Circuit Techniques to Improve Low-Light Characteristics and High-Accuracy Evaluation System for CMOS Image Sensor.

The surveillance cameras we focus on target the volume zone, and area reduction is a top priority. However, by simplifying the ADC comparator, we face a new RUSH current issue, for which we propose a circuit solution. This paper proposes two novel techniques of column-ADC for surveillance cameras to improve low-light characteristics. RUSH current compensation reduces transient current consumption fluctuations during AD conversion and utilizing timing shift ADCs decreases the number of simultaneously operating ADCs. These proposed techniques improve low-light characteristics because they reduce the operating noise of the circuit. In order to support small signal measurement, this paper also proposes a high-accuracy evaluation system that can measure both small optical/electrical signals in low-light circumstances. To demonstrate these proposals, test chips were fabricated using a 55 nm CIS process and their optical/electrical characteristics were measured. As a result, low-light linearity as optical characteristics were reduced by 63% and column interference (RUSH current) as an electrical characteristic was also reduced by 50%. As for the high-accuracy evaluation system, we confirmed that the inter-sample variation of column interference was 0.05 LSB. This ADC achieved a figure-of-merit (FoM) of 0.32 e-·pJ/step, demonstrating its usefulness for other ADC architectures while using a single-slope-based simple configuration.

Coronary artery aneurysm complicated by pneumothorax with a history of Kawasaki disease.

Kawasaki disease (KD) is a common vasculitis disorder of childhood. It can sometimes complicate coronary artery aneurysms, and treatment is required depending on the condition of stenosis. A 20-year-old man was referred for surgery with a coronary artery aneurysm and stenosis in the left coronary artery as sequelae of KD. He had a surgical history of left pneumothorax and bullae remaining on the right lung. We simultaneously performed off-pump coronary artery bypass for coronary artery stenosis and bullectomy. Coronary artery aneurysms with KD complicated by pneumothorax are rare, and we treated them using one-stage surgery.

Assessment of Long-term Depression Induction in Adult Cerebellar Slices.

Synaptic plasticity provides a mechanism for learning and memory. For cerebellar motor learning, long-term depression (LTD) of synaptic transmissions from parallel fibers (PF) to Purkinje cells (PC) is considered the basis for motor learning, and deficiencies of both LTD and motor learning are observed in various gene-manipulated animals. Common motor learning sets, such as adaptation of the optokinetic reflex (OKR), the vestibular-ocular reflex (VOR), and rotarod test were used for evaluation of motor learning ability. However, results obtained from the GluA2-carboxy terminus modified knock-in mice demonstrated normal adaptation of the VOR and the OKR, despite lacking PF-LTD. In that report, induction of LTD was only attempted using one type of stimulation protocol at room temperature. Thus, conditions to induce cerebellar LTD were explored in the same knock-in mutants using various protocols at near physiological temperature. Finally, we found stimulation protocols, by which LTD could be induced in these gene-manipulated mice. In this study, a set of protocols are proposed to evaluate LTD-induction, which will more accurately allow examination of the causal relationship between LTD and motor learning. In conclusion, experimental conditions are crucial when evaluating LTD in gene-manipulated mice.

Dramatic response to nivolumab after local radiotherapy in pulmonary pleomorphic carcinoma with rapid progressive post-surgical recurrence.

Pulmonary pleomorphic carcinoma (PPC) is resistant to anticancer drug treatment, outcomes are poor, and no standard therapy has been established. High PD-L1 expression has been found in PPCs, suggesting the possible efficacy of an immune checkpoint inhibitor (ICI) in cancer immunotherapy; however, this approach requires further investigation through case accumulation. Herein, we report a case of rapid recurrence and progression of PPC early after surgery in a 70-year-old male ex-smoker. Surgery was performed for lung cancer of the right lower lobe, and a pathological examination indicated primary PPC with high PD-L1 expression (tumor proportion score: 90%). Because systemic metastasis recurred only six weeks after surgery, nivolumab was administered as second-line treatment. Marked tumor regression was observed on imaging after three cycles, revealing a near complete response. Palliative radiotherapy was applied to the bone metastasis region for pain relief before nivolumab was administered. This case suggests that an ICI can have an effect on PPC and that the efficacy of ICIs may be enhanced by radiotherapy-induced abscopal effects.

Sudden Death Due to Recent Hemorrhage From an Intrathoracic Chronic Expanding Hematoma.

Chronic expanding hematoma (CEH) is a rare disease that can develop in any region of the body, but it most frequently develops in the thorax. When intrathoracic CEH is left untreated, gradually expanding hematoma can be life-threatening, leading to respiratory failure or hemoptysis. We encountered an 89-year-old man with cardiopulmonary arrest on arrival. He had been healthy, and it was unclear whether CEH had previously been detected. A very large mass was observed on chest computed tomography (CT), but the cause of death could not be determined. In the autopsy, this mass was identified as CEH and no malignant findings were noted. A fresh hemorrhage had occurred in the hematoma and perforated the bronchial lumen, which caused airway obstruction/asphyxia and resulted in sudden death. CEH should be suspected when a very large tumorous lesion occupying the entire hemithorax is observed on chest imaging, and it is important to recognize that sudden death can occur in the natural course of CEH.

Tandem internal models execute motor learning in the cerebellum.

In performing skillful movement, humans use predictions from internal models formed by repetition learning. However, the computational organization of internal models in the brain remains unknown. Here, we demonstrate that a computational architecture employing a tandem configuration of forward and inverse internal models enables efficient motor learning in the cerebellum. The model predicted learning adaptations observed in hand-reaching experiments in humans wearing a prism lens and explained the kinetic components of these behavioral adaptations. The tandem system also predicted a form of subliminal motor learning that was experimentally validated after training intentional misses of hand targets. Patients with cerebellar degeneration disease showed behavioral impairments consistent with tandemly arranged internal models. These findings validate computational tandemization of internal models in motor control and its potential uses in more complex forms of learning and cognition.

Tuberculous pleurisy mimicking Mycoplasma pneumoniae infection in a previously healthy young adult: A case report.

RATONALE: Sometimes, pleural effusion accompanying an acute Mycoplasma pneumoniae infection or tuberculous pleurisy has similar analysis results. We report a case of tuberculous pleurisy which was initially diagnosed as acute M pneumoniae infection, which is of special interest because anti-Mycoplasma antibody results were positive, which served as a red herring. PATIENT CONCERNS: A 20-year-old woman visited the outpatient emergency romm of our hospital for chief complaints of high fever, dry cough, and pleuralgia persiting for 2 days. Since anti-mycoplasma antibody test results were positive, we treated acute M pneumoniae infection and drained her pleural effusion. The condition tended to improve, but on day 16 postadmission, the acid-fast bacterial culture of the pleural effusion was positive for Mycobacterium tuberculosis. DIAGNOSES: Tuberculous pleurisy. INTERVENTIONS: After the diagnosis, the patient received antituberculous drugs. OUTCOMES: She completed treatment with no noticeable adverse events, and the right pleural effusion disappered and diffuse right pleural thickening improved. LESSONS: Exudative pleural effusion with lymphocyte dominance and a high adenosine deaminase level in M pneumoniae infection have been reported. Even though the condition suggests acute M pneumoniae infection, clinicians should be aware that tuberculous pleurisy and M pneumoniae infection can share similar clinical features, and should understand the usefulness and limitations of the anit-Mycoplasma antibody test.

Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus.

Long-term depression (LTD) of synaptic transmission from parallel fibers (PFs) to a Purkinje cell (PC) in the cerebellum has been considered to be a core mechanism of motor learning. Recently, however, discrepancies between LTD and motor learning have been reported in mice with a mutation that targeted the expression of PF-PC LTD by blocking AMPA-subtype glutamate receptor internalization regulated via the phosphorylation of AMPA receptors. In these mice, motor learning behavior was normal, but no PF-PC LTD was observed. We reexamined slices obtained from these GluA2 K882A and GluA2 Δ7 knockin mutants at 3-6 mo of age. The conventional protocols of stimulation did not induce LTD in these mutant mice, as previously reported, but surprisingly, LTD was induced using certain modified protocols. Such modifications involved increases in the number of PF stimulation (from one to two or five), replacement of climbing fiber stimulation with somatic depolarization (50 ms), filling a patch pipette with a Cs(+)-based solution, or extension of the duration of conjunction. We also found that intracellular infusion of a selective PKCα inhibitor (Gö6976) blocked LTD induction in the mutants, as in WT, suggesting that functional compensation occurred downstream of PKCα. The possibility that LTD in the mutants was caused by changes in membrane resistance, access resistance, or presynaptic property was excluded. The present results demonstrate that LTD is inducible by intensified conjunctive stimulations even in K882A and Δ7 mutants, indicating no contradiction against the LTD hypothesis of motor learning.

Oxalate nephropathy in free-living American bullfrog tadpoles.

In February 2014, wild American bullfrog Lithobates catesbeianus tadpoles from an artificial pond in the Kyusyu region, Japan, presented with coelomic and subcutaneous edema and erythema within the skin. A pathological examination of 57 tadpoles of American bullfrogs in the region was conducted to evaluate the disease. Crystal deposition of varying degrees was found in the kidneys of 35 tadpoles (61.4%). The crystals were transparent, pleomorphic in shape, highly birefringent in polarized light, and arranged in a radial pattern within the renal tubular lumen. Using Alizarin Red S stain and liquid chromatography, these crystals were identified as calcium oxalate. Severe coelomic and subcutaneous edema was observed in 7 of these 35 tadpoles (20.0%). Ammonia levels in coelomic fluid were extremely elevated (>1000 µg dl(-1)) in 4 tadpoles examined. These findings suggest that oxalate deposition in kidneys causes metabolic disorder with renal nephropathy. The source of the oxalate could not be determined; however, the presence of calcium oxalates in pond sediments, as revealed by liquid chromatography, suggested that the deposition was most likely due to ingestion of oxalate materials from the environment. This is the first report of oxalate nephropathy in free-living amphibians.

Synergistic regulation of cerebellar Purkinje neuron development by laminin epitopes and collagen on an artificial hybrid matrix construct.

The extracellular matrix (ECM) creates a dynamic environment around the cells in the developing central nervous system, providing them with the necessary biochemical and biophysical signals. Although the functions of many ECM molecules in neuronal development have been individually studied in detail, the combinatorial effects of multiple ECM components are not well characterized. Here we demonstrate that the expression of collagen and laminin-1 (lam-1) are spatially and temporally correlated during embryonic and post-natal development of the cerebellum. These changes in ECM distribution correspond to specific stages of Purkinje neuron (PC) migration, somatic monolayer formation and polarization. To clarify the respective roles of these ECM molecules on PC development, we cultured cerebellar neurons on a hybrid matrix comprised of collagen and a synthetic peptide amphiphile nanofiber bearing a potent lam-1 derived bioactive IKVAV peptide epitope. By systematically varying the concentration and ratio of collagen and the laminin epitope in the matrix, we could demonstrate a synergistic relationship between these two ECM components in controlling multiple aspects of PC maturation. An optimal ratio of collagen and IKVAV in the matrix was found to promote maximal PC survival and dendrite growth, while dendrite penetration into the matrix was enhanced by a high IKVAV to collagen ratio. In addition, the laminin epitope was found to guide PC axon development. By combining our observations in vivo and in vitro, we propose a model of PC development where the synergistic effects of collagen and lam-1 play a key role in migration, polarization and morphological maturation of PCs.

Long-term depression as a model of cerebellar plasticity.

Long-term depression (LTD) here concerned is persistent attenuation of transmission efficiency from a bundle of parallel fibers to a Purkinje cell. Uniquely, LTD is induced by conjunctive activation of the parallel fibers and the climbing fiber that innervates that Purkinje cell. Cellular and molecular processes underlying LTD occur postsynaptically. In the 1960s, LTD was conceived as a theoretical possibility and in the 1980s, substantiated experimentally. Through further investigations using various pharmacological or genetic manipulations of LTD, a concept was formed that LTD plays a major role in learning capability of the cerebellum (referred to as "Marr-Albus-Ito hypothesis"). In this chapter, following a historical overview, recent intensive investigations of LTD are reviewed. Complex signal transduction and receptor recycling processes underlying LTD are analyzed, and roles of LTD in reflexes and voluntary movements are defined. The significance of LTD is considered from viewpoints of neural network modeling. Finally, the controversy arising from the recent finding in a few studies that whereas LTD is blocked pharmacologically or genetically, motor learning in awake behaving animals remains seemingly unchanged is examined. We conjecture how this mismatch arises, either from a methodological problem or from a network nature, and how it might be resolved.

Consensus paper: the cerebellum's role in movement and cognition.

While the cerebellum's role in motor function is well recognized, the nature of its concurrent role in cognitive function remains considerably less clear. The current consensus paper gathers diverse views on a variety of important roles played by the cerebellum across a range of cognitive and emotional functions. This paper considers the cerebellum in relation to neurocognitive development, language function, working memory, executive function, and the development of cerebellar internal control models and reflects upon some of the ways in which better understanding the cerebellum's status as a "supervised learning machine" can enrich our ability to understand human function and adaptation. As all contributors agree that the cerebellum plays a role in cognition, there is also an agreement that this conclusion remains highly inferential. Many conclusions about the role of the cerebellum in cognition originate from applying known information about cerebellar contributions to the coordination and quality of movement. These inferences are based on the uniformity of the cerebellum's compositional infrastructure and its apparent modular organization. There is considerable support for this view, based upon observations of patients with pathology within the cerebellum.

Orexin-neuromodulated cerebellar circuit controls redistribution of arterial blood flows for defense behavior in rabbits.

We investigated a unique microzone of the cerebellum located in folium-p (fp) of rabbit flocculus. In fp, Purkinje cells were potently excited by stimulation of the hypothalamus or mesencephalic periaqueductal gray, which induced defense reactions. Using multiple neuroscience techniques, we determined that this excitation was mediated via beaded axons of orexinergic hypothalamic neurons passing collaterals through the mesencephalic periaqueductal gray. Axonal tracing studies using DiI and biotinylated dextran amine evidenced the projection of fp Purkinje cells to the ventrolateral corner of the ipsilateral parabrachial nucleus (PBN). Because, in defense reactions, arterial blood flow has been known to redistribute from visceral organs to active muscles, we hypothesized that, via PBN, fp adaptively controls arterial blood flow redistribution under orexin-mediated neuromodulation that could occur in defense behavior. This hypothesis was supported by our finding that climbing fiber signals to fp Purkinje cells were elicited by stimulation of the aortic nerve, a high arterial blood pressure, or a high potassium concentration in muscles, all implying errors in the control of arterial blood flow. We further examined the arterial blood flow redistribution elicited by electric foot shock stimuli in awake, behaving rabbits. We found that systemic administration of an orexin antagonist attenuated the redistribution and that lesioning of fp caused an imbalance in the redistribution between active muscles and visceral organs. Lesioning of fp also diminished foot shock-induced increases in the mean arterial blood pressure. These results collectively support the hypothesis that the fp microcomplex adaptively controls defense reactions under orexin-mediated neuromodulation.

Error detection and representation in the olivo-cerebellar system.

Complex spikes generated in a cerebellar Purkinje cell via a climbing fiber have been assumed to encode errors in the performance of neuronal circuits involving Purkinje cells. To reexamine this notion in this review, I analyzed structures of motor control systems involving the cerebellum. A dichotomy was found between the two types of error: sensory and motor errors play roles in the feedforward and feedback control conditions, respectively. To substantiate this dichotomy, here in this article I reviewed recent data on neuronal connections and signal contents of climbing fibers in the vestibuloocular reflex (VOR), optokinetic eye movement response, saccade, hand reaching, cursor tracking, as well as some other cases of motor control. In our studies, various sources of sensory and motor errors were located in the neuronal pathways leading to the inferior olive. We noted that during the course of evolution, control system structures involving the cerebellum changed rather radically from the prototype seen in the flocculonodular lobe and vermis to that applicable to the cerebellar hemisphere. Nevertheless, the dichotomy between sensory and motor errors is maintained.

Cryptic bumblebee species: consequences for conservation and the trade in greenhouse pollinators.

Commercial greenhouse growers in both Japan and China are increasingly using reared orange-tailed bumblebees known previously as Bombus hypocrita Pérez as pollinators. Phylogenetic analysis of the DNA (COI) barcodes with Bayesian methods shows that this "species" is a long-standing confusion of two cryptic species. We find that the orange-tailed bumblebees in North China are actually part of the widespread Russian (otherwise white-tailed) B. patagiatus Nylander (as B. patagiatus ganjsuensis Skorikov, n. comb.), whereas the orange-tailed bees in Japan are true B. hypocrita. This situation has been further complicated because two other cryptic species from North China that were previously confused with the Russian B. patagiatus are now recognised as separate: B. lantschouensis Vogt n. stat. and B. minshanensis Bischoff n. stat.. As demand for pollination services by greenhouse growers inevitably increases, these bees are more likely to be transported between countries. In order to conserve genetic resources of pollinator species for their option value for future food security, we advocate preventing trade and movement of B. patagiatus from China into Japan and of B. hypocrita from Japan into China.

In vitro and in vivo transdermal iontophoretic delivery of naloxone, an opioid antagonist.

AIM: The feasibility of transdermal delivery of naloxone, an opioid antagonist, by anodal iontophoresis patches using Ag/AgCl electrodes was investigated. METHODS: To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24h. RESULTS: The in vitro steady-state skin permeation flux of naloxone current-proportionally (0-360 µA/cm(2)) increased without significant differences between these two different skin types. The in vitro delivery rate through the porcine skin was found to be independent of the concentration of naloxone hydrochloride dehydrate in the donor patch over the range from 1 to 10% (w/v). In the in vivo pharmacokinetic study, plasma concentrations of naloxone steadily increased and sustained steady-state levels from 4h to 24h after the initiation of current application. In vivo steady-state transdermal absorption rates at 90 and 180 µA/cm(2) were 136 and 305 µg/h/cm(2), respectively. CONCLUSION: These results suggest that the transdermal delivery rates of naloxone by anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients.

A hybrid nanofiber matrix to control the survival and maturation of brain neurons.

Scaffold design plays a crucial role in developing graft-based regenerative strategies, especially when intended to be used in a highly ordered nerve tissue. Here we describe a hybrid matrix approach, which combines the structural properties of collagen (type I) with the epitope-presenting ability of peptide amphiphile (PA) nanofibers. Self-assembly of PA and collagen molecules results in a nanofibrous scaffold with homogeneous fiber diameter of 20-30 nm, where the number of laminin epitopes IKVAV and YIGSR can be varied by changing the PA concentrations over a broad range of 0.125-2 mg/ml. Granule cells (GC) and Purkinje cells (PC), two major neuronal subtypes of cerebellar cortex, demonstrate distinct response to this change of epitope concentration. On IKVAV hybrid constructs, GC density increases three-fold compared with the control collagen substrate at a PA concentration of ≥0.25 mg/ml, while PC density reaches a maximum (five-fold vs. control) at 0.25 mg/ml of PA and rapidly decreases at higher PA concentrations. In addition, adjustment of the epitope number allowed us to achieve fine control over PC dendrite and axon growth. Due to the ability to modulate neuron survival and maturation by easy manipulation of epitope density, our design offers a versatile test bed to study the extracellular matrix (ECM) contribution in neuron development and the design of optimal neuronal scaffold biomaterials.

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic.

OBJECTIVES: The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. METHODS: To examine the effect of species variation and current strength on skin permeability of tramadol, in-vitro skin permeation studies were performed using porcine ear skin, guinea-pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in-vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm(2)) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. KEY FINDINGS: The in-vitro steady-state skin permeation flux of tramadol current-dependently increased without significant differences among the three different skin types. In the in-vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in-vivo steady-state transdermal absorption rate was 499 µg/cm(2) per h as calculated by a constrained numeric deconvolution method. CONCLUSIONS: The present study reveals that anodal iontophoresis provides current-controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.

Evolutionarily conserved bias of amino-acid usage refines the definition of PDZ-binding motif.

BACKGROUND: The interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. However, it remains little explored whether PDZ-binding motifs show any preferential location at the C-terminal ends of proteins, at genome-level. RESULTS: Here, we examined the distribution of the type-I (x-x-S/T-x-I/L/V) or type-II (x-x-V-x-I/V) PDZ-binding motifs in proteins encoded in the genomes of five different species (human, mouse, zebrafish, fruit fly and nematode). We first established that these PDZ-binding motifs are indeed preferentially present at their C-terminal ends. Moreover, we found specific amino acid (AA) bias for the 'x' positions in the motifs at the C-terminal ends. In general, hydrophilic AAs were favored. Our genomics-based findings confirm and largely extend the results of previous interaction-based studies, allowing us to propose refined consensus sequences for all of the examined PDZ-binding motifs. An ontological analysis revealed that the refined motifs are functionally relevant since a large fraction of the proteins bearing the motif appear to be involved in signal transduction. Furthermore, co-precipitation experiments confirmed two new protein interactions predicted by our genomics-based approach. Finally, we show that influenza virus pathogenicity can be correlated with PDZ-binding motif, with high-virulence viral proteins bearing a refined PDZ-binding motif. CONCLUSIONS: Our refined definition of PDZ-binding motifs should provide important clues for identifying functional PDZ-binding motifs and proteins involved in signal transduction.