L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

A Passive Tracking System Based on Geometric Constraints in Adaptive Wireless Sensor Networks.

Target tracking technologies in wireless sensor network (WSNs) environments fall into two categories: active and passive schemes. Unlike with the active positioning schemes, in which the targets are required to hold cooperative devices, the research on passive tracking, i.e., tracking device-free targets, has recently showed promise. In the WSN, device-free targets can be tracked by sensing radio frequency tomography (RFT) on the line-of-sight links (LOSLs). In this paper, we propose a passive tracking scheme exploiting both adaptive-networking LOSL webs and geometric constraint methodology for tracking single targets, as well as multiple targets. Regarding fundamental knowledge, we firstly explore the spatial diversity technique for RFT detection in realistic situations. Then, we analyze the power consumption of the WSN and propose an adaptive networking scheme for the purpose of energy conservation. Instead of maintaining a fixed LOSL density, the proposed scheme can adaptively adjust the networking level to save energy while guaranteeing tracking accuracy. The effectiveness of the proposed scheme is evaluated with computer simulations. According to the results, it is observed that the proposed scheme can sufficiently reduce power consumption, while providing qualified tracking performance.

Causal Effect of Chondroitin, Glucosamine, Vitamin, and Mineral Intake on Kidney Function: A Mendelian Randomization Study.

The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a two-sample summary-level Mendelian randomization (MR) analysis to test for causal associations between regular dietary supplement intake and kidney function. Genetic instruments for chondroitin, glucosamine, and vitamin/mineral supplement intake were obtained from a genome-wide association study of European ancestry. Summary statistics for the log-transformed estimated glomerular filtration rate (log-eGFR) were provided by the CKDGen consortium. The multiplicative random-effects inverse-variance weighted method showed that genetically predicted chondroitin and glucosamine intake was causally associated with a lower eGFR (chondroitin, eGFR change beta = -0.113%, standard error (SE) = 0.03%, p-value = 2 × 10-4; glucosamine, eGFR change beta = -0.240%, SE = 0.035%, p-value = 6 × 10-12). However, a genetically predicted vitamin/mineral supplement intake was associated with a higher eGFR (eGFR change beta = 1.426%, SE = 0.136%, p-value = 1 × 10-25). Validation analyses and pleiotropy-robust MR results for chondroitin and vitamin/mineral supplement intake supported the main results. Our MR study suggests a potential causal effect of chondroitin and glucosamine intake on kidney function. Therefore, clinicians should carefully monitor their long-term effects.

Optimal target blood pressure for major adverse cardiovascular and cerebrovascular events in hypertensive patients: a nationwide population-based study.

BACKGROUND: Generalizing an 'optimal' blood pressure (BP) level for individuals with hypertension remains controversial due to the implementation of different medical guidelines. This study investigated the association of BP with major adverse cardiovascular and cerebrovascular events (MACCE) and determined the optimal BP for patients with hypertension. METHOD: A total of 934 179 individuals who received antihypertensive medications were selected from the National Health Insurance Service Examination Database between 2003 and 2011 in Korea. Their BP was measured at the index date, which was the first health examination. The study outcomes were MACCE, including acute myocardial infarction, heart failure, stroke, and all-cause mortality. The participants were monitored until in December, 2017. The hazard ratios were calculated using Cox proportional hazard models. The cumulative incidence of MACCE for each BP group was estimated using the Kaplan-Meier method. RESULTS: A lower risk of MACCE was observed at a SBP of 120-129 mmHg and a DBP of 80-89 mmHg. The endpoint-specific incidence rates and hazard ratios for acute myocardial infarction, heart failure, stroke, and all-cause mortality were the lowest at a SBP of 120-129 mmHg and a DBP of 80-89 mmHg. CONCLUSION: Even though this observational study did not support inference of a causal relationship, a SBP of 120-129 mmHg and a DBP of 80-89 mmHg may be safely recommended considering the possibility of MACCE in Korean patients with hypertension. In addition, the target BP should be tailored individually according to age, sex, and comorbidities.

A minimally invasive flexible electrode array for simultaneous recording of ECoG signals from multiple brain regions.

The minimal invasiveness of electrocorticography (ECoG) enabled its widespread use in clinical areas as well as in neuroscience research. However, most existing ECoG arrays require that the entire surface area of the brain that is to be recorded be exposed through a large craniotomy. We propose a device that overcomes this limitation, i.e., a minimally invasive, polyimide-based flexible array of electrodes that can enable the recording of ECoG signals in multiple regions of the brain with minimal exposure of the surface of the brain. Magnetic force-assisted positioning of a flexible electrode array enables recording from distant brain regions with a small cranial window. Also, a biodegradable organic compound used for attaching a magnet on the electrodes allows simple retrieval of the magnet. We demonstrate with an in vivo chronic recording that an implanted ECoG electrode array can record ECoG signals from the visual cortex and the motor cortex during a rat's free behavior. Our results indicate that the proposed device induced minimal damage to the animal. We expect the proposed device to be utilized for experiments for large-scale brain circuit analyses as well as clinical applications for intra-operative monitoring of epileptic activity.

Causal Effects of Serum Levels of n-3 or n-6 Polyunsaturated Fatty Acids on Coronary Artery Disease: Mendelian Randomization Study.

We aimed to investigate the causal effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on the risk of coronary artery disease (CAD) through Mendelian randomization (MR) analysis. This MR study utilized a genetic instrument developed from previous genome-wide association studies for various serum n-3 and n-6 PUFA levels. First, we calculated the allele scores for genetic predisposition of PUFAs in individuals of European ancestry in the UK Biobank data (N = 337,129). The allele score-based MR was obtained by regressing the allele scores to CAD risks. Second, summary-level MR was performed with the CARDIoGRAMplusC4D data for CAD (N = 184,305). Higher genetically predicted eicosapentaenoic acid and dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD both in the allele-score-based and summary-level MR analyses. Higher allele scores for linoleic acid level were significantly associated with lower CAD risks, and in the summary-level MR, the causal estimates by the pleiotropy-robust MR methods also indicated that higher linoleic acid levels cause a lower risk of CAD. Arachidonic acid showed significant causal estimates for a higher risk of CAD. This study supports the causal effects of certain n-3 and n-6 PUFA types on the risk of CAD.

A MEMS ultrasound stimulation system for modulation of neural circuits with high spatial resolution in vitro.

Neuromodulation by ultrasound has recently received attention due to its noninvasive stimulation capability for treating brain diseases. Although there have been several studies related to ultrasonic neuromodulation, these studies have suffered from poor spatial resolution of the ultrasound and low repeatability with a fixed condition caused by conventional and commercialized ultrasound transducers. In addition, the underlying physics and mechanisms of ultrasonic neuromodulation are still unknown. To determine these mechanisms and accurately modulate neural circuits, researchers must have a precisely controllable ultrasound transducer to conduct experiments at the cellular level. Herein, we introduce a new MEMS ultrasound stimulation system for modulating neurons or brain slices with high spatial resolution. The piezoelectric micromachined ultrasonic transducers (pMUTs) with small membranes (sub-mm membranes) generate enough power to stimulate neurons and enable precise modulation of neural circuits. We designed the ultrasound transducer as an array structure to enable localized modulation in the target region. In addition, we integrated a cell culture chamber with the system to make it compatible with conventional cell-based experiments, such as in vitro cell cultures and brain slices. In this work, we successfully demonstrated the functionality of the system by showing that the number of responding cells is proportional to the acoustic intensity of the applied ultrasound. We also demonstrated localized stimulation capability with high spatial resolution by conducting experiments in which cocultured cells responded only around a working transducer.

Ultrasonic Neuromodulation via Astrocytic TRPA1.

Low-intensity, low-frequency ultrasound (LILFU) is the next-generation, non-invasive brain stimulation technology for treating various neurological and psychiatric disorders. However, the underlying cellular and molecular mechanism of LILFU-induced neuromodulation has remained unknown. Here, we report that LILFU-induced neuromodulation is initiated by opening of TRPA1 channels in astrocytes. The Ca2+ entry through TRPA1 causes a release of gliotransmitters including glutamate through Best1 channels in astrocytes. The released glutamate activates NMDA receptors in neighboring neurons to elicit action potential firing. Our results reveal an unprecedented mechanism of LILFU-induced neuromodulation, involving TRPA1 as a unique sensor for LILFU and glutamate-releasing Best1 as a mediator of glia-neuron interaction. These discoveries should prove to be useful for optimization of human brain stimulation and ultrasonogenetic manipulations of TRPA1.

Facile approach to synthesize highly fluorescent multicolor emissive carbon dots via surface functionalization for cellular imaging.

Luminescent nanomaterials are encouraging scaffolds for diverse applications such as chemical sensors and biosensors, imaging, drug delivery, diagnostics, catalysis, energy, photonics, medicine, and so on. Carbon dots (CDs) are a new class of luminescent carbonaceous nanomaterial that have appeared recently and reaped tremendous scientific interest. Herein, we have exploited a simple approach to prepare tuneable and highly fluorescent CDs via surface functionalization. The successful synthesis of CDs is manifested from several investigations like high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The CDs exhibit excellent water solubility and with increasing nitrogen content fluorescence quantum yield increases whereas cell toxicity decreases. The CD synthesized at high temperature (180 °C) shows very high quantum yield (more than 56%). The tuneable optical properties of CDs are systematically studied using UV-vis and fluorescence spectroscopy. The cell viability evaluation and in vitro imaging study reveals that the synthesized CDs can be employed as a potential fluorescent probe for bio-imaging without further modification.

Reduced Tacrolimus Trough Level Is Reflected by Estimated Glomerular Filtration Rate (eGFR) Changes in Stable Renal Transplantation Recipients: Results of the OPTIMUM Phase 3 Randomized Controlled Study.

BACKGROUND Minimizing the tacrolimus dosage in patients with stable allograft function needs further investigation. MATERIAL AND METHODS We performed an open-label, randomized, controlled study from 2010 to 2016 in 7 tertiary teaching hospitals in Korea and enrolled 345 kidney transplant recipients with a stable graft status. The study group received reduced-dose tacrolimus, 1080-1440 mg/day of enteric-coated mycophenolate sodium (EC-MPS), and corticosteroids. The control group received the standard tacrolimus dosage and 540-720 mg/day of EC-MPS with steroids. The primary endpoint was the mean estimated glomerular filtration rate (eGFR) and change in the eGFR at 12 months after randomization. RESULTS The mean tacrolimus trough level of the study group was 4.51±1.62 ng/mL, which was lower than that of the control group, at 6.75±2.82 ng/mL (P<0.001). The primary endpoint was better in the study group in terms of change in eGFR (P<0.001). The month 12 eGFRs were 73.6±28.4 and 68.3±18.1 mL/min/1.73 m² in the study and the control groups, respectively, but the difference did not reach statistical significance (P=0.07). The incidence of adverse events was similar between the study and the control groups. CONCLUSIONS Minimizing tacrolimus to a trough level below 5 ng/mL combined with conventional EC-MPS can be considered in patients with a steady follow-up, as it was associated with small benefits in the changes of the eGFR (Clinicaltrials.gov number: NCT01159080).

Amorphous Phosphorus-Incorporated Cobalt Molybdenum Sulfide on Carbon Cloth: An Efficient and Stable Electrocatalyst for Enhanced Overall Water Splitting over Entire pH Values.

The development of economical, proficient, and highly stable catalysts to substitute the expensive noble metal electrodes for electrocatalytic water-splitting applications is exceedingly desirable. In this context, the most fascinating and challenging approach is the rational design of a nanocomposite encompassing multiple components with unique functionalities. Herein, we describe the fabrication of a strongly catalytic and superb durable phosphorus-incorporated cobalt molybdenum sulfide electrocatalyst grown on carbon cloth (P-CoMoS/CC). The hybrid material exhibited excellent activity for hydrogen and oxygen evolution reactions over a wide range of pH (1-14) with extremely high stability (∼90% retention of the initial current density) after 24 h of electrolysis. Importantly, when P-CoMoS/CC was used as both cathode and anode for overall water splitting, a very low cell voltage of 1.54 V is required to attain the 10 mA cm-2 current density, and the hybrid material exhibited a long-term stability (89.8% activity retention after 100 h). The outstanding overall water-splitting performance compared to an electrolyzer consisting of the noble-metal-based catalysts Pt/C and RuO2 makes P-CoMoS one of the most efficient earth-abundant water-splitting catalysts. Phosphorus incorporation was proved to be a vital aspect for the improved charge-transfer properties and catalytic durability of the P-CoMoS/CC catalyst.

Graphene-Iodine Nanocomposites: Highly Potent Bacterial Inhibitors that are Bio-compatible with Human Cells.

Graphene-composites, capable of inhibiting bacterial growth which is also bio-compatible with human cells have been highly sought after. Here we report for the first time the preparation of new graphene-iodine nano-composites via electrostatic interactions between positively charged graphene derivatives and triiodide anions. The resulting composites were characterized by X-ray photoemission spectroscopy, UV-spectroscopy, Raman spectroscopy and Scanning electron microscopy. The antibacterial potential of these graphene-iodine composites against Klebsiella pneumonia, Pseudomonas aeruginosa, Proteus mirobilis, Staphylococcus aureus, and E. coli was investigated. In addition, the cytotoxicity of the nanocomposite with human cells [human white blood cells (WBC), HeLa, MDA-MB-231, Fibroblast (primary human keratinocyte) and Keratinocyte (immortalized fibroblast)], was assessed. DGO (Double-oxidizes graphene oxide) was prepared by the additional oxidation of GO (graphene oxide). This generates more oxygen containing functional groups that can readily trap more H(+), thus generating a positively charged surface area under highly acidic conditions. This step allowed bonding with a greater number of anionic triiodides and generated the most potent antibacterial agent among graphene-iodine and as-made povidone-iodine (PVP-I) composites also exhibited nontoxic to human cells culture. Thus, these nano-composites can be used to inhibit the growth of various bacterial species. Importantly, they are also very low-cytotoxic to human cells culture.

Applying the bacterial meningitis score in children with cerebrospinal fluid pleocytosis: a single center's experience.

PURPOSE: The widespread introduction of bacterial conjugate vaccines has decreased the risk of cerebrospinal fluid (CSF) pleocytosis due to bacterial meningitis (BM) in children. However, most patients with CSF pleocytosis are hospitalized and treated with parenteral antibiotics for several days. The bacterial meningitis score (BMS) is a validated multivariate model derived from a pediatric population in the postconjugate vaccine era and has been evaluated in several studies. In the present study, we examined the usefulness of BMS in South Korean patients. METHODS: This study included 1,063 patients with CSF pleocytosis aged between 2 months and 18 years. The BMS was calculated for all patients, and the sensitivity and negative predictive value (NPV) of the test were evaluated. RESULTS: Of 1,063 patients, 1,059 (99.6%) had aseptic meningitis (AM). Only four patients (0.4%) had BM. The majority of patients (98%) had a BMS of ≤1, indicating a diagnosis of AM. The BMS was 0 in 635 patients (60%) and 1 in 405 patients (38%). All four BM patients had a BMS of ≥4. CONCLUSION: To our knowledge, this is the first study to investigate the diagnostic strength of the BMS in South Korea. In our study, the BMS showed 100% sensitivity and 100% NPV. Therefore, we believe that the BMS is a good clinical prediction rule to identify children with CSF pleocytosis who are at a risk of BM.

Experience of meningovascular syphilis in human immunodeficiency virus infected patient.

Since the start of the antibiotic era, syphilis has become rare. However, in recent times, it has tended to be prevalent concomitantly with human immunodeficiency virus (HIV) infection and coinfection in North America and Europe. Now, such cases are expected to increase in elsewhere including Korea. A 40-year-old male patient visited hospital complaining of a headache for about one month. Brain computed tomography and magnetic resonance imaging, showed leptomeninged enhancing mass with edema an right porisylvian region, which was suspected to be glioma. Patient underwent a blood test and was diagnosed with syphilis and acquired immune deficiency syndrome. Partial cortical and subcortical resection were performed after small craniotomy. The dura was thick, adhered to the brain cortex, and was accompanied by hyperemic change of the cortex. The pathologic diagnosis was meningovascular syphilis (MS) in HIV infection. After the operation, the patient was treated with aqueous penicillin G. Thereafter, he had no neurological deficit except intermittent headache. At first, this case was suspected to be glioma, but it was eventually diagnosed as MS in HIV coinfection. At this point the case was judged to be worth reporting.

A morphometric aspect of the brachial plexus in the periclavicular region.

OBJECTIVE: The purpose of this study was to determine the normal morphometric landmarks of the uniting and dividing points of the brachial plexus (BP) in the periclavicular region to provide useful guidance in surgery of BP injuries. METHODS: A total of 20 brachial plexuses were obtained from 10 adult, formalin-fixed cadavers. Distances were measured on the basis of the Chassaignac tubercle (CT), and the most lateral margin of the BP (LMBP) crossing the superior and inferior edge of the clavicle. RESULTS: LMBP was located within 25 mm medially from the midpoint in all subjects. In the supraclavicular region, the upper trunk uniting at 21 +/- 7 mm from the CT, separating into divisions at 42 +/- 5 mm from the CT, and dividing at 19 +/- 4 mm from the LMBP crossing the superior edge of the clavicle. In the infraclavicular region, the distance from the inferior edge of the clavicle to the musculocutaneous nerve (MCN) origin was 49 +/- 1 mm, to the median nerve origin 57 +/- 7 mm, and the ulnar nerve origin 48 +/- 6 mm. From the lateral margin of the pectoralis minor to the MCN origin the distance averaged 3.3 +/- 10 mm. Mean diameter of the MCN was 4.3 +/- 1.1 mm (range, 2.5-6.0) in males (n = 6), and 3.1 +/- 1.5 mm (range, 1.6-4.0) in females (n = 4). CONCLUSION: We hope these data will aid in understanding the anatomy of the BP and in planning surgical treatment in BP injuries.

Fragile maintenance of allograft tolerance induced by lymphocyte sequestration and co-stimulation blockade.

The induction of long-term graft survival has been a goal for the last decade. Nevertheless, the issues of stable maintenance of allograft have not yet been evaluated thoroughly. Here, we studied new approaches for induction of tolerance by lymphocyte sequestration (FTY720) and co-stimulatory blockade (MR1) in skin graft model (DBA/2 to BALB/c), thus evaluating the mechanisms incorporated into the maintenance of allograft in proper function. FTY720+MR1 treatment significantly prolonged graft survival than single agent treatment did, and induced long-term graft survival in 60% of recipients expressing the up-regulation of IL-4 and FoxP3. To assess the stability of graft maintenance, we performed the second transplantation on recipients that had shown long-term graft survival. While recipients accepted the second graft from the same strain of first donor, the recipients not only rejected the third-party skin (C57BL/6) promptly but also rejected the first graft soon after the third-party skin was transplanted. The expression patterns of IL-4 and FoxP3 were changed according to the strains of second graft in lymph nodes and in the first graft. T(reg) cells from tolerant recipients effectively suppressed allo-antigen driven T cell proliferation, but T(reg) cells from recipients primed with third-party antigen had significantly hampered suppressive capacity against previously tolerant antigens. Our data indicate that the combination treatment provides effective tool for the induction of long-term graft survival, and the maintenance of allograft in proper function is an actively regulated process.