bluuebunny/crossref_metadata_2025 huggingface dataset:
Subunit Arrangement in P2X Receptors
Authors: Jiang Lin-Hua , Kim Miran , Spelta Valeria , Bo Xuenong , Surprenant Annmarie , North R. Alan
Published: April 2018

ATP-gated ionotropic receptors (P2X receptors) are distributed widely in the nervous system. For example, a hetero-oligomeric receptor containing both P2X2and P2X3subunits is involved in primary afferent sensation. Each subunit has two membrane-spanning domains. We have used disulfide bond formation between engineered cysteines to demonstrate close proximity between the outer ends of the first transmembrane domain of one subunit and the second transmembrane domain of another. After expression in HEK 293 cells of such modified P2X2or P2X4subunits, the disulfide bond formation is evident because an ATP-evoked channel opening requires previous reduction with dithiothreitol. In the hetero-oligomeric P2X2/3receptor the coexpression of doubly substituted subunits with wild-type partners allows us to deduce that the hetero-oligomeric channel contains adjacent P2X3subunits but does not contain adjacent P2X2subunits. The results suggest a “head-to-tail” subunit arrangement in the quaternary structure of P2X receptors and show that a trimeric P2X2/3receptor would have the composition P2X2(P2X3)2.
The Neurofibromatosis 1 Gene Product Neurofibromin Regulates Pituitary Adenylate Cyclase-Activating Polypeptide-Mediated Signaling in Astrocytes
Authors: Dasgupta Biplab , Dugan Laura L. , Gutmann David H.
Published: April 2018

Individuals with the neurofibromatosis 1 (NF1)-inherited tumor predisposition syndrome develop low-grade astrocytomas. TheNF1tumor suppressor gene product neurofibromin exhibits GTPase-activating activity (GAP) toward RAS, such that loss of neurofibromin expression leads to high levels of activated RAS and increased cell proliferation. Previous work has demonstrated thatNf1inactivation in astrocytes leads to increased cell proliferationin vitroandin vivo, accompanied by increased RAS pathway activation. Studies onNf1mutantDrosophilahave suggested that neurofibromin might also regulate cAMP signaling. Because intracellular cAMP levels have profound effects on astrocyte growth control, we sought to determine the contribution of neurofibromin to astrocyte cAMP regulation. In this report, we demonstrate thatNf1inactivation in astrocytes results in reduced cAMP generation in response to PACAP and attenuated calcium influx and Rap1 activation. Based on the differential effects of forskolin and dibutyryl-cAMP onNf1-/- astrocytes, neurofibromin likely functions at the level of adenylyl cyclase activation. Last, the reintroduction of a fragment of neurofibromin containing residues sufficient for restoring RAS-GAP function inNf1-/- cells resulted in only partial restoration of neurofibromin-mediated cAMP regulation. These results demonstrate that neurofibromin positively influences cAMP generation and activation of cAMP growth regulatory targets in astrocytes and expands the role of theNF1gene in astrocyte growth regulation.
Inhibitory Interconnections Control Burst Pattern and Emergent Network Synchrony in Reticular Thalamus
Authors: Sohal Vikaas S. , Huguenard John R.
Published: April 2018

Inhibitory connections between neurons of the thalamic reticular (RE) nucleus are thought to help prevent spike-wave discharge (SWD), characteristic of generalized absence epilepsy, in thalamic and thalamocortical circuits. Indeed, oscillations in thalamic slices resemble SWD when intra-RE inhibition is blocked and are suppressed when intra-RE inhibition is enhanced. To elucidate the cellular mechanisms underlying these network changes, we recorded from RE cells during oscillations in thalamic slices and either blocked intra-RE inhibition with picrotoxin or enhanced it with clonazepam. We found that intra-RE inhibition limits the number and synchrony, but not the duration, of RE cell bursts. We then performed simulations that demonstrate how inhibition can shift network activity into a desynchronized mode simply by vetoing occasional RE cell bursts. In contrast, when intra-RE inhibition is blocked, RE cells burst synchronously, enabling even short RE cell bursts to promote epileptogenesis in two ways: first, by activating GABABreceptors, and second, through the GABABreceptor-independent emergence of network synchrony.
PS2APP Transgenic Mice, Coexpressing hPS2mut and hAPPswe, Show Age-Related Cognitive Deficits Associated with Discrete Brain Amyloid Deposition and Inflammation
Authors: Richards J. Grayson , Higgins Guy A. , Ouagazzal Abdel-Mouttalib , Ozmen Laurence , Kew James N. C. , Bohrmann Bernd , Malherbe Pari , Brockhaus Manfred , Loetscher Hansruedi , Czech Christian , Huber Gerda , Bluethmann Horst , Jacobsen Helmut , Kemp John A.
Published: April 2018

Transgenic mice, expressing mutant β-amyloid precursor proteins (βAPPs), have lead to a better understanding of the pathophysiological processes in Alzheimer's disease (AD). In many of these models, however, the temporal development of cognitive decline and the relationship to Aβ deposition and inflammation are unclear. We now report a novel transgenic mouse line, PS2APP (PS2N141I× APPswe), which develops a severe cerebral amyloidosis in discrete brain regions, and present a cross-sectional analysis of these mice at 4, 8, 12, and 16 months of age. Each age cohort was investigated for changes in behavior, electrophysiology of synapse efficacy, ELISA-determined Aβ load, histopathology, and in immunoelectron microscopy. Cognitive deficits were first observed at 8 months when Aβ deposits and inflammation were restricted to discrete brain regions, namely the subiculum and frontolateral (motor and orbital) cortex. As early as 5 months, electron microscopy revealed the presence, in these regions, of pre-plaque, immunogold-labeled extracellular fibrillar Aβ. At the same age, increased levels of insoluble Aβ were detected by ELISA, with Aβ1-40levels exceeding those of Aβ1-42. Further cognitive decline occurred in an age-related manner, and this was accompanied by the spread of amyloidosis to ultimately affect not only neo- and limbic cortices, but also thalamic and pontine nuclei. Dentate gyrus post-tetanic potentiation was significantly attenuated at 17 months, and there were also significant differences in paired-pulse parameters. This systematic cross-sectional study of the behavioral and pathological changes in the PS2APP mouse indicates that it develops age-related cognitive decline associated with severe amyloidosis and inflammation in discrete brain regions and therefore is suitable for testing a range of potential symptomatic and disease-modifying therapies for AD.
Enriched Environment Confers Resistance to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine and Cocaine: Involvement of Dopamine Transporter and Trophic Factors
Authors: Bezard Erwan , Dovero Sandra , Belin David , Duconger Sophie , Jackson-Lewis Vernice , Przedborski Serge , Piazza Pier Vincenzo , Gross Christian E. , Jaber Mohamed
Published: April 2018

We investigated, in mice, the influence of life experience on the vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a major neurotoxin that induces a Parkinson's disease-like syndrome in humans, and to cocaine, a potent psychostimulant that promotes drug addiction. Our findings show that adult C57BL/6 mice raised in an enriched environment (EE) for only 2 months are significantly more resistant to both drugs compared with mice raised in a standard environment (SE). Indeed, EE mice showed decreased locomotor activity in response to cocaine (10 and 20 mg/kg) as well as a different pattern of c-fosexpression in the striatum compared with SE mice. After MPTP treatment, SE mice showed a 75% loss of dopamine neurons, whereas EE mice showed only a 40% loss. The dopamine transporter plays a key role in mediating the effects of both drugs. We thus investigated the regulation of its expression. EE mice showed less dopamine transporter binding in the striatum and less dopamine transporter mRNA per dopamine neuron at the cellular level as demonstrated byin situhybridization. In addition, enriched environment promoted an increase in the expression of brain-derived neurotrophic factor in the striatum. These data provide a direct demonstration of the beneficial consequences that a positive environment has in preventing neurodegeneration and in decreasing responsiveness to cocaine. Furthermore, they suggest that the probability of developing neurological disorders such as Parkinson's disease or vulnerability to psychostimulants may be related to life experience.
Subcellular Localization of Metabotropic GABABReceptor Subunits GABAB1a/band GABAB2in the Rat Hippocampus
Authors: Kulik Ákos , Vida Imre , Luján Rafael , Haas Carola A. , López-Bendito Guillermina , Shigemoto Ryuichi , Frotscher Michael
Published: April 2018

Metabotropic GABABreceptors mediate slow inhibitory effects presynaptically and postsynaptically. Using preembedding immunohistochemical methods combined with quantitative analysis of GABABreceptor subunit immunoreactivity, this study provides a detailed description of the cellular and subcellular localization of GABAB1a/band GABAB2in the rat hippocampus. At the light microscopic level, an overlapping distribution of GABAB1a/band GABAB2was revealed in the dendritic layers of the hippocampus. In addition, expression of the GABAB1a/bsubunit was found in somata of CA1 pyramidal cells and of a subset of GABAergic interneurons. At the electron microscopic level, immunoreactivity for both subunits was observed on presynaptic and, more abundantly, on postsynaptic elements. Presynaptically, subunits were mainly detected in the extrasynaptic membrane and occasionally over the presynaptic membrane specialization of putative glutamatergic and, to a lesser extent, GABAergic axon terminals. Postsynaptically, the majority of GABABreceptor subunits were localized to the extrasynaptic plasma membrane of spines and dendritic shafts of principal cells and shafts of interneuron dendrites. Quantitative analysis revealed enrichment of GABAB1a/baround putative glutamatergic synapses on spines and an even distribution on dendritic shafts of pyramidal cells contacted by GABAergic boutons. The association of GABABreceptors with glutamatergic synapses at both presynaptic and postsynaptic sides indicates their intimate involvement in the modulation of glutamatergic neurotransmission. The dominant extrasynaptic localization of GABABreceptor subunits suggests that their activation is dependent on spillover of GABA requiring simultaneous activity of populations of GABAergic cells as it occurs during population oscillations or epileptic seizures.
Cannabinoids Decrease Corticostriatal Synaptic Transmission via an Effect on Glutamate Uptake
Authors: Brown Timothy M. , Brotchie Jonathan M. , Fitzjohn Stephen M.
Published: April 2018

Activation of cannabinoid CB1receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. Here we investigated CB1receptor regulation of glutamate release and uptake and synaptic transmission in the rat striatum. We show that CB1receptor activation reduces both the release and uptake of [3H]glutamate in striatal slices. We also demonstrate that both activation of CB1receptors and inhibition of glutamate uptake reduce corticostriatal synaptic transmission in a mutually occlusive manner and that both forms of depression are dependent on metabotropic glutamate receptor (mGluR) activation. We propose that CB1receptor activation in the striatum decreases glutamate transporter activity and that the resulting increase in synaptic cleft glutamate concentration causes the activation of presynaptic mGluRs, which then decrease glutamate release.
Activity-Dependent Feedforward Inhibition Modulates Synaptic Transmission in a Spinal Locomotor Network
Authors: Parker David
Published: April 2018

The analysis of synaptic properties in neural networks has focused on the properties of individual synapses. As a result, little is known of how neural assemblies arise from the connectivity and functional properties of different classes of network neurons.

I examined synaptic properties in the lamprey locomotor network. Here I show that, in addition to their monosynaptic inputs to motor neurons, a proportion of the excitatory network interneurons (EINs) evoke an activity-dependent disynaptic feedforward inhibitory input. Connections from the excitatory interneurons to small ipsilateral inhibitory interneurons were found that could account for the feedforward inhibition. Both synapses in the disynaptic pathway exhibited activity-dependent facilitation during physiologically relevant spike trains, which could contribute to the delayed, activity-dependent development of the feedforward IPSP. Although it was not as common as the feedforward inhibition, the excitatory interneurons could also evoke feedforward excitatory inputs in motor neurons.

EIN inputs to motor neurons usually depress during spike trains. In connections in which a delayed IPSP occurred, blocking the feedforward inhibition in motor neurons or preventing the activation of the disynaptic pathway abolished the depression of the direct EPSP during the spike train and could reveal an underlying facilitation. The feedforward inhibition thus heterosynaptically depressed the direct excitatory input to motor neurons. Activity-dependent heterosynaptic effects acting within network cellular assemblies can thus influence the integration of synaptic inputs in motor neurons. This could help to terminate ipsilateral motor neuron spiking during network activity.
The Proapoptotic Activities of Bax and Bak Limit the Size of the Neural Stem Cell Pool
Authors: Lindsten Tullia , Golden Jeffrey A. , Zong Wei-Xing , Minarcik Jeremy , Harris Marian H. , Thompson Craig B.
Published: April 2018

The proapoptotic Bcl-2 family members Bak and Bax play central and redundant roles in the regulation of apoptosis. In this study, we investigated the effect of loss of Bax and Bak in the CNS. The adultbax-/-bak-/-mice display masses of densely staining cells in the proliferative zones of the brain. These cells are shown to be a mix of neural progenitor cells and postmitotic cells at different stages of neural and glial differentiation. Both neural progenitor cells and mature neurons derived frombax-/-bak-/-mice were resistant to various apoptotic stimuli. Despite this resistance, postmitotic maturebax-/-bak-/-neurons remain as sensitive to excitoxic death as wild-type neurons. Thus, Bax and Bak play a critical role in regulating the number of neural progenitor cells in the adult brain but are not absolutely required for the initiation of neuronal cell death after neurotoxic injury.
Matrix Metalloproteinase-9 Facilitates Remyelination in Part by Processing the Inhibitory NG2 Proteoglycan
Authors: Larsen Peter H. , Wells Jennifer E. , Stallcup William B. , Opdenakker Ghislain , Yong V. Wee
Published: April 2018

Remyelination is a critical repair process that is initiated after a demyelinating insult. The failure to remyelinate contributes to neurological diseases such as multiple sclerosis. Here, we test the hypothesis that proteinase activity is required for the extensive remodeling of the extracellular matrix that occurs during remyelination. We show that mice lacking matrix metalloproteinase (MMP)-9 are impaired in myelin reformation after lysolecithin-induced demyelination. This deficiency may be explained at least in part by the failure to clear the accumulation of NG2, an inhibitory proteoglycan that retards the maturation and differentiation of oligodendrocytes that are needed for remyelination. These results emphasize for the first time that upregulation of MMP activity can be important for facilitating regeneration from some types of CNS injury.
Cannabinoid CB2Receptors and Fatty Acid Amide Hydrolase Are Selectively Overexpressed in Neuritic Plaque-Associated Glia in Alzheimer's Disease Brains
Authors: Benito Cristina , Núñez Estefanía , Tolón Rosa M. , Carrier Erica J. , Rábano Alberto , Hillard Cecilia J. , Romero Julián
Published: April 2018

The endocannabinoid system is still poorly understood. Recently, the basic elements that constitute it, i.e., membrane receptors, endogenous ligands, and mechanisms for termination of the signaling process, have been partially characterized. There is a considerable lack of information, however, concerning the distribution, concentration, and function of those components in the human body, particularly during pathological events. We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1and CB2receptors, in postmortem brains from patients with Alzheimer's disease. Using specific polyclonal antibodies, we have performed immunohistochemical analysis in hippocampus and entorhinal cortex sections from brains of Alzheimer's disease patients. Our results show that both fatty acid amide hydrolase and cannabinoid CB2receptors are abundantly and selectively expressed in neuritic plaque-associated astrocytes and microglia, respectively, whereas the expression of CB1receptors remains unchanged. In addition, the hydrolase activity seems to be elevated in the plaques and surrounding areas. Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response associated with this neurodegenerative process and as possible targets for new therapeutic approaches.
Physiology of Cells in the Central Lobes of the Mormyrid Cerebellum
Authors: Han Victor Z. , Bell Curtis C.
Published: April 2018

The cerebellum of mormyrid electric fish is unusual for its size and for the regularity of its histology. The circuitry of the mormyrid cerebellum is also different from that of the mammalian cerebellum in that mormyrid Purkinje cell axons terminate locally within the cortex on efferent cells, and the cellular regions of termination for climbing fibers and parallel fibers are well separated. These and other features suggest that the mormyrid cerebellum may be a useful site for addressing some functional issues regarding cerebellar circuitry. We have therefore begun to examine the physiology of the mormyrid cerebellum by recording intracellularly from morphologically identified Purkinje cells, efferent cells, Golgi cells, and stellate cells inin vitroslices. Mormyrid Purkinje cells respond to parallel fiber input with an AMPA-mediated EPSP that shows paired pulse facilitation and to climbing fiber input with a large all-or-none AMPA-mediated EPSP that shows paired pulse depression. Recordings from the somas of Purkinje cells show three types of spikes in response to injected current: a small, narrow sodium spike; a large, broad sodium spike; and a large broad calcium spike. Efferent cells, Golgi cells, and stellate cells respond to parallel fiber input with an EPSP or EPSP-IPSP sequence and show only large, narrow spikes in response to intracellular current injection. We conclude that the physiology of the mormyrid cerebellum is similar in many ways to the mammalian cerebellum but is also different in ways that may prove instructive concerning the functional circuitry of the cerebellum.
Neuronal Avalanches in Neocortical Circuits
Authors: Beggs John M. , Plenz Dietmar
Published: April 2018

Networks of living neurons exhibit diverse patterns of activity, including oscillations, synchrony, and waves. Recent work in physics has shown yet another mode of activity in systems composed of many nonlinear units interacting locally. For example, avalanches, earthquakes, and forest fires all propagate in systems organized into a critical state in which event sizes show no characteristic scale and are described by power laws. We hypothesized that a similar mode of activity with complex emergent properties could exist in networks of cortical neurons. We investigated this issue in mature organotypic cultures and acute slices of rat cortex by recording spontaneous local field potentials continuously using a 60 channel multielectrode array. Here, we show that propagation of spontaneous activity in cortical networks is described by equations that govern avalanches. As predicted by theory for a critical branching process, the propagation obeys a power law with an exponent of -3/2 for event sizes, with a branching parameter close to the critical value of 1. Simulations show that a branching parameter at this value optimizes information transmission in feedforward networks, while preventing runaway network excitation. Our findings suggest that “neuronal avalanches” may be a generic property of cortical networks, and represent a mode of activity that differs profoundly from oscillatory, synchronized, or wave-like network states. In the critical state, the network may satisfy the competing demands of information transmission and network stability.
Genetic Control of Interconnected Neuronal Populations in the Mouse Primary Visual System
Authors: Seecharan Dave J. , Kulkarni Anand L. , Lu Lu , Rosen Glenn D. , Williams Robert W.
Published: April 2018

Proliferation and survival of different cell types is thought to be modulated by cell interactions during development that achieve numerical and functional balance. We tested the precision of coregulation of numbers of neurons, glial cells, and endothelial cells in the dorsal lateral geniculate nucleus (LGN) in 58 isogenic strains of mice. We acquired matched counts of retinal ganglion cells (RGCs) in these strains and tested the precision of numerical matching between retina and LGN. Cells were counted using unbiased counting protocols and tissue from the Mouse Brain Library (www.mbl.org). Classification criteria were assessed using immunohistochemical criteria. The LGN contains an average of 17,000 neurons, 12,000 glial cells, and 10,000 endothelial cells. Variation around these means is typically twofold, and cell ratios vary widely. Strain differences in LGN volume correlate moderately well with glial cell number (r= 0.69) and less well with RGC number (r= 0.35) and with LGN neuron number (r= 0.32). Populations of LGN neurons and glial cells correlate only modestly (r= 0.44;p< 0.01). The single most surprising and unequivocal finding was the lack of any detectable correlation between populations of LGN neurons and RGCs, a correlation of merely 0.01 across 56 strains. In contrast, RGC number correlates significantly with LGN glial cell number, a surprising twist on the numerical matching hypothesis (r= 0.33;p< 0.01). We conclude that numbers of these two functionally coupled neuron populations are modulated over a wide range by independent genetic and developmental mechanisms.
NPY Induces Stress Resilience via Downregulation ofIhin Principal Neurons of Rat Basolateral Amygdala
Authors: Silveira Villarroel Heika , Bompolaki Maria , Mackay James P. , Miranda Tapia Ana Pamela , Michaelson Sheldon D. , Leitermann Randy J. , Marr Robert A. , Urban Janice H. , Colmers William F.
Published: April 2018

Neuropeptide Y (NPY) expression is tightly linked with the development of stress resilience in rodents and humans. Local NPY injections targeting the basolateral amygdala (BLA) produce long-term behavioral stress resilience in male rats via an unknown mechanism. Previously, we showed that activation of NPY Y1receptors hyperpolarizes BLA principal neurons (PNs) through inhibition of the hyperpolarization-activated, depolarizing H-current,Ih. The present studies tested whether NPY treatment induces stress resilience by modulatingIh. NPY (10 pmol) was delivered daily for 5 d bilaterally into the BLA to induce resilience; thereafter, the electrophysiological properties of PNs and the expression ofIhin the BLA were characterized. As reported previously, increases in social interaction (SI) times persisted weeks after completion of NPY administration.In vitrointracellular recordings showed that repeated intra-BLA NPY injections resulted in hyperpolarization of BLA PNs at 2 weeks (2W) and 4 weeks (4W) after NPY treatment. At 2W, spontaneous IPSC frequencies were increased, whereas at 4W, restingIhwas markedly reduced and accompanied by decreased levels of HCN1 mRNA and protein expression in BLA. Knock-down of HCN1 channels in the BLA with targeted delivery of lentivirus containing HCN1-shRNA increased SI beginning 2W after injection and induced stress resilience. NPY treatment induced sequential, complementary changes in the inputs to BLA PNs and their postsynaptic properties that reduce excitability, a mechanism that contributes to less anxious behavior. Furthermore, HCN1 knock-down mimicked the increases in SI and stress resilience observed with NPY, indicating the importance ofIhin stress-related behavior.

SIGNIFICANCE STATEMENTResilience improves mental health outcomes in response to adverse situations. Neuropeptide Y (NPY) is associated with decreased stress responses and the expression of resilience in rodents and humans. Single or repeated injections of NPY into the basolateral amygdala (BLA) buffer negative behavioral effects of stress and induce resilience in rats, respectively. Here, we demonstrate that repeated administration of NPY into the BLA unfolds several cellular mechanisms that decrease the activity of pyramidal output neurons. One key mechanism is a reduction in levels of the excitatory ion channel HCN1. Moreover, shRNA knock-down of HCN1 expression in BLA recapitulates some of the actions of NPY and causes potent resilience to stress, indicating that this channel may be a possible target for therapy.
Treatment of Addison’s disease during pregnancy
Authors: Oliveira Diana , Lages Adriana , Paiva Sandra , Carrilho Francisco
Published: April 2018

Addison’s disease, or primary adrenocortical insufficiency, is a long-term, potentially severe, rare endocrine disorder. In pregnancy, it is even rarer. We report the case of a 30-year-old pregnant patient with Addison’s disease, referred to Obstetrics-Endocrinology specialty consult at 14 weeks gestation. She had been to the emergency department of her local hospital various times during the first trimester presenting with a clinical scenario suggestive of glucocorticoid under-replacement (nausea, persistent vomiting and hypotension), but this was interpreted as normal pregnancy symptoms. Hydrocortisone dose was adjusted, and the patient maintained regular follow-up. No complications were reported for the remainder of gestation and delivery. Pregnant patients with Addison’s disease should be monitored during gestation and in the peripartum period by multidisciplinary teams. Adjustments in glucocorticoid and mineralocorticoid replacement therapy are often necessary, and monitoring should be based mainly on clinical findings, which becomes increasingly difficult during pregnancy. Patient education and specialized monitoring are key to avoiding complications from under- or over-replacement therapy in this period.

Learning points:

An increase in glucocorticoid replacement dose is expected to be necessary during pregnancy in a woman with Addison’s disease.

Patient education regarding steroid cover and symptoms of acute adrenal crisis are fundamental.

Monitoring in this period is challenging and remains mainly clinical.

The increase in hydrocortisone dose often obviates the need to increase fludrocortisone dose.
Successful neoadjuvant peptide receptor radionuclide therapy for an inoperable pancreatic neuroendocrine tumour
Authors: da Silva Tiago Nunes , van Velthuysen M L F , van Eijck Casper H J , Teunissen Jaap J , Hofland J , de Herder Wouter W
Published: April 2018

Non-functional pancreatic neuroendocrine tumours (NETs) can present with advanced local or distant (metastatic) disease limiting the possibility of surgical cure. Several treatment options have been used in experimental neoadjuvant settings to improve the outcomes in such cases. Peptide receptor radionuclide therapy (PPRT) using beta emitting radiolabelled somatostatin analogues has been used in progressive pancreatic NETs. We report a 55-year-old female patient with a 12.8 cm pancreatic NET with significant local stomach and superior mesenteric vein compression and liver metastases. The patient underwent treatment with [177Lutetium-DOTA0,Tyr3]octreotate (177Lu-octreotate) for the treatment of local and metastatic symptomatic disease. Six months after 4 cycles of 177lutetium-octreotate, resolution of the abdominal complaints was associated with a significant reduction in tumour size and the tumour was rendered operable. Histology of the tumour showed a 90% necrotic tumour with abundant hyalinized fibrosis and haemorrhage compatible with PPRT-induced radiation effects on tumour cells. This report supports that PPRT has a role in unresectable and metastatic pancreatic NET.

Learning points:

PRRT with 177Lu-octreotate can be considered a useful therapy for symptomatic somatostatin receptor-positive pancreatic NET.

The clinical benefits of PRRT with 177Lu-octreotate can be seen in the first months while tumour reduction can be seen up to a year after treatment.

PRRT with 177Lu-octreotate was clinically well tolerated and did not interfere with the subsequent surgical procedure.

PRRT with 177Lu-octreotate can result in significant tumour reduction and may improve surgical outcomes. As such, this therapy can be considered as a neoadjuvant therapy.
The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes
Authors: Sun Feng , Zhang Jun-Xiu , Yang Chang-Yi , Gao Guan-Qi , Zhu Wen-Bin , Han Bing , Zhang Le-Le , Wan Yue-Yue , Ye Xiao-Ping , Ma Yu-Ru , Zhang Man-Man , Yang Liu , Zhang Qian-Yue , Liu Wei , Guo Cui-Cui , Chen Gang , Zhao Shuang-Xia , Song Ke-Yi , Song Huai-Dong
Published: April 2018

Objective

Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited.

Design and methods

One hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees.

Results

Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands.

Conclusions

Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.
Role of MRI T2-DRIVE in the assessment of pituitary stalk abnormalities without gadolinium in pituitary diseases
Authors: Godano Elisabetta , Morana Giovanni , Di Iorgi Natascia , Pistorio Angela , Allegri Anna Elsa Maria , Napoli Flavia , Gastaldi Roberto , Calcagno Annalisa , Patti Giuseppa , Gallizia Annalisa , Notarnicola Sara , Giaccardi Marta , Noli Serena , Severino Mariasavina , Tortora Domenico , Rossi Andrea , Maghnie Mohamad
Published: April 2018

Objective

To investigate the role of T2-DRIVE MRI sequence in the accurate measurement of pituitary stalk (PS) size and the identification of PS abnormalities in patients with hypothalamic–pituitary disorders without the use of gadolinium.

Design

This was a retrospective study conducted on 242 patients who underwent MRI due to pituitary dysfunction between 2006 and 2015. Among 135 eligible patients, 102 showed eutopic posterior pituitary (PP) gland and 33 showed ‘ectopic’ PP (EPP).

Methods

Two readers independently measured the size of PS in patients with eutopic PP at the proximal, midpoint and distal levels on pre- and post-contrast T1-weighted as well as T2-DRIVE images; PS visibility was assessed on pre-contrast T1 and T2-DRIVE sequences in those with EPP. The length, height, width and volume of the anterior pituitary (AP), PP height and length and PP area were analyzed.

Results

Significant agreement between the two readers was obtained for T2-DRIVE PS measurements in patients with ‘eutopic’ PP; a significant difference was demonstrated between the intraclass correlation coefficient calculated on the T2-DRIVE and the T1-pre- and post-contrast sequences. The percentage of PS identified by T2-DRIVE in EPP patients was 72.7% compared to 30.3% of T1 pre-contrast sequences. A significant association was found between the visibility of PS on T2-DRIVE and the height of AP.

Conclusion

T2-DRIVE sequence is extremely precise and reliable for the evaluation of PS size and the recognition of PS abnormalities; the use of gadolinium-based contrast media does not add significant information and may thus be avoided.
Criterios de empleabilidad en la educación técnico-profesional. Tensiones y retos en la especialidad salud, Araucanía, Chile
Authors: Riquelme-Brevis Hernán , Rivas-Burgos Maira , Riquelme-Brevis Matías
Published: April 2018

The present research analyzes the employability criteria, when hiring the services of nursery graduates from three secondary technical schools in La Araucanía, Chile. This research project used a mixed methodology, so it was possible to contact health employees from public and private areas, such as teachers, graduates and students from three secondary technical schools and apply to them various research techniques such as questionnaires, in-depth interviews, and focus groups. Among the main results, it is worth mentioning: the re-articulation experienced by the technical and professional high schools in Chile, related to civil society and health system; the need to reinforce the dialog among institutions in the health and sanitary system; technical training and development of socio-emotional abilities of students and research graduates, and finally the demand to advance towards social validity of professional technicians in the health area. Finally, this research aims to contribute to finding mechanisms to improve the work performance of health technicians, as well as identifying obstacles that impede the development of secondary technical education in the country.
Dinamización del recreo como resolución de conflictos y participación en actividades físico-deportivas
Authors: Castillo-Rodríguez Gema , Picazo-Córdoba Celestino Carlos , Gil-Madrona Pedro
Published: April 2018

This research paper aims to see to what extent a project of revitalization of playgrounds contributes to improving coexistence, conflict resolution, and the participation of boys and girls in sport and physical activities. The paper also aims to know the level of motivation and interest the project could have for the students. For this, after initial assessment, a project of revitalization of recreations was designed, and after a few days of training, it was implemented for a month in a primary school in Spain, with 179 students (98 boys and 81 girls) from 1 to 6 grades; it was carried out in the school playground during a 30-minute recess period. The project consisted of two phases of training; the first one explained different games through training days; the second phase featured free recreation and independent work. The project opted for a mixed methodology of collecting information; this methodology included an information questionnaire and participant observation. The study concludes by highlighting the students’ high interest and motivation, the increasing participation, both boys and girls in physical and sports activities, and the reduction of conflicts between students of the center.
Reflecting on Basic Art Education in Aguascalientes, Mexico. Implications for Higher Education
Authors: Capistrán-Gracia Raúl Wenceslao
Published: April 2018

The basic art education in Aguascalientes, Mexico, faces a significant number of challenges that must be overcome and problems that must be addressed. Among other challenges, the public education system must train a high number of teachers who lack professional qualifications. The system also has to promote the training of its whole teaching staff and satisfy the demand for sufficient pedagogical materials. Thus, the author proposes that higher education must actively get involved with basic education by implementing remedial programs for unqualified teachers. It also must propose continuous education programs to foster a better preparation of the teaching staff and develop research projects that generate knowledge to promote more comprehensive and better-quality art education. The contributions made to the improvement of art education will impact on more sensitive, creative and harmonious human beings.
Kartellordnungswidrigkeitenrecht nach der 9. GWB-Novelle
Authors: Haus Florian C.
Published: April 2018

Der Gesetzgeber der 9. GWB-Novelle hat das bestehende Bußgeldregime für Kartellverstöße tiefgreifend umgestaltet. Die Regelungen sind komplex und stellen die größte Zäsur seit der 7. GWB-Novelle dar. Mit der Einführung einer Konzernhaftung und enorm strengen Haftungsmechanismen für Fälle der Gesamt- und Einzelrechtsnachfolge sind zahlreiche rechtliche und rechtspraktische Fragen aufgeworfen, die von der (neuen) Normadressatenstellung über die Tatbestandsmerkmale insbesondere der Rechtsnachfolgeregelungen im Einzelnen bis hin zur drängenden Frage der Verfassungsmäßigkeit der sogenannten Ausfallhaftung für den Übergangszeitraum reichen.
Timing and Location of Emergency Department Revisits
Authors: Michelson Kenneth A. , Lyons Todd W. , Bachur Richard G. , Monuteaux Michael C. , Finkelstein Jonathan A.
Published: April 2018

BACKGROUND:

Emergency department (ED) revisits are used as a measure of care quality. Many EDs measure only revisits to the same facility, underestimating true rates. We sought to determine the frequency, location, and predictors of ED revisits to the same or a different ED.

METHODS:

We studied ED discharges for children <18 years old in Maryland and New York in the statewide ED and inpatient databases. Revisits were defined as ED visits within 7 days of an index visit. Our primary outcome was the proportion of revisits that were different-hospital revisits (DHRs). We measured the underestimation of total revisits when only same-hospital revisits were measured. We determined the risk of DHR by quartile of annual ED pediatric volume, adjusting for case mix, insurance, state, and urban location.

RESULTS:

Revisits across 261 EDs occurred after 5.9% of 4.3 million discharges. A per-ED median 21.9% of revisits were DHRs (interquartile range 14.2%–34.6%). Measuring only same-hospital revisits underestimated total revisits by 17.4%. The proportions of revisits that were DHRs by increasing volume quartile were 28.1%, 25.5%, 22.6%, and 14.5%. The adjusted risk of DHR was lower for increasing quartiles of pediatric volume (adjusted odds ratio for highest versus lowest quartile 0.27; 95% confidence interval, 0.19–0.36).

CONCLUSIONS:

Measuring ED revisits only at the index ED significantly underestimates total revisits. Lower pediatric volume is associated with higher DHRs as a proportion of revisits. When using revisits as a measure of emergency care quality, effort should be made to assess revisits to different EDs.
The personality, motivational, and need-based background of problematic Tinder use
Authors: Orosz Gábor , Benyó Mária , Berkes Bernadett , Nikoletti Edina , Gál Éva , Tóth-Király István , Bőthe Beáta
Published: April 2018

Background and aims

Tinder is a geo-located online dating application, which is present in almost 200 countries and has 10 million daily users. The aim of the present research was to investigate the motivational, personality, and basic psychological need-related background of problematic Tinder use.

Methods

After qualitative pretest and item construction, in Study 1 (N = 414), confirmatory factor analysis was conducted to corroborate the different motivational factors behind Tinder use. In Study 2 (N = 346), the associations between Big Five traits, Tinder motivations, and problematic Tinder use were examined with structural equation modeling (SEM). In Study 3 (N = 298), the potential role of general self-esteem, relatedness need satisfaction, and frustration in relation to Tinder-use motivations and problematic Tinder use was examined with SEM.

Results

In Study 1, a 16-item first-order factor structure was identified with four motivational factors, such as sex, love, self-esteem enhancement, and boredom. In Study 2, problematic Tinder use was mainly related to using Tinder for self-esteem enhancement. The Big Five personality factors were only weakly related to the four motivations and to problematic Tinder use. Counterintuitively, Study 3 showed that instead of global self-esteem, relatedness need frustration was the strongest predictor of self-esteem enhancement Tinder-use motivation which, in turn, was the strongest predictor of problematic Tinder use.

Discussion

Four motivational factors were identified as predictors of problematic use with need frustration being a relevant background variable instead of general personality traits.
Strict CV without government
Authors: Enguehard Guillaume
Published: April 2018

In this paper, I aim to unify the Empty Category Principle of Government Phonology with another (more general) principle: the Obligatory Contour Principle. I show that these principles share numerous structural properties: (i) they prevent sequences of identical entities, and (ii) they trigger the same repair mechanisms. The main difference is substantial: ECP handles empty syllabic components, when OCP handles phonological features. I propose to broaden the definition of OCP in including all phonological entities and I show to what extent this definition can account for the effects of ECP. Finally, I point out that this analysis can also account for some specificities of word-edges.
Outcomes are what matter: Competency-based medical education gets us to our goal
Authors: Ross Shelley , Hauer Karen E. , van Melle Elaine
Published: April 2018

This article was migrated. The article was marked as recommended. Health professions education is undergoing a major paradigm shift to competency-based medical education. When shifts in thinking are profound and result in transformations of existing paradigms, there is often an accompanying criticism. While competency-based medical education is an evidence guided change in approach to curriculum and assessment, it is not immune to critique and concerns. Some criticisms are valid, and must be addressed as competency-based medical education is implemented; other concerns raised about competency-based medical education highlight the importance of clarity in language and purpose when discussing new paradigms. In this commentary, we aim to offer a balanced view of competency-based medical education by presenting an overview of the origins and conceptual assumptions of competency-based medical education and acknowledging valid criticisms of the approach.
In Situ and Operando Spectroscopy: A Powerful Approach Towards Understanding Catalysts
Authors: Lukashuk Liliana , Foettinger Karin
Published: April 2018

The improvement of catalytic processes is strongly related to the better performance of catalysts (higher conversion, selectivity, yield and stability). Additionally, the desired catalysts should meet the requirements of being low cost as well as environmentally and user-friendly. All these requirements can only be met by catalyst development and optimisation following new approaches in design and synthesis. This article discusses three major approaches in the design and development of catalysts: (a) high-throughput synthesis; (b) reaction kinetic studies; (c) in situ and operando spectroscopy for studying catalysts under process conditions. In contrast to approaches based on high-throughput synthesis and reaction kinetic studies, an emerging approach of studying catalysts under process conditions using in situ and operando spectroscopy and transferring the gained knowledge to design of new catalysts or the optimisation of existing catalysts is not yet widely employed in the chemical industry. In this article, examples of using in situ or operando spectroscopy for studying the surface and bulk of catalysts under process conditions are discussed, with an overview of applying in situ X-ray absorption spectroscopy (XAS), in situ infrared (IR) spectroscopy and in situ near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) for monitoring the bulk and surface composition of PdZn/ZnO and Pd2Ga/Ga2O3 methanol steam reforming catalysts.
FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia
Authors: Norsworthy Kelly J. , Ko Chia-Wen , Lee Jee Eun , Liu Jiang , John Christy S. , Przepiorka Donna , Farrell Ann T. , Pazdur Richard
Published: April 2018

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose “fractionated” schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%–40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen.

Implications for Practice

Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.
The Eighth Edition of TNM Staging of Lung Cancer: Reference Chart and Diagrams
Authors: Lababede Omar , Meziane Moulay A.
Published: April 2018

Lung cancer is the leading cause of cancer-related mortality in the U.S. TNM staging of lung cancer is implemented to define the extent of disease and consequently assign prognosis and guide treatment. The newest edition of TNM staging of lung cancer has been released recently. In this article, we present the TNM staging of lung cancer in a concise, yet comprehensive, visual format.