THE NATIONWIDE INCIDENCE OF RETINAL ARTERY OCCLUSION FOLLOWING DIALYSIS AS A RESULT OF END-STAGE RENAL DISEASE: 2004 Through 2013.

PURPOSE: To examine the incidence and risk of retinal artery occlusion (RAO) in patients who have undergone dialysis in Korea. METHODS: A nationwide, population-based study using South Korean national health insurance data from 2004 to 2013 was used for analysis. All patients who began dialysis between 2004 and 2013 and the same number of control subjects were selected via propensity score matching. The incidence of RAO in the dialysis and control cohorts was calculated for 2004 to 2013 using washout data from 2003. The multivariable Cox proportional hazards model was used to evaluate the risk of developing RAO in dialysis patients. Cumulative RAO incidence curves were generated using the Kaplan-Meier method. Whether dialysis modalities influenced the incidence of RAO was also evaluated. RESULTS: Seventy-six thousand seven hundred and eighty-two end-stage renal disease patients on dialysis were included in the dialysis cohort, and 76,782 individuals were included in the control cohort. During the study period, 293 patients in the dialysis cohort and 99 patients in the control cohort developed RAO. The person-years incidence of RAO was significantly higher in the dialysis cohort than in the control cohort (dialysis = 1.1/1,000 person-years; control = 0.3/1,000 person-years; P < 0.001). The incidence of RAO was not significantly different between the two methods of dialysis (hemodialysis vs. peritoneal dialysis; P = 0.25, log-rank test). CONCLUSION: The current study provided epidemiological evidence that undergoing dialysis for end-stage renal disease was associated with an increased risk of developing RAO. The incidence of RAO rapidly increased as the duration of dialysis increased. These results strengthen the significant role of the renal function in retinal vascular disease.

Hydrangeae Dulcis Folium Attenuates Physical Stress by Supressing ACTH-Induced Cortisol in Zebrafish.

OBJECTIVE: To determine the effects of Hydrangeae Dulcis Folium (EHDF) on physical stress, changes in the whole-body cortisol level and behaviour in zebrafish (Danio rerio). METHODS: One hundred and seventy-four fish were randomly divided into 4 [adrenocorticotropin hormone (ACTH) challenge test: 4 fish per group] or 6 groups (behavioural test: 10-12 fish per group, whole-body cortisol: 4 fish per group). Net handling stress (NHS) was used to induce physical stress. Fish were treated with vehicle or EHDF (5-20 mg/L) for 6 min before they were exposed to stress. And then, fish were sacrificed for collecting body fluid from whole-body or conducted behavioural tests, including novel tank test and open field test, and were evaluated to observe anxiety-like behaviours and locomotion. In addition, to elucidate the mode of action of the anti-stress effects of EHDF, ACTH (0.2 IU/g, i.p.) challenge test was performed. RESULTS: The increased anxiety-like behaviours in novel tank test and open field test under stress were prevented by treatment with EHDF at 5-20 mg/L (P <0.05). Moreover, compared with the unstressed group, which was not treated with NHS, the whole-body cortisol level was significantly increased by treatment with NHS (P <0.05). Compared with the NHS-treated stressed control group, pre-treatment with EHDF at concentrations of 5-20 mg/L for 6 min significantly prevented the NHS-increased whole-body cortisol level (<0.05). In addition, ACTH challenge test showed that EHDF completely blocked the effects of ACTH on cortisol secretion (P <0.05). CONCLUSION: EHDF may be a good antistress candidate and its mechanism of action may be related to its positive effects on cortisol release.

The enhancing effect of Aubang Gahl Soo on the hippocampal synaptic plasticity and memory through enhancing cholinergic system in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Aubang Gahl Soo (AGS) is a Korean traditional drink manufactured from medicinal plants and fruits using sugar or honey. Although traditional old book stated its effects on body, there is no scientific evidence yet. Therefore, in the present study, we tested AGS on brain functions. AIM OF THIS STUDY: In this study, we tried to uncover the effect of on brain functions. To do this we examined the action of AGS on the hippocampal synaptic function and memory in mice. MATERIALS AND METHODS: To examine the effect of AGS on synaptic plasticity, we observed input-output curves (I/O curve), paired-pulse facilitation (PPF), and long-term potentiation (LTP) using mouse hippocampal slices. Moreover, to investigate the functional relevance of the effect of AGS on synaptic plasticity, we conducted passive avoidance, Y-maze and Morris water maze tests. To examine relevant mechanism, acetylcholinesterase (AChE) activity and acetylcholine (ACh) level assay were also conducted. RESULTS: In the basal synaptic transmission study, we found that AGS did not affect I/O curves and PPF. However, AGS facilitated hippocampal LTP in a concentration-dependent manner. Moreover, AGS blocked AChE activity (IC50 = 485 µg/ml). Moreover, ACh level was increased by AGS (100 µg/ml) treatment. Along with this, facilitating effect of AGS on hippocampal LTP also blocked by scopolamine, a muscarinic acetylcholine receptor antagonist. Moreover, AGS also ameliorated memory impairments induced by scopolamine in passive avoidance, Y-maze, and Morris water maze tests. CONCLUSIONS: These results suggest that AGS facilitates hippocampal LTP through activating cholinergic system and ameliorates cholinergic dysfunction-induced memory deficit.

The Seed of Zizyphus jujuba var. spinosa Attenuates Alzheimer's Disease-Associated Hippocampal Synaptic Deficits through BDNF/TrkB Signaling.

Ziziphus jujuba is a plant, which bears fruits and seeds that are used for medicinal purposes in Traditional oriental medicine. The seed of Zizyphus jujuba var. spinosa (EZJ) has been also traditionally used for psychiatric disorders in Chinese and Korean medicines. Recent findings have indicated that EZJ improves memory impairment, a common symptom of various neurological diseases. However, the effects of EZJ on amyloid ß (Aß) toxicity, which is a main cause of Alzheimer's disease (AD), remain to be elucidated. To illuminate the potential anti-AD effect and mechanism in the mouse hippocampal tissue, we examined the effect of standardized EZJ on Aß-induced synaptic long-term potentiation (LTP) deficit in the hippocampal tissue. EZJ blocked Aß-induced LTP deficits in a concentration-dependent manner. Moreover, EZJ increased brain-derived neurotrophic factor (BDNF) level in naïve hippocampal slices. The finding that the blockade of BDNF receptor reduced the effect of EZJ suggests that EZJ ameliorates the Aß-induced LTP deficit through BDNF/topomyosin receptor kinase B (TrkB) signaling. However, transcription or translation inhibitors failed to block the effect of EZJ, suggesting that BDNF synthesis is not required for the action of EZJ on LTP. Finally, we found that EZJ stimulates plasmin activity. In contrast, plasmin inhibitor blocked the effect of EZJ on the Aß-induced LTP deficit. Our findings indicate that EZJ ameliorates Aß-induced LTP deficits through BDNF/TrkB signaling. This phenomenon is induced by a regulatory effect of EZJ on the post-translation modification of BDNF.

Clinical Characteristics and Treatment Outcomes of Patients with Acquired Macrolide-Resistant Mycobacterium abscessus Lung Disease.

Macrolide antibiotics are mainstays in the treatment of lung disease due to the Mycobacterium abscessus complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant Mycobacterium abscessus subsp. abscessus This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of M. abscessus subsp. abscessus We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant M. abscessus subsp. abscessus lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form of the disease, and two (15%) patients had the fibrocavitary form. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for M. abscessus subsp. abscessus, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range, 16.0 to 43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at position 2058 (n = 10) or 2059 (n = 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with M. abscessus subsp. abscessus lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant M. abscessus subsp. abscessus lung disease.

Ethanol extract of the seed of Zizyphus jujuba var. spinosa potentiates hippocampal synaptic transmission through mitogen-activated protein kinase, adenylyl cyclase, and protein kinase A pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: As the seed of Zizyphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow (Rhamnaceae) has been used to sleep disturbances in traditional Chinese and Korean medicine, many previous studies have focused on its sedative effect. AIM OF THE STUDY: Recently, we reported the neuroprotective effect of the effect of Z. jujuba var. spinosa. However, its effects on synaptic function have not yet been studied. In this project, we examined the action of ethanol extract of the seed of Z. jujuba var. spinosa (DHP1401) on synaptic transmission in the hippocampus. MATERIALS AND METHODS: To investigate the effects of DHP1401, field recordings were conducted using hippocampal slices (400µm). Object recognition test was introduced to examine whether DHP1401 affect normal recognition memory. RESULTS: DHP1401 (50µg/ml) induced a significant increase in synaptic activity in Shaffer collateral pathway in a concentration-dependent manner. This increase of synaptic responses was blocked by NBQX, a broad spectrum α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, but not IEM-1460, a Ca2+-permeable AMPAR blocker. Moreover, U0126, a mitogen-activated protein kinase inhibitor, SQ22536, an adenylyl cyclase inhibitor, and PKI, a protein kinase A inhibitor, blocked DHP1401-induced increase in synaptic transmission. Finally, DHP1401 facilitated object recognition memory. CONCLUSIONS: These results suggest that DHP1401 increase synaptic transmission through increase of synaptic AMPAR transmission via MAPK, AC and PAK.

Cassia obtusifolia seed ameliorates amyloid ß-induced synaptic dysfunction through anti-inflammatory and Akt/GSK-3ß pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Tea infused with the seed of Cassia obtusifolia has been traditionally used as an herbal remedy for liver, eye, and acute inflammatory diseases. Recent pharmacological reports have indicated that Cassiae semen has neuroprotective effects, attributable to its anti-inflammatory actions, in ischemic stroke and Parkinson's disease models. AIM OF THE STUDY: Previously, the ethanol extract of C. obtusifolia seeds (COE) was reported to have memory enhancing properties. However, the effects of COE in an Alzheimer's disease (AD) model are currently unknown. In this study, we investigated the effect(s) of COE on aberrant synaptic plasticity and memory impairment induced by amyloid ß (Aß), a key toxic component found in the AD brain. MATERIALS AND METHODS: To determine the effect of COE on Aß-induced aberrant synaptic plasticity, we used acute mouse hippocampal slices and delivered theta burst stimulation to induce long-term potentiation (LTP). Western blots were used to detect Aß- and/or COE-induced changes in signaling proteins. The novel object location recognition test was conducted to determine the effect of COE on Aß-induced recognition memory impairment. RESULTS: COE was found to ameliorate Aß-induced LTP impairment in the acute hippocampal slices. Glycogen synthase kinase-3ß (GSK-3ß), a key molecule in LTP impairment, was activated by Aß. However, this process was inhibited by COE via Akt signaling. Moreover, COE was found to attenuate Aß-induced microglia, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX) activation. In the in vivo studies performed, COE ameliorated the Aß-induced object recognition memory impairment. CONCLUSION: These results suggest that COE exhibits neuroprotective activities against Aß-induced brain disorders.

Danggui-Jakyak-San enhances hippocampal long-term potentiation through the ERK/CREB/BDNF cascade.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui-Jakyak-San (DJS), a traditional herbal prescription, has long been used to treat gerontological disorders due to insufficient blood supply. AIM OF THE STUDY: Previously, we reported that DJS increased hippocampal neurogenesis and enhanced learning and memory. However, the precise mechanism of DJS and its effects on learning and memory are still not well understood. In this study, we investigated the effect of DJS on hippocampal long-term potentiation (LTP), a cellular mechanism thought to underlie learning and memory. MATERIALS AND METHODS: To understand the effect of DJS on LTP, we used acute mouse hippocampal slices and delivered one train of high frequency stimulation (100 Hz, 100 pulses). Western blots were used to analyze the changes in protein levels induced by DJS. Morris water maze test was used to evaluate the effect of DJS on spatial long-term memory. RESULTS: DJS enhanced LTP in the Schaffer-collateral pathway of the hippocampus in a concentration-dependent manner. Extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) were activated by DJS. Moreover, brain-derived neurotropic factor (BDNF) was also increased by DJS. Blockade of ERK1/2 activation with PD198306 blocked the DJS-induced activation of the ERK1/2/CREB/BDNF cascade and LTP enhancement. In vivo, DJS improved spatial long-term memory and upregulated the hippocampal CREB/BDNF cascade. CONCLUSION: These results suggest that DJS enhances hippocampal LTP and spatial memory through the ERK/CREB/BDNF cascade.

Involvement of histaminergic system in the anxiolytic-like activities of Morus alba leaves in mice.

The aim of this study was to identify the effects of 85% methanolic extract of Morus alba leaves (EMA), which is a traditional herb, in mice. The effects of EMA on the anxiolytic-like behaviour were studied using the elevated plus maze (EPM) and hole-board test. To elucidate the mode of action of the anxiolytic-like effects of EMA, the mice were subjected to the co-administration of EMA (200 mg/kg, per os (p.o.)) and either antagonist. EMA (at 200 or 400 mg/kg) significantly increased the percentages of time-spent in the open arms and entries into the open arms of the EPM versus vehicle-treated control group (p<0.05). Moreover, in the hole-board test, EMA (200 and 400 mg/kg) significantly increased the number of head-dips versus vehicle-treated control group (p<0.05). However, there were no changes in the locomotor activity and myorelaxant effects in any group compared with the vehicle-treated control group. In addition, the anxiolytic-like effects of EMA were abolished by thioperamide (10 mg/kg, intraperitoneally (i.p.)), which is a histamine H3 receptor antagonist. Moreover, results from reverse transcription polymerase chain reaction (RT-PCR) also revealed that the amygdalal histidine decarboxylase mRNA expression levels in EMA (200 mg/kg)-treated group were significantly higher than those in the vehicle-treated controls (p<0.05). These results suggest that EMA might prove to be an effective anxiolytic agent and that EMA acts via the histaminergic system in central nerve system.

Downregulation of pro-inflammatory mediators by a water extract of Schisandra chinensis (Turcz.) Baill fruit in lipopolysaccharide-stimulated RAW 264.7 macrophage cells.

Schisandra chinensis has a long-standing history of medicinal use as a tonic, a sedative, an anti-tussive, and an anti-aging drug. Nevertheless, the antagonistic effects of S. chinensis against lipopolysaccharide (LPS)-stimulated responses have not yet been studied. In this study, we investigated whether water extract of S. chinensis fruit (WESC) has the ability to attenuate the expression of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α) in LPS-stimulated RAW 264.7 macrophage cells. WESC inhibited the expression of LPS-induced pro-inflammatory mediators, namely, NO, PGE2, and TNF-α. Furthermore, gene expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α was inhibited both at mRNA and protein synthesis levels, without any cytotoxic effect. Moreover, WESC significantly suppressed LPS-induced DNA-binding activity of NF-κB by inhibiting degradation of IκBα. It was found that pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor, downregulates the expression of these pro-inflammatory genes to be closely regulated by NF-κB activity. Furthermore, we found that WESC retains dephosphorylation of Akt in response to LPS, and consequently suppressed the DNA-binding activity of NF-κB in RAW 264.7 macrophage cells. LY294002, a specific Akt inhibitor, attenuated LPS-induced pro-inflammatory gene expression via suppression of NF-κB activity. Taken together, our results indicate that WESC downregulates the expression of pro-inflammatory genes involved in the synthesis of NO, PGE2, and TNF-α in LPS-stimulated RAW 264.7 macrophage cells by suppressing Akt-dependent NF-κB activity.

Treatment of refractory Mycobacterium avium complex lung disease with a moxifloxacin-containing regimen.

Moxifloxacin (MXF) has in vitro and in vivo activity against Mycobacterium avium complex (MAC) in experimental models. However, no data are available concerning its treatment effect in patients with MAC lung disease. The aim of this study was to evaluate the clinical efficacy of an MXF-containing regimen for the treatment of refractory MAC lung disease. Patients with MAC lung disease who were diagnosed between January 2002 and December 2011 were identified from our hospital database. We identified 41 patients who received MXF for ≥ 4 weeks for the treatment of refractory MAC lung disease. A total of 41 patients were treated with an MXF-containing regimen because of a persistent positive culture after at least 6 months of clarithromycin-based standardized antibiotic therapy. The median duration of antibiotic therapy before MXF administration was 410 days (interquartile range [IQR], 324 to 683 days). All patients had culture-positive sputum when MXF treatment was initiated. The median duration of MXF administration was 332 days (IQR, 146 to 547 days). The overall treatment success rate was 29% (12/41), and the median time to sputum conversion was 91 days (IQR, 45 to 190 days). A positive sputum acid-fast-bacillus smear at the start of treatment with MXF-containing regimens was an independent predictor of an unfavorable microbiological response. Our results indicate that MXF may improve treatment outcomes in about one-third of patients with persistently culture-positive MAC lung disease who fail to respond to clarithromycin-based standardized antibiotic treatment. Prospective studies are required to assess the clinical efficacy of MXF treatment for refractory MAC lung disease.

Water extract of processed Hydrangea macrophylla (Thunb.) Ser. leaf attenuates the expression of pro-inflammatory mediators by suppressing Akt-mediated NF-κB activation.

Although Hydrangea macrophylla is native to Northeast Asia and widely cultivated in many parts of the world, no studies on its anti-inflammatory effects have been reported. In this study, we evaluated the anti-inflammatory effect of a water extract of processed H. macrophylla leaf (WH) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. WH inhibited the expression of LPS-stimulated pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α), as well as their regulatory genes inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α without any accompanying cytotoxicity. Moreover, WH significantly suppressed the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB), as well as the nuclear translocation of the NF-κB subunits, p65 and p50 by suppressing of IκBα phosphorylation and degradation. WH also increased Akt dephosphorylation, leading to the suppression of the DNA-binding activity of NF-κB in LPS-stimulated RAW264.7 macrophage cells. Our results indicate that WH downregulates the expression of pro-inflammatory mediators such as NO, PGE2, and TNF-α by suppressing the Akt-mediated NF-κB activity in LPS-stimulated RAW264.7 macrophage cells.

Prunella vulgaris attenuates prepulse inhibition deficit and attention disruption induced by MK-801 in mice.

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it has been traditionally used to treat inflammation or hypertension. In the present study, we investigated the effects of the ethanolic extract of the spikes of Prunella vulgaris var. lilacina (EEPV) on dizocilpine (MK-801)-induced schizophrenia-like phenotype behaviors such as the disruption of prepulse inhibition and attention deficits in mice. We also determined the effect of EEPV on MK-801-induced alterations in phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phospho-glycogen synthase kinase 3-ß, and phosphorylated cAMP response element-binding protein levels in the cortex and hippocampus of mice. MK-801-induced prepulse inhibition deficits were ameliorated by the administration of EEPV, as shown in the acoustic startle response test. Furthermore, EEPV attenuated the MK-801-induced attention deficits in the water finding test. We also found that EEPV attenuated the increased phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, or phospho-glycogen synthase kinase 3-ß levels induced by MK-801 in the cortex but not in the hippocampus. These results suggest that EEPV could be useful for treating schizophrenia because EEPV ameliorates prepulse inhibition disruption and attention deficits induced by MK-801.

Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients.

RATIONALE: The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established. OBJECTIVES: To assess the efficacy of a standardized combination antibiotic therapy for the treatment of M. abscessus lung disease. METHODS: Sixty-five patients (11 males, 55 females, median age 55 yr) with M. abscessus lung disease were treated with clarithromycin, ciprofloxacin, and doxycycline, together with an initial regimen of amikacin and cefoxitin for the first 4 weeks of hospitalization. MEASUREMENTS AND MAIN RESULTS: Treatment response rates were 83% for symptoms and 74% for high-resolution computed tomography. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. These rates were significantly lower in patients whose isolates were resistant to clarithromycin (17%, 2/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (64%, 21/33; P = 0.007). Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days. CONCLUSIONS: Standardized combination antibiotic therapy was moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential for long-duration hospitalization are important problems that remain to be solved.