Acute Liver Failure Secondary to Hepatic Infiltration of Malignant Melanoma

Acute liver failure due to malignant melanoma is uncommon. We presents a case of acute liver failure secondary to hepatic infiltration of a malignant melanoma. An 86-year-old man was admitted with elevated liver enzymes and an increased lactate dehydrogenase level. His condition progressed to acute liver failure, but the etiology of liver failure was unclear. Esophagogastroduodenoscopy was performed to evaluate dyspepsia, which showed signs indicative of malignant melanoma. Based on the endoscopy findings and elevated liver enzyme levels, liver biopsy was performed to confirm the presence of malignant melanoma. Hepatic infiltration of malignant melanoma was observed histologically. However, massive and diffuse liver metastasis is very rare and difficult to identify on imaging studies. If the etiology of liver failure is unclear, diffuse metastatic melanoma infiltration should be considered as differential diagnosis. Early liver biopsy can help to clarify the diagnosis.

Endoscopic Ultrasound-guided Fine-needle Aspiration Biopsy of a Renal Mass

Traditionally, tissue biopsies of kidney lesions are usually performed with CT or percutaneous ultrasound guidance, but biopsies using EUS have rarely been reported. In this report, we describe a case of renal cell carcinoma (RCC) diagnosed using EUS-guided fine-needle aspiration biopsy. A 75-year-old woman taking aspirin due to stable angina continued to exhibit weight loss and anemia and visited the gastroenterology department. No bleeding was observed on upper and lower gastrointestinal endoscopy. A contrast-enhanced mass was observed in the left kidney, accompanied by 8.9×10.8 cm-sized necrosis suggesting RCC on abdominal CT. Chest CT showed masses in both lungs. We planned to administer targeted therapy after pathological confirmation using EUS. Aspirin was continued, and we performed fine-needle biopsy using a 22-gauge needle three times. No adverse events were observed after the procedure. Pathological examination confirmed RCC, clear cell type, and the patient is currently undergoing treatment with sunitinib. EUS-guided fine-needle aspiration biopsy is safe for liver, pancreatic, or other tumors accessible from the upper gastrointestinal tract. This technique shows fewer adverse events. To the best of our knowledge, there have been no other reports on EUS-guided fine-needle aspiration biopsy to identify RCC in Korea.

COVID-19 Mimicking Acute Colitis / 대한내과학회지

On 11 February, 2020, the World Health Organization announced that COVID-19 was a novel coronavirus disease first detected in Wuhan, Hubei Province, China. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete clinical picture is not fully known. Illness ranges from mild to fatal. The common symptoms include fever, cough, and dyspnea usually developing 2-14 days after exposure. However, diarrhea was present in a few patients with COVID-19. We report a case of COVID-19 mimicking acute colitis.

Endoscopic Ultrasound-guided Fine-needle Aspiration Biopsy of a Renal Mass

Traditionally, tissue biopsies of kidney lesions are usually performed with CT or percutaneous ultrasound guidance, but biopsies using EUS have rarely been reported. In this report, we describe a case of renal cell carcinoma (RCC) diagnosed using EUS-guided fine-needle aspiration biopsy. A 75-year-old woman taking aspirin due to stable angina continued to exhibit weight loss and anemia and visited the gastroenterology department. No bleeding was observed on upper and lower gastrointestinal endoscopy. A contrast-enhanced mass was observed in the left kidney, accompanied by 8.9×10.8 cm-sized necrosis suggesting RCC on abdominal CT. Chest CT showed masses in both lungs. We planned to administer targeted therapy after pathological confirmation using EUS. Aspirin was continued, and we performed fine-needle biopsy using a 22-gauge needle three times. No adverse events were observed after the procedure. Pathological examination confirmed RCC, clear cell type, and the patient is currently undergoing treatment with sunitinib. EUS-guided fine-needle aspiration biopsy is safe for liver, pancreatic, or other tumors accessible from the upper gastrointestinal tract. This technique shows fewer adverse events. To the best of our knowledge, there have been no other reports on EUS-guided fine-needle aspiration biopsy to identify RCC in Korea.

COVID-19 Mimicking Acute Colitis / 대한내과학회지

On 11 February, 2020, the World Health Organization announced that COVID-19 was a novel coronavirus disease first detected in Wuhan, Hubei Province, China. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete clinical picture is not fully known. Illness ranges from mild to fatal. The common symptoms include fever, cough, and dyspnea usually developing 2-14 days after exposure. However, diarrhea was present in a few patients with COVID-19. We report a case of COVID-19 mimicking acute colitis.

Effects of Instability Tools on Muscles Activities in Lunge Exercise in Healthy Adult Males

PURPOSE@#This study was to investigate the effect of instability on the activation of lower limb muscles during lunge exercise.@*METHODS@#The study subjects were healthy twenties and were selected to have no orthopedic or neurological diseases. 1) Flat lunge exercise (Lunge 1, 2) Lunge exercise on TOGU (Lunge 2, 3) Holding the olympic bar and moving the lunge on TOGU (Lunge 3, 4) Holding the Surge and moving the lunge on TOGU (Lunge 4). Through the above four actions, we can see how the top-down instability influences the lower limb unlike the Bottom-up instability. EMG attachment sites were gluteus medius, vastus medialis, gastrocnemius, tibialis anterior.@*RESULTS@#These result suggest that exercise using Lunge 4 activity was the highest in muscle activity compared to other exercises, but vastus medialis showed the highest muscle activity in Lunge 2 exercise(p<0.05).@*CONCLUSION@#This study showed the muscular activity of the lower extremities according to the lunge exercise using the instability tools.

Two Cases of Successful ERCP during ERCP-Related Iatrogenic Duodenal Perforation / 대한췌담도학회지

Endoscopic retrograde cholangiopancreatography (ERCP)-related perforations of the duodenum are rare but serious complications. Some ERCP-related perforations can be successfully managed without surgery. However, the presence of duodenal perforation may lead to premature termination of the ERCP and need for additional procedure such as percutaneous biliary drainage. If the ERCP-related perforation is identified early during the procedure, primary closure of the perforation can be attempted first or after completion of ERCP. We report two cases of duodenal perforation during ERCP in which ERCP was successfully completed after primary closure of the perforation.

Electrophysiological Evidence for Functional Astrocytic P2X₃ Receptors in the Mouse Trigeminal Caudal Nucleus

Recently, we reported that astrocytes in the trigeminal caudal nucleus (Vc) of the brain stem express a purinergic receptor P2X₃, which is involved in the craniofacial pathologic pain. Although we observed protein expression of P2X₃ receptors (P2X₃ Rs) in the astrocyte of the Vc, it is still unclear that astrocyte has functional P2X₃Rs in Vc. To address this issue, we recorded asrtocytic P2X₃Rs by using whole cell voltage-clamp recording in the Vc of the GFAP-GFP mice, which was used as a guide to astrocytes with green fluorescence. While measuring voltage ramp-induced astrocytic membrane current, we found the amplitude of the current was increased when we applied P2-purinoreceptor agonist, α,β-meATP. This increase was blocked by co-application of A317491, P2X₃R antagonist. These results demonstrate that astrocytes in the Vc express functional P2X₃Rs, which might be critical in craniofacial pathologic pain.

Expression of µ-Opioid Receptor in CA1 Hippocampal Astrocytes

µ-opioid receptor (MOR) is a class of opioid receptors with a high affinity for enkephalins and beta-endorphin. In hippocampus, activation of MOR is known to enhance the neuronal excitability of pyramidal neurons, which has been mainly attributed to a disinhibition of pyramidal neurons via activating Gαi subunit to suppress the presynaptic release of GABA in hippocampal interneurons. In contrast, the potential role of MOR in hippocampal astrocytes, the most abundant cell type in the brain, has remained unexplored. Here, we determine the cellular and subcellular distribution of MOR in different cell types of the hippocampus by utilizing MOR-mCherry mice and two different antibodies against MOR. Consistent with previous findings, we demonstrate that MOR expression in the CA1 pyramidal layer is co-localized with axon terminals from GABAergic inhibitory neurons but not with soma of pyramidal neurons. More importantly, we demonstrate that MOR is highly expressed in CA1 hippocampal astrocytes. The ultrastructural analysis further demonstrates that the astrocytic MOR is localized in soma and processes, but not in microdomains near synapses. Lastly, we demonstrate that astrocytes in ventral tegmental area and nucleus accumbens also express MOR. Our results provide the unprecedented evidence for the presence of MOR in astrocytes, implicating potential roles of astrocytic MOR in addictive behaviors.

Astrocytic proBDNF and Tonic GABA Distinguish Active versus Reactive Astrocytes in Hippocampus

Astrocytes are the most abundant cell type in the brain and they make close contacts with neurons and blood vessels. They respond dynamically to various environmental stimuli and change their morphological and functional properties. Both physiological and pathological stimuli can induce versatile changes in astrocytes, as this phenomenon is referred to as ‘astrocytic plasticity’. However, the molecular and cellular mechanisms of astrocytic plasticity in response to various stimuli remain elusive, except for the presence of hypertrophy, a conspicuous structural change which is frequently observed in activated or reactive astrocytes. Here, we investigated differential characteristics of astrocytic plasticity in a stimulus-dependent manner. Strikingly, a stab wound brain injury lead to hypertrophy of astrocytes accompanied by increased GABA expression and tonic GABA release in mouse CA1 hippocampus. In contrast, the mice experiencing enriched environment exhibited astrocytic hypertrophy with enhanced proBDNF immunoreactivity but without GABA signal. Based on the results, we define proBDNF-positive/GABA-negative hypertrophic astrocytes as ‘active’ astrocytes and GABA-positive hypertrophic astrocytes as ‘reactive’ astrocytes, respectively. We propose for the first time that astrocytic proBDNF can be a bona fide molecular marker of the active astrocytes, which are distinct from the reactive astrocytes which show hypertrophy but with aberrant GABA.

Fluoride Induces a Volume Reduction in CA1 Hippocampal Slices Via MAP Kinase Pathway Through Volume Regulated Anion Channels

Regulation of cell volume is an important aspect of cellular homeostasis during neural activity. This volume regulation is thought to be mediated by activation of specific transporters, aquaporin, and volume regulated anion channels (VRAC). In cultured astrocytes, it was reported that swelling-induced mitogen-activated protein (MAP) kinase activation is required to open VRAC, which are thought to be important in regulatory volume decrease and in the response of CNS to trauma and excitotoxicity. It has been also described that sodium fluoride (NaF), a recognized G-protein activator and protein phosphatase inhibitor, leads to a significant MAP kinase activation in endothelial cells. However, NaF's effect in volume regulation in the brain is not known yet. Here, we investigated the mechanism of NaF-induced volume change in rat and mouse hippocampal slices using intrinsic optical signal (IOS) recording, in which we measured relative changes in intracellular and extracellular volume as changes in light transmittance through brain slices. We found that NaF (1~5 mM) application induced a reduction in light transmittance (decreased volume) in CA1 hippocampus, which was completely reversed by MAP kinase inhibitor U0126 (10 µM). We also observed that NaF-induced volume reduction was blocked by anion channel blockers, suggesting that NaF-induced volume reduction could be mediated by VRAC. Overall, our results propose a novel molecular mechanism of NaF-induced volume reduction via MAP kinase signaling pathway by activation of VRAC.

Fluoride Induces a Volume Reduction in CA1 Hippocampal Slices Via MAP Kinase Pathway Through Volume Regulated Anion Channels

Regulation of cell volume is an important aspect of cellular homeostasis during neural activity. This volume regulation is thought to be mediated by activation of specific transporters, aquaporin, and volume regulated anion channels (VRAC). In cultured astrocytes, it was reported that swelling-induced mitogen-activated protein (MAP) kinase activation is required to open VRAC, which are thought to be important in regulatory volume decrease and in the response of CNS to trauma and excitotoxicity. It has been also described that sodium fluoride (NaF), a recognized G-protein activator and protein phosphatase inhibitor, leads to a significant MAP kinase activation in endothelial cells. However, NaF's effect in volume regulation in the brain is not known yet. Here, we investigated the mechanism of NaF-induced volume change in rat and mouse hippocampal slices using intrinsic optical signal (IOS) recording, in which we measured relative changes in intracellular and extracellular volume as changes in light transmittance through brain slices. We found that NaF (1~5 mM) application induced a reduction in light transmittance (decreased volume) in CA1 hippocampus, which was completely reversed by MAP kinase inhibitor U0126 (10 µM). We also observed that NaF-induced volume reduction was blocked by anion channel blockers, suggesting that NaF-induced volume reduction could be mediated by VRAC. Overall, our results propose a novel molecular mechanism of NaF-induced volume reduction via MAP kinase signaling pathway by activation of VRAC.

Disinhibitory Action of Astrocytic GABA at the Perforant Path to Dentate Gyrus Granule Neuron Synapse Reverses to Inhibitory in Alzheimer's Disease Model

Like neurons, astrocytes produce and release GABA to influence neuronal signaling. At the perforant path to dentate gyrus granule neuron synapse, GABA from astrocyte was found to be a strong inhibitory factor, which impairs synaptic transmission, synaptic plasticity and memory in Alzheimer's disease. Although astrocytic GABA is observed in many brain regions, its physiological role has not been clearly demonstrated yet. Here, we show that astrocytic GABA exerts disinhibitory action to dentate granule neurons by targeting GABA(B) receptors of GABAergic interneurons in wild-type mice. This disinhibitory effect is specific to a low intensity of electrical stimulation at perforant path fibers. Inversely in Alzheimer's disease model mice, astrocytic GABA targets GABA(A) receptors and exerts inhibitory action by reducing release probability of glutamatergic perforant path terminals. These results suggest that astrocytic GABA differentially modulates the signaling from cortical input to dentate gyrus under physiological and pathological conditions.

Ca2+ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca2+ oscillations. ATP is known to be released from astrocytes by Ca2+-dependent manner. However, the precise source of Ca2+, whether it is Ca2+ entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca2+ was released from intracellular stores by activation of Galpha(q)-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca2+ was omitted. Our results suggest that Ca2+ entry, but not release from intracellular Ca2+ store, is critical for MS-induced ATP release from astrocyte.

Attenuated Glial K+ Clearance Contributes to Long-Term Synaptic Potentiation Via Depolarizing GABA in Dorsal Horn Neurons of Rat Spinal Cord

It has been reported that long-term enhancement of superficial dorsal horn (DHs) excitatory synaptic transmission underlies central sensitization, secondary hyperalgesia, and persistent pain. We tested whether impaired clearance of K+ and glutamate by glia in DHs may contribute to initiation and maintenance of the CNS pain circuit and sensorimotor abnormalities. Transient exposure of the spinal cord slice to fluorocitrate (FC) is shown to be accompanied by a protracted decrease of the DHs optical response to repetitive electrical stimulation of the ipsilateral dorsal root, and by a similarly protracted increase in the postsynaptic response of the DHs like LTP. It also is shown that LTP(FC) does not occur in the presence of APV, and becomes progressively smaller as [K+]o in the perfusion solution decreased from 3.0 mM to 0.0 mM. Interestingly LTP(FC) is reduced by bath application of Bic. Whole-cell patch recordings were carried out to evaluate the effects of FC on the response of DHs neurons to puffer-applied GABA. The observations reveal that transient exposure to FC is reliably accompanied by a prolonged (>1 hr) depolarizing shift of the equilibrium potential for the DHs neuron transmembrane ionic currents evoked by GABA. Considered collectively, the findings demonstrate that LTP(FC) involves (1) elevation of [K+]o in the DHs, (2) NMDAR activation, and (3) conversion of the effect of GABA on DHs neurons from inhibition to excitation. It is proposed that a transient impairment of astrocyte energy production can trigger the cascade of dorsal horn mechanisms that underlies hyperalgesia and persistent pain.

Developmental Role of Anoctamin-1/TMEM16A in Ca2+-Dependent Volume Change in Supporting Cells of the Mouse Cochlea

Mammalian cochlea undergoes morphological and functional changes during the postnatal period, around the hearing onset. Major changes during the initial 2 postnatal weeks of mouse include maturation of sensory hair cells and supporting cells, and acquisition of afferent and efferent innervations. During this period, supporting cells in the greater epithelial ridge (GER) of the cochlea exhibit spontaneous and periodic activities which involves ATP, increase in intracellular Ca2+, and cell volume change. This Ca2+-dependent volume change has been proposed to involve chloride channels or transporters. We found that the spontaneous volume changes were eliminated by anion channel blocker, 100 microM NPPB. Among candidates, expression of Anoctamin-1 (Ano1 or TMEM16A), bestriphin-1 and NKCC1 were investigated in whole-mount cochlea of P9-10 mice. Immunolabeling indicated high level of Ano1 expression in the GER, but not of betrophin-1 or NKCC1. Double-labeling with calretinin and confocal image analysis further elucidated the cellular localization of Ano1 immunoreactivity in supporting cells. It was tested if the Ano1 expression exhibits similar time course to the spontaneous activities in postnatal cochlear supporting cells. Cochlear preparations from P2-3, P5-6, P9-10, P15-16 mice were subjected to immunolabeling. High level of Ano1 immunoreactivity was observed in the GER of P2-3, P5-6, P9-10 cochleae, but not of P15-17 cochleae. Taken together, the localization and time course in Ano1 expression pattern correlates with the spontaneous, periodic volume changes recorded in postnatal cochlear supporting cells. From these results we propose that Ano1 is the pacemaker of spontaneous activities in postnatal cochlea.