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Expression of neuronal NO synthase in the sympathetic cranial cervical ganglion and stellate ganglion in rats during postnatal ontogeny was studied by immunohistochemistry and Western blotting. In the sympathetic ganglia, neuronal NO synthase-immunoreactive neurons were absent in all rats. In the stellate and cranial cervical ganglia, the expression of neuronal NO synthase and the density of immunoreactive fibers increased in early postnatal ontogeny from the moment of birth to the age of 30 days and then decreased. Thus, we observed heterochroneous expression of neuronal NOS in the preganglionic somata in the spinal cord and in the preganglionic fibers in the sympathetic ganglia during ontogeny.

Introduction: Stellate ganglion block (SGB) provides diagnostic and therapeutic benefits in pain syndromes in the head, neck, and upper extremity, including complex regional pain syndrome Types I and II, Raynaud's disease, hyperhidrosis, arterial embolism in the region of the arm. Methods: We present a novel ultrasound‐guided supraclavicular stellate ganglion block. Considering the existing anatomical structures of the targeted area. Results and Conclusions: We hope that we can provide fewer complications and additional benefits with this new approach. [ABSTRACT FROM AUTHOR]

Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF. [ABSTRACT FROM AUTHOR]

[Display omitted] • FABP7 is an early SGC marker in the postnatal development of Sup-CG. • S100B, Kir4.1, and SK3 are late SGC markers in the postnatal development of Sup-CG. • AQP4 and GS are absent in Sup-CG. • CX43 is expressed on both SGCs and neurons within Sup-CG. • GFAP is a hallmark of SGC activation in Sup-CG. The sympathetic ganglia represent a final motor pathway that mediates homeostatic "fight and flight" responses in the visceral organs. Satellite glial cells (SGCs) form a thin envelope close to the neuronal cell body and synapses in the sympathetic ganglia. This unique morphological feature suggests that neurons and SGCs form functional units for regulation of sympathetic output. In the present study, we addressed whether SGC-specific markers undergo age-dependent changes in the postnatal development of rat sympathetic ganglia. We found that fatty acid-binding protein 7 (FABP7) is an early SGC marker, whereas the S100B calcium-binding protein, inwardly rectifying potassium channel, Kir4.1 and small conductance calcium-activated potassium channel, SK3 are late SGC markers in the postnatal development of sympathetic ganglia. Unlike in sensory ganglia, FABP7 + SGC was barely detectable in adult sympathetic ganglia. The expression of connexin 43, a gap junction channel gradually increased with age, although it was detected in both SGCs and neurons in sympathetic ganglia. Glutamine synthetase was expressed in sensory, but not sympathetic SGCs. Unexpectedly, the sympathetic SGCs expressed a water-selective channel, aquaporin 1 instead of aquaporin 4, a pan-glial marker. However, aquaporin 1 was not detected in the SGCs encircling large neurons. Nerve injury and inflammation induced the upregulation of glial fibrillary acidic protein, suggesting that this protein is a hall marker of glial activation in the sympathetic ganglia. In conclusion, our findings provide basic information on the in vivo profiles of specific markers for identifying sympathetic SGCs at different stages of postnatal development in both healthy and diseased states. [ABSTRACT FROM AUTHOR]

The celiac, cranial mesenteric and celiacomesenteric ganglia of the paca (Cuniculus paca) were found between the celiac and cranial mesenteric arteries. Two predominant patterns were found: isolated celiac and cranial mesenteric ganglion and the celiacomesenteric ganglion. At the microscopic level, the ganglia are constituted by an agglomeration of neurons surrounded by capsule of connective tissue. Most of these neurons had a single eccentric nucleus. Satellite cells and mast cells were found around the soma. The mast cells were also found ar ound blood vessels and in the capsule of the ganglia. [ABSTRACT FROM AUTHOR]

Interoceptive and exteroceptive signals, and the corresponding coordinated control of internal organs and sensory functions, including pain, are received and orchestrated by multiple neurons within the peripheral, central and autonomic nervous systems. A central aim of the present report is to obtain a molecularly informed basis for analgesic drug development aimed at peripheral rather than central targets. We compare three key peripheral ganglia: nodose, sympathetic (superior cervical), and dorsal root ganglia in the rat, and focus on their molecular composition using next-gen RNA-Seq, as well as their neuroanatomy using immunocytochemistry and in situ hybridization. We obtained quantitative and anatomical assessments of transmitters, receptors, enzymes and signaling pathways mediating ganglion-specific functions. Distinct ganglionic patterns of expression were observed spanning ion channels, neurotransmitters, neuropeptides, G-protein coupled receptors (GPCRs), transporters, and biosynthetic enzymes. The relationship between ganglionic transcript levels and the corresponding protein was examined using immunohistochemistry for select, highly expressed, ganglion-specific genes. Transcriptomic analyses of spinal dorsal horn and intermediolateral cell column (IML), which form the termination of primary afferent neurons and the origin of preganglionic innervation to the SCG, respectively, disclosed pre- and post-ganglionic molecular-level circuits. These multimodal investigations provide insight into autonomic regulation, nodose transcripts related to pain and satiety, and DRG-spinal cord and IML-SCG communication. Multiple neurobiological and pharmacological contexts can be addressed, such as discriminating drug targets and predicting potential side effects, in analgesic drug development efforts directed at the peripheral nervous system. [ABSTRACT FROM AUTHOR]

Objectives. To determine the location and immunohistochemical characteristics of neurons in the superior cervical (SCG) and stellate (CG) ganglia of the sympathetic part of the peripheral nervous system in cats. Materials and methods. Studies were carried out on cats aged 1, 10, 20, and 30 days using retrograde axonal transport of fast blue (FB) given into the muscles of the neck, along with immunohistochemical methods. Results. FB-labeled neurons were detected in both of the sympathetic ganglia studied in kittens from birth. Most of these neurons were immunoreactive (IR) for tyrosine hydroxylase in all age groups. The proportion of labeled neurons simultaneously reacting to antibody to TH and neuropeptide Y in both ganglia increased in the first 10 days of life. The percentage content of calbindin-IR neurons in the SCG decreased from birth to day 30 of life while the number in the CG increased in the first 10 days and then decreased by day 30. Reactions for antibody to choline acetyltransferase, vasoactive intestinal polypeptide, and neuronal nitric oxide synthase were seen in fewer than 1% of labeled neurons in kittens of all age groups. Somatostatin-IR-labeled neurons were not seen in the SCG. Conclusions. The composition of neurons in the sympathetic ganglia completed ontogenetic rearrangement in kittens by day 20 of life. [ABSTRACT FROM AUTHOR]

Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab. Subsequent studies including detailed morphologic investigations of the nervous system did reveal fulranumab-related changes in adult cynomolgus monkeys; this article is focused on those findings. A single dose of ≥1 mg/kg fulranumab administered subcutaneously (SC) caused a decrease in neuron and sympathetic ganglion size (superior cervical ganglion), observed morphologically and stereologically, with a resulting appearance of increased glial cell density. Similar results were observed in repeat-dose (15 to 52 weeks) toxicity studies at ≤50 mg/kg/wk fulranumab SC. These effects recovered after a 3-month treatment-free period. Fulranumab did not cause any neuronal death, necrosis, apoptosis, or any apparent decrease in function of sympathetic neurons/ganglia at any time point examined. A no observed effect level (NOEL) was established at 0.25 mg/kg fulranumab SC every 4 weeks for 28 weeks. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is an embryonal malignancy derived from the abnormal differentiation of the sympathetic nervous system. The Anaplastic Lymphoma Kinase (ALK) gene is frequently altered in NB, through copy number alterations and activating mutations, and represents a predisposition in NB-genesis when mutated. Our previously published data suggested that ALK activating mutations may impair the differentiation potential of neural crest (NC) progenitor cells. Here, we demonstrated that the expression of the endogenous ALK gene starts at E10.5 in the developing sympathetic ganglia (SG). To decipher the impact of deregulated ALK signaling during embryogenesis on the formation and differentiation of sympathetic neuroblasts, Sox10-Cre;LSL-ALK-F1174L embryos were produced to restrict the expression of the human ALK-F1174L transgene to migrating NC cells (NCCs). First, ALK-F1174L mediated an embryonic lethality at mid-gestation and an enlargement of SG with a disorganized architecture in Sox10-Cre;LSL-ALK-F1174L embryos at E10.5 and E11.5. Second, early sympathetic differentiation was severely impaired in Sox10-Cre;LSL-ALK-F1174L embryos. Indeed, their SG displayed a marked increase in the proportion of NCCs and a decrease of sympathetic neuroblasts at both embryonic stages. Third, neuronal and noradrenergic differentiations were blocked in Sox10-Cre;LSL-ALK-F1174L SG, as a reduced proportion of Phox2b+ sympathoblasts expressed βIII-tubulin and almost none were Tyrosine Hydroxylase (TH) positive. Finally, at E10.5, ALK-F1174L mediated an important increase in the proliferation of Phox2b+ progenitors, affecting the transient cell cycle exit observed in normal SG at this embryonic stage. Altogether, we report for the first time that the expression of the human ALK-F1174L mutation in NCCs during embryonic development profoundly disturbs early sympathetic progenitor differentiation, in addition to increasing their proliferation, both mechanisms being potential crucial events in NB oncogenesis. [ABSTRACT FROM AUTHOR]

Sympathetic ganglions located in the cervical region are important organs that make the final synapse of the sympathetic nerve fibers reached to the head, neck, and forelimbs. As far as we know, there are not any anatomical data about cervical sympathetic ganglia in Saanen goat. In this study, we determined the nerve branches separated from the ganglia and the location of the ganglia. We also determined the expression of some enzymes and proteins such as tyrosine hydroxylase (TH), dopamine β-hydroxylase (DβH), neuropeptide Y (NPY) and substance P (SP) in ganglia. Ganglion cervicale craniale (GCC) was on the medial side of bulla tympanica. Mainly branches named as nn. carotici interni, n. jugularis and nn. carotici externi was found to be separated from this ganglion and thin branches joined to the nearby nerve. It was found that n. vertebralis, the two branches that constitute the ansa subclavian, and the thin nerve branches involved in the surrounding tissues and organs separated from ganglion cervicothoracicum (GCT) that located in the first intercostal space. A total of five ganglion cervicale medium (GCM) found at the junction of the two branches forming the ansa subclavia. Another ganglion was not found on where cervical part of truncus sympathicus in all dissections and histological examinations. DβH, TH, NPY and SP were revealed to be express in all ganglia. DβH and NPY in CCG, TH in MCG, DβH, NPY and TH in GCT were found to be more intense staining. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to assess the frequency of PSMA-HBED uptake in coeliac and stellate ganglia in patients presenting for PSMA-HBED PET/CT scan.Methods: Prostate-specific membrane antigen-HBED PET/CT scans of 100 consecutive patients were analysed. Coeliac and stellate ganglia were identified by their anatomical location. PSMA-HBED uptake in these ganglia was recorded as either present or absent. If present, the SUVmax value for each ganglion was measured and compared to SUVmax of mediastinal blood pool.Results: Of the 100 patients, 45 had PSMA-HBED uptake in the right coeliac ganglion and 81 had PSMA-HBED uptake in the left coeliac ganglion. The mean SUVmax for the right coeliac ganglion was 2.6 (range 1.2-4.0) and for the left, 2.7 (range 1.2-6.5). An SUVmax 1.5 times greater than that of mediastinal blood pool activity was found in 25 of right and 47 of left coeliac ganglia. Stellate ganglion uptake of PSMA-HBED was identified in 54 of right and 74 of left stellate ganglia. The mean SUVmax for the right and left stellate ganglia were 2.2 (range 1.6-3.6) and 2.4 (range 1.4-4.2) respectively. An SUVmax 1.5 times greater than that of mediastinal blood pool activity was found in 12 of right and 32 of left coeliac ganglia.Conclusion: Uptake in coeliac and stellate ganglia is a frequent finding on PSMA-HBED PET/CT imaging. Often this uptake can be sufficiently high to cause potential diagnostic confusion. It is important to be aware of this physiologic uptake to avoid incorrect diagnosis of metastatic prostate carcinoma. [ABSTRACT FROM AUTHOR]

Background: The location and the number of lumbar sympathetic ganglia (LSG) vary between individuals. The aim of this study was to determine the appropriate level for a lumbar sympathetic ganglion block (LSGB), corresponding to the level at which the LSG principally aggregate. Methods: Seventy-four consecutive subjects, including 31 women and 31 men, underwent LSGB either on the left (n = 31) or the right side (n = 43). The primary site of needle entry was randomly selected at the L3 or L4 vertebra. A total of less than 1 ml of radio opaque dye with 4% lidocaine was injected, taking caution not to traverse beyond the level of one vertebral body. The procedure was considered responsive when the skin temperature increased by more than 1°C within 5 minutes. Results: The median responsive level was significantly different between the left (lower third of the L4 body) and right (lower margin of the L3 body) sides (P = 0.021). However, there was no significant difference in the values between men and women. The overall median responsive level was the upper third of the L4 body. The mean responsive level did not correlate with height or BMI. There were no complications on short-term follow-up. Conclusions: Selection of the primary target in the left lower third of the L4 vertebral body and the right lower margin of the L3 vertebral body may reduce the number of needle insertions and the volume of agents used in conventional or neurolytic LSGB and radiofrequency thermocoagulation. [ABSTRACT FROM AUTHOR]

Expression of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT) and calcitonin gene-related peptide (CGRP) in the sympathetic ganglia was investigated by immunohistochemistry in the superior cervical ganglion (SCG), stellate ganglion (SG) and celiac ganglion (CG) from cats of different ages (newborn, 10-day-old, 20-day-old, 30-day-old and 2-month-old). Non-catecholaminergic TH-negative VIP-immunoreactive (IR) and nNOS-IR sympathetic ganglionic neurons are present from the moment of birth. In all studied age groups, substantial populations of VIP-IR (up to 9.8%) and nNOS-IR cells (up to 8.3%) was found in the SG, with a much smaller population found in the SCG (<1%) and only few cells observed in the CG. The percentage of nNOS-IR and VIP-IR neurons in the CG and SCG did not significantly change during development. The proportion of nNOS-IR and VIP-IR neuron profiles in the SG increased in first 20 days of life from 2.3 ± 0.15% to 8.3 ± 0.56% and from 0.3 ± 0.05% to 9.2 ± 0.83%, respectively. In the SG, percentages of nNOS-IR sympathetic neurons colocalizing VIP increased in the first 20 days of life. ChAT-IR and CGRP-IR neurons were not observed in the sympathetic ganglia of newborn animals and did not appear until 10 days after birth. In the SG of newborn and 10-day-old kittens, the majority of NOS-IR neurons were calbindin (CB)-IR, whereas in the SCG and CG of cats of all age groups and in the SG of 30-day-old and older kittens, the vast majority of NOS-IR neurons lacked CB. We conclude that the development of various non-catecholaminergic neurons in different sympathetic ganglia has its own time dynamics and is concluded at the end of the second month of life. [ABSTRACT FROM AUTHOR]

Abstract: The goal of this study was to create a heat map indicating the probabilistic location of major ganglia of the cervical sympathetic trunk (CST). Detailed dissections of human cadaveric specimens, followed by spatial registration and analysis of the cervical sympathetic ganglia in the neck and upper thorax regions (C1–T1) were performed in 104 neck specimens (both sides from 52 cadavers). Unbiased parametric mapping, visualized with a heat map, revealed a general pattern of two major ganglia located on both sides of the neck: The superior cervical ganglion (SCG) was located 80–90mm superior to the point at which the vertebral artery entered the transverse foramen (VA–TF); the stellate ganglion (SG) was located approximately 10mm inferior to the VA–TF in 80% of our sample, or surrounding the VA–TF in the remaining 20% of our sample. In between these ganglia, a highly variable number of smaller and less prevalent ganglia were present on either side of the neck. The middle ganglia on the right side of the neck were located closer to the SCG, possibly indicative of the middle cervical ganglion. On the left side the middle ganglia were located closer to the SG, perhaps indicative of the vertebral ganglion or the inferior cervical ganglion. Individual specimens could be classified into one of seven different patterns of cervical trunks. The results may help surgeons and anesthesiologists more accurately target and preserve these structures during medical procedures. [Copyright &y& Elsevier]

Calbindin (CB)-containing neurons in the cranial cervical, stellate, and celiac sympathetic ganglia of rats ( n = 60) aged 3-90 days were studied using an immunohistochemical method. The results obtained demonstrated that the stellate ganglion contained the greatest proportion of CB-immunopositive neurons. The proportions of CB-immunopositive neurons in the para- and prevertebral sympathetic ganglia decreased with age. The formation of the group of CB-immunopositive neurons in sympathetic ganglia was complete by the end of the first month of life. [ABSTRACT FROM AUTHOR]

Abstract: Expression of CB in the sympathetic ganglia was investigated by immunohistochemistry. The distribution of CB immunoreactivity was studied in the superior cervical ganglion (SCG), stellate ganglion (SG) and celiac ganglion (CG) from rats and cats of different ages (newborn, 10-day-old, 20-day-old, 30-day-old, two-month-old, six-month-old). We observed that the percentage of CB-immunoreactive (IR) neurons decreased during early postnatal development in rats and cats. In all studied ganglia of both species, the percentage of CB-IR neurons was high in newborn and 10-day-old animals and significantly decreased up to 30days of life. In rats of all ages, the largest percentage of CB-IR neurons was observed in the SG compared to the SCG and CG. In the cat sympathetic ganglia, the number of CB-IR neurons decreased more rapidly during the first two months of life, and only scattered CB-IR neurons were found in the sympathetic ganglia of two-month-old and six-month-old cats. In cats, the highest percentage of CB-IR neurons was observed in the SG, while the lowest percentage was found in the CG. The difference in size between CB+ and CB− neurons equally changed during development. Finally, the changes in the size and percentages of CB-IR neurons were complete in rats at the first month of life, and in cats at the end of the second month. [Copyright &y& Elsevier]

Abstract: The Akita mouse is a robust model of diabetic autonomic neuropathy which develops severe diabetes following beta cell death, which occurs reproducibly at 3–4weeks of age, and maintains the diabetic state without therapy for as long as 11 additional months. Neuritic dystrophy and neuronopathy involving prevertebral sympathetic superior mesenteric and celiac ganglia begin to develop within the first two months of onset of diabetes and are progressive with time. We have examined the effect of insulin implants resulting in normoglycemia and injections of ARA290, a small erythropoietin peptide which has no effect on glycemic parameters, on the reversal of established neuritic dystrophy and neuronopathy. We have found that 4weeks of insulin therapy beginning at 2months of diabetes resulted in normalization of blood glucose, body weight and HbA1c. Insulin therapy successfully reversed established neuritic dystrophy and neuronopathy to control levels. Numbers of sympathetic neurons were not significantly changed in either 3month diabetic or insulin-treated Akita mice. Treatment with ARA290 for 7weeks beginning at 4months of diabetes did not result in altered metabolic severity of diabetes as measured by blood glucose, body weight or HbA1c levels. ARA290 treatment was able to decrease neuritic dystrophy by 55–74% compared to untreated diabetics or in comparison to a separate group of diabetic animals representing the 4month treatment onset point. Surprisingly, there was no effect of ARA290 on ganglionic neuron number or ongoing neuronopathy (pale/degenerating neurons) in diabetic Akita mice during this time period. The development of neuroprotective EPO-like peptides may provide a possible future therapy for this debilitating complication of diabetes; however, it appears that discrete elements may be differentially targeted by the diabetic state and may require selective therapy. [Copyright &y& Elsevier]

Abstract: Central nervous system glial cells as astrocytes and microglia have been investigated in vitro and many intracellular pathways have been clarified upon various stimuli. Peripheral glial cells, however, are not as deeply investigated in vitro despite its importance role in inflammatory and neurodegenerative diseases. Based on our previous experience of culturing neuronal cells, our objective was to standardize and morphologically characterize a primary culture of mouse superior cervical ganglion glial cells in order to obtain a useful tool to study peripheral glial cell biology. Superior cervical ganglia from neonatal C57BL6 mice were enzymatically and mechanically dissociated and cells were plated on diluted Matrigel coated wells in a final concentration of 10,000cells/well. Five to 8 days post plating, glial cell cultures were fixed for morphological and immunocytochemical characterization. Glial cells showed a flat and irregular shape, two or three long cytoplasm processes, and round, oval or long shaped nuclei, with regular outline. Cell proliferation and mitosis were detected both qualitative and quantitatively. Glial cells were able to maintain their phenotype in our culture model including immunoreactivity against glial cell marker GFAP. This is the first description of immunocytochemical characterization of mouse sympathetic cervical ganglion glial cells in primary culture. This work discusses the uses and limitations of our model as a tool to study many aspects of peripheral glial cell biology. [ABSTRACT FROM AUTHOR]

Abstract: We compared the excitability of secretomotor B and vasomotor C neurons using virtual nicotinic synapses implemented with the dynamic clamp technique. In response to fast synaptic conductance (g syn) waveforms modeled after B cell synaptic currents, it took 17.1±1.2nS to elicit spikes in 104 B cells and 3.3±0.3nS in 35 C cells. After normalizing for whole-cell capacitance, C cells were still more excitable than B cells (76±5pS/pF vs. 169±8pS/pF). Stimulating C cells with slower g syn waveforms, identical to synaptic currents in C cells, further accentuated the difference between cell types. The phenotypic excitability difference did not correlate with time in culture (1–12days) and could not be explained by resting potential (B cells: −65.6±0.9mV, C cells: −63.1±1.6mV) or input conductance density, which was greater in C cells (24.4±4.3pS/pF) than B cells (14.5±1.5pS/pF). Action potentials elicited by virtual EPSPs had a threshold voltage for firing that was −28.4±0.7mV in C cells and −19.7±0.4mV B cells, and an upstroke velocity and peak spike potential that were greater in B cells. The repetitive firing properties of B and C cells were similar; 69–78% phasic, 11–16% adapting and 11–15% tonic. We propose that B and C neurons express different types of Na+ channels that shape how they integrate nicotinic synaptic potentials. [Copyright &y& Elsevier]

Abstract: The neural crest is an excellent model system to study cell fate and cell guidance signaling. Neural crest cells emerge from a common multipotent subpopulation and follow stereotypical migratory pathways to contribute to many diverse peripheral structures throughout the vertebrate embryo. The neural tube and diverse embryonic microenvironments from which the neural crest originate and migrate through are important sources of signals, yet it is still unclear how a common pool of neural crest stem and progenitor cells diversify and become distributed along specific stereotypical migratory paths. In the post-otic hindbrain and trunk, the neural crest emerge and contribute to the autonomic nervous system, and failure of proper cell navigation and differentiation often leads to congenital disorders that include dysautonomias, Hirschprung''s disease, and neuroblastoma cancer. Recent exciting studies of neural crest cell behaviors have revealed the interplay of several molecular signaling pathways that guide and shape autonomic precursor cells to and into proper target structures, suggesting further work may help to better understand autonomic nervous system assembly, derived from a convergence of time-lapse imaging and molecular analyses. In this mini-review, we summarize recent fluorescent cell labeling strategies and cell behavior analyses that elucidate the role of molecular signals on the migration of autonomic precursor cells. We highlight advances in our understanding of the autonomic precursor cell behaviors and fate determination studied within the embryonic microenvironment. [Copyright &y& Elsevier]