survive the initial complications without residual organ dysfunction will be able to receive full regimen chemotherapy and subsequently more available lifespan-prolonging therapies. However, no ICU study has evaluated the impact of the ICU support on long-term and disease-free survival.7) Recent studies suggest survival benefits from early admission to the ICU . However8) An appraisal of classic prognostic factors is timely. There are data that suggest that neutropenia and autologous BMT may no longer have prognostic relevance . New det9) There is an emerging interest for adding NIV to routine supportive care provided in hematology/oncology wards -90. This10) Mortality in patients who receive palliative NIV has been reported in various subgroups of patients -101. PatIn patients with cancer who require ICU admission, the survival rate has improved. Besides refinements in the selection criteria of patients for ICU admission, advances in hematology and oncology as well as enhancements in ICU management have contributed to this improved survival. In this changing context, clinicians' beliefs regarding the results of ICU management of patients with cancer must be appraised. Also, admission policies must be broadened and closely evaluated to avoid depriving patients who may benefit from life-sustaining therapies.The authors declare that they have no competing interests.All authors contributed to the preparation of this manuscript and critical review of the material.


Both environmental heterogeneity and mode of dispersal may affect species co-occurrence in metacommunities. Aquatic invertebrates were sampled in 20–30 streams in each of three drainage basins, differing considerably in environmental heterogeneity. Each drainage basin was further divided into two equally sized sets of sites, again differing profoundly in environmental heterogeneity. Benthic invertebrate data were divided into three groups of taxa based on overland dispersal modes: passive dispersers with aquatic adults, passive dispersers with terrestrial winged adults, and active dispersers with terrestrial winged adults. The co-occurrence of taxa in each dispersal mode group, drainage basin, and heterogeneity site subset was measured using the C-score and its standardized effect size. The probability of finding high levels of species segregation tended to increase with environmental heterogeneity across the drainage basins. These patterns were, however, contingent on both dispersal mode and drainage basin. It thus appears that environmental heterogeneity and dispersal mode interact in affecting co-occurrence in metacommunities, with passive dispersers with aquatic adults showing random patterns irrespective of environmental heterogeneity, and active dispersers with terrestrial winged adults showing increasing segregation with increasing environmental heterogeneity. Understanding patterns and underlying mechanisms of species co-occurrence is a core area of community ecology. In general, biotic , abiotic , and historical  factors are considered important for the co-occurrence of species among sites Diamond . ConsideA second reason for the degree of co-occurrence of species is related to environmental heterogeneity across a set of sites Bell . Given tA third potential reason to account for the degree of co-occurrence of species relates to differential colonization and extinction history  a meaningfully defined abiotic template  and (ii) biotic context  for ecological studies  Is environmental heterogeneity related to the degree of species co-occurrence in drainage basins differing profoundly in environmental variation and within subsets of sites in each drainage basin? (ii) Are there differences in the level of species co-occurrence among groups of species differing in mode of dispersal? (iii) Do environmental heterogeneity and mode of dispersal interact in affecting species co-occurrence? I hypothesized that increasing environmental heterogeneity among sites should lead to increased species segregation due to the fact that more niche opportunities are available for individual species. I also expected that active dispersal should lead to increased segregation of species, because active dispersers are able to track environmental variation better than passive dispersers. I tested these expectations using data on stream macroinvertebrates from three high-latitude drainage basins.oN, 27oE), Koutajoki  and Tenojoki , are in northern Finland. The sets of streams in each study drainage basin are characterized by extremely high environmental heterogeneity among sites, although overall among-drainage basin differences are also evident in this respect . The drainage basins studied support poor to moderately diverse stream macroinvertebrate communities in terms of species richness, beta diversity, and trait diversity, with the Tenojoki drainage basin being the least diverse and the Koutajoki drainage basin the most diverse . The regional species pools and individual streams are characterized by very low species-to-genus and species-to-family ratios, implying that only a few congeneric species are present and potentially coexist at a stream site  woodlands at low altitude and barren fell tundra at higher altitude. Headwater streams in the drainage basin range from near-pristine to pristine, as forestry and associated land uses are not generally feasible at these latitudes. Thirty, first-to-fourth order streams were surveyed in the Tenojoki drainage basin in the first half of June 2010. The total area of the Tenojoki drainage basin is 16386 km2 of which this study area covered about 5370 km2.The northernmost study area was located in the Tenojoki drainage basin. This subarctic study area is characterized by arctic-alpine vegetation, comprising mountain birch  at the whole study section. Current velocity (at 0.6 × depth) and depth were measured at 30 random locations along cross-stream transects, the number of which depended on stream width. Stream wetted width was measured at each site based on five cross-stream transects. Moss cover (%) and substratum particle class cover (%) were assessed in 10 randomly spaced 50 × 50 cm quadrats. Visual estimates of the percentage cover of five particle size classes were made for each quadrat using a modified Wentforth scale: (i) sand (diameter 0.25–2 mm), (ii) gravel (2–16 mm), (iii) pebble (16–64 mm), (iv) cobble (64–256 mm), (v) boulder (256–1024 mm). Mean values were used in the analyses. Standard deviations of velocity, depth, and moss cover were also used as indices of local, site-level habitat heterogeneity. Water samples were collected simultaneously with the field sampling, and they were analyzed for pH, conductivity, water color, and total phosphorus using Finnish national standards  sample covering most microhabitats present in a riffle of approximately 100 mMacroinvertebrates were assigned into one of three groups based on their overland dispersal mode  Principal coordinates analysis . Thus, in each drainage basin, the low heterogeneity site subsets included half of the sites with short distances to drainage basin centroid, and the high heterogeneity site subsets comprised the other half of the sites with higher distances to drainage basin centroid. The high and low heterogeneity groups were, in a way, arbitrary, as half of the sites with higher distance to a drainage basin centroid were designated to comprise the high heterogeneity site group, and the other half of the sites with shorter distance to a drainage basin centroid were designated to comprise the low heterogeneity group. Thus, there was no clear boundary value of distance to centroid in this regard, but the data were only divided into two equally sized parts in each drainage basin. PCoA was again used to visualize the distribution of sites in unconstrained ordination space, and PERMDISP was used to test quantitatively for differences in environmental heterogeneity between the low hetero-geneity and high heterogeneity site subsets within each drainage basin. Low heterogeneity site subset should thus include much less environmental variation than the high heterogeneity site subset across the streams. This can be visualized even in two-dimensional ordination plots, where most sites in the low heterogeneity subset are likely to be located within the high heterogeneity subset. However, this may not always be apparent in two-dimensional ordination solutions. PCoA, CAP, and PERMDISP were run using PERMANOVA+ for PRIMER . Furthermore, the drainage basins differed in within-drainage basin environmental heterogeneity based on PERMDISP , with the Koutajoki drainage basin showing highest environmental variation (mean Euclidean distance to group centroid ± SE: 3.874 ± 0.320), followed by the Iijoki drainage basin (3.017 ± 0.220) and the Tenojoki drainage basin (2.551 ± 0.169).There was much variation in environmental variables among and within the drainage basins , and thiF = 13.284, P = 0.003), and the same self-evident pattern was found for the Koutajoki drainage basin  and the Tenojoki drainage basin .Within each drainage basin, PCoA  showed tIn the across-all-sites analyses in each drainage basin a, AqPa sIn the analyses of environmental heterogeneity subsets within each drainage basin b, AqPa sMost previous studies on species co-occurrence have been based on the underlying expectation that segregated distributions are caused by competitive  was clearly highest in the drainage basin with the highest environmental heterogeneity, whereas for the other two dispersal mode groups, no such association was found. This finding suggests that, for the group with most potential for active dispersal and capacity to track environmental variation, increasing environmental heterogeneity may indeed beget higher levels of species segregation. It is also notable that aquatic passive dispersers (AqPa) showed always random distributions, suggesting that environmental heterogeneity does not affect segregation or aggregation in this group of taxa with aquatic adults and passive dispersal mode. This finding is in agreement with the idea that weak dispersers are not able to track efficiently environmental variation across a set of sites  factors on the degree of co-occurrence among species . Alternatively, if one is interested only in differences in environmental heterogeneity across a large number of drainage basins, one could associate SES with environmental heterogeneity  using regression analysis. Unfortunately, in the present example, data set, the number of drainage basins was too low for direct statistical comparisons of the degree of co-occurrence in relation to environmental heterogeneity. Data sets that cover a larger number of regions, comprising both species lists and environmental variables at the level of sites, are likely to be already available for at least mammals, birds, fish and vascular plants, so other researchers should test the idea proposed in this study in other organism groups, environmental settings and regional contexts. Statistically testing variation in SES values among different factors is common in meta-analyses  and drainage basin . Such drainage basin-related context dependency is high in environmentally heterogeneous systems, such as high-latitude drainage basins. I thus urge other researchers to use a similar approach to study the effects of environmental heterogeneity on patterns in the co-occurrence of species, as such an approach is obviously important in advancing our understanding of community ecology.


Systemic hypertension is a highly prevalent potentially modifiable cardiovascular risk factor. Imaging plays an important role in the diagnosis of underlying causes for hypertension, in assessing cardiovascular complications of hypertension, and in understanding the pathophysiology of the disease process. Cardiovascular magnetic resonance (CMR) provides accurate and reproducible measures of ventricular volumes, mass, function and haemodynamics as well as uniquely allowing tissue characterization of diffuse and focal fibrosis. In addition, CMR is well suited for exclusion of common secondary causes for hypertension. We review the current and emerging clinical and research applications of CMR in hypertension. Systemic hypertension is a highly prevalent  chronic A number of imaging techniques are available in the assessment of hypertension, including echocardiography, cardiovascular magnetic resonance (CMR), cardiac computed tomography (CCT) and cardiac scintigraphy. 2D echocardiography is widely available and extensive literature supports its indication for left ventricular (LV) mass measurement. This technique can quantify global and regional systolic function, as well as diastolic function. 3D echocardiography has partially overcome problems with accuracy and reproducibility, while difficulties due to poor acoustic windows and attenuation still persist. CCT has a high negative predictive value for ruling out coronary artery disease and it is also appropriate for ventricular mass and volume measurement and for assessing vascular disease, while more extensive research is needed before its use for myocardial tissue characterization can be promoted. Modern CT scanners generate significantly lower doses of ionizing radiation, but these are not widely available and issues with the use of nephrotoxic contrast still remain. Equally, scintigraphic techniques can be used in the assessment of hypertensive heart disease but their use is greatly limited by the limited spatial resolution and thus limited accuracy in determining LV mass. Thus, CMR appears as the one technique to provide a comprehensive assessment of hypertensive cardiovascular disease, including accurate and reproducible measurement of biventricular function and volumes, the possibility of serial evaluation, assessment of valvular disease and vascular pathology, myocardial perfusion and tissue characterization.Cardiac specific sequences are usually implemented in 1.5 T scanners, though 3 T and 1 T open scanners can be also used. They all yield good image quality with high spatial resolution. Steady state free precession (SSFP) cines, phase contrast sequences, T2-weighted short-tau inversion recovery (STIR), T1- and T2-weighted fast spin-echo, perfusion and myocardial late gadolinium enhancement (LGE) sequences along with 3D-magnetic resonance angiography (MRA), are the most widely used sequences in hypertension. Other CMR techniques such as spectroscopy, myocardial tagging, T1 relaxometry-based techniques and myocardial velocity mapping could be useful in the future though at present they are limited to the research arena. The utility and advantages of CMR in the characterization of hypertensive cardiac and vascular disease, as well as in detection of secondary hypertension, are reviewed below.Longstanding hypertension has deleterious effects on several target organs, including heart, brain, kidneys, eyes and vessels. Regarding the cardiovascular system, hypertensive heart diseases includes left ventricular hypertrophy, myocardial fibrosis, diastolic prior to systolic ventricular dysfunction and heart failure, atrial myopathy, atrial fibrillation, microangiopathy with decreased coronary reserve, and development of epicardial coronary stenoses . With reCMR has a unique potential to visualize and assess all of these alterations in hypertensive patients, leading to an accurate diagnosis.According to the Joint National Committee VII report on the prevention, detection, evaluation and therapy of hypertension (JNC-VII) , two of The 2007 ESH/ESC guidelines  recommenA proposed standard CMR protocol in hypertension is depicted in Figure Both the heart and the aorta are target organs of systemic hypertension. Hypertensive heart disease is characterized by LVH, left atrial dilatation, myocardial fibrosis, diastolic prior to systolic dysfunction, and increased incidence of coronary artery disease. Hypertensive vascular disease manifests as aortic wall pathology such as increased prevalence of atheromatous plaques and higher risk of aneurysm, dissection, penetrating ulcer, intramural hematoma or peripheral obstructive disease.The Framingham Study showed that increases in LV mass are associated with significant increments in cardiovascular morbidity and mortality independent of the presence of coronary artery disease, systemic hypertension or other cardiovascular risk factors ,9, with Electrocardiographic criteria of LVH have been in use for several decades ,13 but tImplementation of echocardiography in its M-mode and especially 2D modalities dramatically changed cardiac assessment. This technique has great advantages such as availability, safety and price, for which it is considered the first line imaging technique in the assessment of heart dimensions and function. Nonetheless, it has several significant limitations such as its dependency on observer, patient anatomy and position, problems with acoustic window and with attenuation. M-mode echocardiography has been widely used in the past but, due to the need for geometric assumptions, its accuracy and reproducibility are very low . More reCMR is currently considered the gold standard for the measurement of right and left ventricular volumes, mass and function, boasting high accuracy and reproducibility ,19. RefeImportantly, recent data have shown that LV mass should be indexed to height to the power of 1.7, which is more sensitive than body surface area indexed LV-mass in identifying obesity-related LVH, and appears to be most consistently associated with cardiovascular events and all-cause mortality .CMR can not only quantify LV mass but also assess the pattern of hypertrophy, that is, LV geometry, which may have prognostic importance. The assessment of LV remodelling by echocardiography has the same limitations as related above. By contrast, the unfettered full myocardial coverage of CMR offers a precise measurement of LV wall thickness  and geomEjection fraction as well as endocardial and mid-wall fractional shortening have all been proposed as possible additional predictors of cardiovascular events in hypertension , though While LVH of whatever aetiology confers increased cardiovascular risk, regression of LVH has been shown to be associated with decreased risk . Due to Determination of the aetiology of LVH is a common clinical problem that can be challenging, because pathological forms of LVH present with overlapping cardiac hypertrophy phenotypes. A number of other conditions can mimic LVH such as infiltrative diseases, hypertrophic cardiomyopathy (HCM), Fabry’s disease, cardiac sarcoidosis, aortic stenosis, and exercise-induced ventricular hypertrophy or athlete’s heart. While aortic stenosis is a straightforward differential diagnosis, other conditions can be difficult. The unique capacity of CMR to non-invasively characterise myocardial tissue represents an important advantage over other non-invasive imaging modalities. Regarding infiltrative conditions, a specific pattern of late gadolinium enhancement has been described for amyloid heart disease ,40 with In a recently published study multiparametric CMR imaging was used to differentiate hypertensive LVH from HCM and distinctive hypertrophic phenotypes were detectable . While h2 /ml, is said to have a 99% specificity for sport-related LVH. However this finding requires further validation and confirmation in larger cohorts. Figure Also, athlete’s heart can be distinguished from other forms of pathological hypertrophy with the CMR-derived diastolic wall-to-volume ratio . A cut-oAnimal and human studies have shown that in hypertensive LVH accumulation of type I and III collagen fibres occurs both in the interventricular septum and free wall . This inInterest has recently grown in the possibility of assessing the degree of myocardial fibrosis in order to refine the ability to predict outcome in hypertensive LVH, and several methods have been proposed. Serum markers of fibrosis have been proposed, mainly the carboxyterminal propeptide of procollagen type I (PIP), a marker of collagen synthesis whose serum levels correlate with the presence of severe myocardial fibrosis . CollageLGE-CMR is able to show focal myocardial fibrosis, as demonstrated in several conditions including hypertension ,44,52-54In longstanding systemic hypertension, diastolic heart failure, characterized by heart failure symptoms, preserved ejection fraction and diastolic dysfunction, often develops and carries an ominous prognosis . The tecAtrial dilatation correlates with the chronicity of hypertension and with the severity of diastolic dysfunction. Importantly, atrial size is independently associated with cardiovascular morbidity and mortality  and withAssessing coronary disease in the hypertensive patient with chest pain is particularly challenging. Systemic hypertension is an established risk factor for epicardial coronary artery disease ,71, but,Saturation-recovery sequences acquired on first pass of gadolinium during vasodilator stress with either adenosine or dipyridamole have a good diagnostic yield for detection of ischaemia and significant epicardial coronary disease -79, whilSystemic hypertension is an established risk factor for aortic and peripheral vascular disease. On the other hand, the relationship between cardiovascular risk factors including hypertension ,83 and vPlaque imaging may be important as part of risk assessment, which may alter thresholds for treatment, and may be of utility in plaque-regression studies. It has been shown that patients with prior major cardiovascular events have greater plaque burden and plaque eccentricity . Likewisin vivo plaque imaging. Protocols for assessing aortic wall anatomy and structure usually include high resolution T1 and T2-weighted TSE and STIR sequences and/or 3D angiography. Images obtained are eventually processed in order to quantify plaque volume and characterize plaque composition, which have been histologically validated [Black blood CMR imaging is highly accurate and reproducible for assessment and volumetric quantification of atheroma plaques in the carotid arteries  and aortalidated ,92.A functional assessment of the aorta can be carried out with CMR by acquiring flow-sensitive and cine sequences. Blood flow affects arterial remodelling, and decreased arterial distensibility is an early manifestation of adverse structural and functional changes within the vessel wall . FurtherResistant hypertension is defined as failure to achieve target blood pressure when a patient adheres to optimal doses of three or more antihypertensive drugs usually including a diuretic . The preCommon secondary causes are renal parenchymal disease, renal arterial disease, primary hyperaldosteronism and obstructive sleep apnoea. Less common causes are Cushing’s syndrome, phaeochromocytoma, thyroid disease, aortic coarctation, and intracranial tumours. The main physiopathological mechanisms are depicted in Figure This may be present in up to 35% of patients with resistant hypertension . Of all Screening techniques for renal artery stenosis are warranted when there is a high level of suspicion (young women and older patients). There are a number of non-invasive tests available including duplex ultrasound, which provides anatomical information as well as flow velocity quantification and assessment of pressure wave morphology, CT-angiography, and nuclear captopril renal scintigraphy. The gold standard diagnostic test has traditionally been intra-arterial digital subtraction contrast angiography but this technique is invasive and not free of complications . While f2) chronic kidney disease, but also with other conditions such as liver failure, liver or kidney transplant, hypercoagulability, deep vein thrombosis and proinflammatory processes. NSF is a scleroderma-like fibrosing entity which affects the skin and several organs including pleura, pericardium, lungs, joints, and striated muscle including diaphragm and myocardium [In the context of renal artery stenosis, which is usually associated with a degree of renal impairment, the issue of nephrogenic systemic fibrosis (NSF) must be considered prior to administration of gadolinium contrast. NSF is an extremely rare but important complication of gadolinium administration, associated with acute renal failure or severe chronic renal failure due to advanced (glomerular filtration rate less than 30 mL/min/1.73 mocardium . Though ocardium . Thus, aThis is a much more common cause of hypertension than previously thought and is present in up to 20% of patients with resistant hypertension . Given tThe exact prevalence of Cushing’s syndrome amongst patients with resistant hypertension is uncertain, but it is estimated that approximately 3 to 6% of cases of secondary hypertension are due to corticosteroid overproduction . HyperteThis is an unusual but prognostically important secondary cause of hypertension. Again, the prevalence of this condition in resistant hypertension is unknown but it is considered to be up to 0.6% in the general hypertensive population . PhaeochThis congenital defect is present in 0.2% of hypertensive adults . CoarctaEchocardiography, both transthoracic and transoesophageal, is usually the imaging technique of choice for initial assessment , but forAortic coarctation is associated with functional aorto-ventricular disturbances, such as abnormal myocardial perfusion reserve with sub-endocardial ischaemia, and increased central aortic stiffness that leads to ascending aorta dilatation and increased LV mass. These conditions persist after surgery and may contribute to increase cardiovascular mortality and morbidity. Finally, re-coarctation of the aorta may lead to worsening systemic hypertension, coronary artery disease and/or congestive cardiac failure. CMR follow-up after coarctation repair will detect re-coarctation as well as those with aortoventricular disturbances, who require more frequent non-invasive surveillance .The unique potential of CMR in hypertensive heart disease implies a high number of indications to be developed in the future, both in diagnosis and in risk stratification of future cardiovascular events. These include analysis and quantification of regional myocardial mechanics, which will allow detection of subtle decay in systolic function, detection and quantification of diffuse myocardial fibrosis, assessment of atrial mechanics, and assessment and quantification of aortic flow mechanics.The prognostic value of measuring diffuse and focal myocardial fibrosis in predicting future cardiovascular events such as heart failure or arrhythmias also hold promise with a potential role for monitoring the response to antihypertensive, antifibrotic drugs. Parameters of atrial function and wall fibrosis should also be tested for prediction of developing atrial fibrillation.CMR provides a comprehensive assessment of hypertensive cardiovascular disease. In less than an hour, ventricular and aortic measurements are obtained with high accuracy and reproducibility, the pathophysiological consequences of hypertension can be assessed and several quantitative parameters can be obtained with high reproducibility and accuracy that can be of use in the follow up of these patients. Concurrently, several secondary causes of hypertension can be ruled out in the same study. With respect to prognostic assessment, the development of T1 mapping sequences for quantification of myocardial fibrosis might play an important role in the risk stratification of hypertensive heart disease.The authors declare that they have no competing interests.AMMG carried out the review of literature, manuscript design and drafting. RHM has been involved in revising the manuscript critically for important intellectual content, carried out the final revision and approved the manuscript to be submitted. Both authors have read and approved the final manuscript.