Two-dimensional heavy fermion in a monoatomic-layer Kondo lattice YbCu2.

The Kondo effect between localized f-electrons and conductive carriers leads to exotic physical phenomena. Among them, heavy-fermion (HF) systems, in which massive effective carriers appear due to the Kondo effect, have fascinated many researchers. Dimensionality is also an important characteristic of the HF system, especially because it is strongly related to quantum criticality. However, the realization of the perfect two-dimensional (2D) HF materials is still a challenging topic. Here, we report the surface electronic structure of the monoatomic-layer Kondo lattice YbCu2 on a Cu(111) surface observed by synchrotron-based angle-resolved photoemission spectroscopy. The 2D conducting band and the Yb 4f state, located very close to the Fermi level, are observed. These bands are hybridized at low-temperature, forming the 2D HF state, with an evaluated coherence temperature of about 30 K. The effective mass of the 2D state is enhanced by a factor of 100 by the development of the HF state. Furthermore, clear evidence of the hybridization gap formation in the temperature dependence of the Kondo-resonance peak has been observed below the coherence temperature. Our study provides a new candidate as an ideal 2D HF material for understanding the Kondo effect at low dimensions.

Mixtures of strategies underlie rodent behavior during reversal learning.

In reversal learning tasks, the behavior of humans and animals is often assumed to be uniform within single experimental sessions to facilitate data analysis and model fitting. However, behavior of agents can display substantial variability in single experimental sessions, as they execute different blocks of trials with different transition dynamics. Here, we observed that in a deterministic reversal learning task, mice display noisy and sub-optimal choice transitions even at the expert stages of learning. We investigated two sources of the sub-optimality in the behavior. First, we found that mice exhibit a high lapse rate during task execution, as they reverted to unrewarded directions after choice transitions. Second, we unexpectedly found that a majority of mice did not execute a uniform strategy, but rather mixed between several behavioral modes with different transition dynamics. We quantified the use of such mixtures with a state-space model, block Hidden Markov Model (block HMM), to dissociate the mixtures of dynamic choice transitions in individual blocks of trials. Additionally, we found that blockHMM transition modes in rodent behavior can be accounted for by two different types of behavioral algorithms, model-free or inference-based learning, that might be used to solve the task. Combining these approaches, we found that mice used a mixture of both exploratory, model-free strategies and deterministic, inference-based behavior in the task, explaining their overall noisy choice sequences. Together, our combined computational approach highlights intrinsic sources of noise in rodent reversal learning behavior and provides a richer description of behavior than conventional techniques, while uncovering the hidden states that underlie the block-by-block transitions.

KIF24 depletion induces clustering of supernumerary centrosomes in PDAC cells.

Clustering of supernumerary centrosomes, which potentially leads to cell survival and chromosomal instability, is frequently observed in cancers. However, the molecular mechanisms that control centrosome clustering remain largely unknown. The centrosomal kinesin KIF24 was previously shown to restrain the assembly of primary cilia in mammalian cells. Here, we revealed that KIF24 depletion suppresses multipolar spindle formation by clustering centrosomes in pancreatic ductal adenocarcinoma (PDAC) cells harboring supernumerary centrosomes. KIF24 depletion also induced hyper-proliferation and improved mitotic progression in PDAC cells. In contrast, disruption of primary cilia failed to affect the proliferation and spindle formation in KIF24-depleted cells. These results suggest a novel role for KIF24 in suppressing centrosome clustering independent of primary ciliation in centrosome-amplified PDAC cells.

Kinetics of Thallium-201 in Acute Phase of Myocardial Infarction: A Case Report.

BACKGROUND Thallium-201 has been widely used in clinical practice for the management of coronary heart disease, but little is known regarding its kinetics in the acute phase of myocardial infarction. CASE REPORT We report a 78-year-old man who developed acute inferior myocardial infarction during exercise thallium-201 scintigraphy. The patient underwent exercise testing with thallium-201 myocardial scintigraphy because of a single episode of chest pain. The workload was started with 25 watts and increased by 25 watts every 2 min on a bicycle ergometer with continuous monitoring of 12-lead electrocardiography. Thallium-201 was injected intravenously at 85% of the age-predicted maximal heart rate, and ST-segment elevations refractory to medication subsequently developed in the inferior leads, followed by chest pain. Scintigraphic image acquisition was deferred and he was transferred to the catheter laboratory in this hospital. Emergency coronary angiography showed occlusion in the right coronary artery, and stent implantation was successfully performed. The peak level of creatine kinase in the clinical course was 201 U/l. Scintigraphic images obtained 4 h after the onset of ST-segment elevation showed severely reduced activity in the left ventricular inferior wall, with partial redistribution 24 h later. Follow-up imaging performed 4 months later revealed increased accumulation of thallium-201 in the inferior wall. CONCLUSIONS Our case highlights the kinetics of thallium-201 during acute myocardial infarction.

Pharmacist's Intervention Considering the Prognosis for a Terminal Cancer Patient: A Case Report.

Prognostic prediction has been reported to affect the decision of doctors and non-physician health care providers such as nurses, social workers, pastors, and hospice volunteers on the selection of appropriate medical interventions. This was a case of a 65-year-old woman who presented with a poor oral intake. The patient had a history of sigmoid colon cancer with abdominal wall metastasis and peritoneal dissemination. On the day of admission, nausea, anorexia, and malaise were noted, requiring immediate intervention. The patient's prognosis was predicted using the Palliative Prognostic Index. The pharmacist suggested the use of dexamethasone tablets in order to alleviate the patient's symptoms. Indeed, the administration of dexamethasone alleviated the symptoms of nausea, loss of appetite, and malaise. To the best of our knowledge, this is the first case report to demonstrate that prognosis prediction is important not only for other medical staff but also for pharmacists when deciding the need to initiate a treatment and continue such treatment, and when providing pharmacist interventions.

Quantitative third-harmonic generation imaging of mouse visual cortex areas reveals correlations between functional maps and structural substrates.

The structure of brain regions is assumed to correlate with their function, but there are very few instances in which the relationship has been demonstrated in the live brain. This is due to the difficulty of simultaneously measuring functional and structural properties of brain areas, particularly at cellular resolution. Here, we performed label-free, third-harmonic generation (THG) microscopy to obtain a key structural signature of cortical areas, their effective attenuation lengths (EAL), in the vertical columns of functionally defined primary visual cortex and five adjacent visual areas in awake mice. EALs measured by THG microscopy in the cortex and white matter showed remarkable correspondence with the functional retinotopic sign map of each area. Structural features such as cytoarchitecture, myeloarchitecture and blood vessel architecture were correlated with areal EAL values, suggesting that EAL is a function of these structural features as an optical property of these areas. These results demonstrate for the first time a strong relationship between structural substrates of visual cortical areas and their functional representation maps in vivo. This study may also help in understanding the coupling between structure and function in other animal models as well as in humans.

The Bezold-Jarisch reflex in a patient with coronary spastic angina.

Acute inferior myocardial damage can induce transient bradycardia and hypotension-the Bezold-Jarisch reflex, which is explained by the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a 76-year-old man who showed a perfusion defect in the inferior wall with redistribution on exercise scintigraphy with thallium-201. Of note, during exercise at an intensity of 100 watts, the patient's heart rate transiently decreased from 122 to 95 bpm in sinus rhythm, accompanied by ST-segment depression. A diagnosis of coronary spastic angina was made since no stenotic lesions were observed on conventional coronary angiography.

Myocardial damage of the entire ventricular region in a patient with acute myocardial infarction.

 Technetium-99m-pyrophosphate (99mTc-PYP) has been used, in combination with thallium-201, to estimate the site and extent of myocardial infarcts. We report a case of acute myocardial infarction with severe coronary disease in which the distribution of 99mTc-PYP was extensive. A 78-year-old man presented with dyspnea, and a diagnosis of non-ST-segment elevation acute myocardial infarction was made. Emergency coronary angiography revealed total occlusion of the proximal portion of the right coronary artery and left circumflex coronary artery with collateral flow from the left anterior descending coronary artery, which also had severe stenoses. Given his comorbidities and preferences, subsequent angioplasty was waived. Dual myocardial scintigraphic imaging, which was performed four days after admission, demonstrated slightly reduced thallium-201 uptake in the inferior wall and apex, whereas 99mTc-PYP was positive in the entire left ventricular subendocardial region and the free wall of the right ventricle. His clinical course was uneventful with conservative treatment and the patient was discharged 20 days after admission in a stable condition.

A Case of Isolated Septal Myocardial Infarction: Myocardial Perfusion-metabolism Mismatch as a Tool for Diagnosis.

Isolated septal myocardial infarction is an uncommon condition with diagnostic difficulty due to small infarction size and anatomical variations. We report a case of isolated septal myocardial infarction, in which the diagnosis was confirmed not by electrocardiographic, echocardiographic, or angiographic findings, but by nuclear imaging. A 46-year-old man with chest discomfort exhibited ST-segment elevations in leads V1 and V2, and borderline abnormalities of the septal wall motion on echocardiography. Emergency coronary angiography demonstrated delayed flow in the second septal branch of the left anterior descending coronary artery. Intravascular ultrasound showed plaque in the proximal portion of the septal branch without evidence of plaque rupture. No balloon angioplasty or stent implantation was required because the flow delay in the septal branch disappeared after the intravascular ultrasound procedure. Myocardial perfusion-metabolism mismatch, as assessed by resting thallium-201 and iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid, was seen in the mid-septal region.

Functional imaging of visual cortical layers and subplate in awake mice with optimized three-photon microscopy.

Two-photon microscopy is used to image neuronal activity, but has severe limitations for studying deeper cortical layers. Here, we developed a custom three-photon microscope optimized to image a vertical column of the cerebral cortex > 1 mm in depth in awake mice with low (<20 mW) average laser power. Our measurements of physiological responses and tissue-damage thresholds define pulse parameters and safety limits for damage-free three-photon imaging. We image functional visual responses of neurons expressing GCaMP6s across all layers of the primary visual cortex (V1) and in the subplate. These recordings reveal diverse visual selectivity in deep layers: layer 5 neurons are more broadly tuned to visual stimuli, whereas mean orientation selectivity of layer 6 neurons is slightly sharper, compared to neurons in other layers. Subplate neurons, located in the white matter below cortical layer 6 and characterized here for the first time, show low visual responsivity and broad orientation selectivity.

Electrocardiographic changes as a marker of improved subendocardial ischemia in a patient with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) patients sometimes develop subendocardial ischemia without coronary artery stenosis. We report a case of non-obstructive HCM, in which electrocardiographic changes were observed with improvement of subendocardial ischemia. A 76-year-old man presented with chest pain on exertion. The electrocardiogram revealed left ventricular (LV) hypertrophy with repolarization abnormalities. No coronary stenosis was found on computed tomography angiography, but thallium-201 exercise scintigraphy revealed transient LV cavity dilation after exercise, consistent with subendocardial ischemia. His chest symptoms disappeared after starting verapamil. Transient LV cavity dilation improved without a reduction in exercise tolerance, as did electrocardiographic abnormalities without any changes on echocardiography.

Cell-specific modulation of plasticity and cortical state by cholinergic inputs to the visual cortex.

Acetylcholine (ACh) modulates diverse vital brain functions. Cholinergic neurons from the basal forebrain innervate a wide range of cortical areas, including the primary visual cortex (V1), and multiple cortical cell types have been found to be responsive to ACh. Here we review how different cell types contribute to different cortical functions modulated by ACh. We specifically focus on two major cortical functions: plasticity and cortical state. In layer II/III of V1, ACh acting on astrocytes and somatostatin-expressing inhibitory neurons plays critical roles in these functions. Cell type specificity of cholinergic modulation points towards the growing understanding that even diffuse neurotransmitter systems can mediate specific functions through specific cell classes and receptors.

Direct modulation of GFAP-expressing glia in the arcuate nucleus bi-directionally regulates feeding.

Multiple hypothalamic neuronal populations that regulate energy balance have been identified. Although hypothalamic glia exist in abundance and form intimate structural connections with neurons, their roles in energy homeostasis are less known. Here we show that selective Ca2+ activation of glia in the mouse arcuate nucleus (ARC) reversibly induces increased food intake while disruption of Ca2+ signaling pathway in ARC glia reduces food intake. The specific activation of ARC glia enhances the activity of agouti-related protein/neuropeptide Y (AgRP/NPY)-expressing neurons but induces no net response in pro-opiomelanocortin (POMC)-expressing neurons. ARC glial activation non-specifically depolarizes both AgRP/NPY and POMC neurons but a strong inhibitory input to POMC neurons balances the excitation. When AgRP/NPY neurons are inactivated, ARC glial activation fails to evoke any significant changes in food intake. Collectively, these results reveal an important role of ARC glia in the regulation of energy homeostasis through its interaction with distinct neuronal subtype-specific pathways.

Clinical features and treatment outcome of very elderly patients over 80 years old with multiple myeloma: comparison with patients in different age groups in the era of novel agents.

We retrospectively analyzed the outcomes of 175 consecutive patients admitted to our hospital between April 2004 and June 2014, and identified 42 (24%), 80 (46%), and 53 (30%) patients ≥ 80, 66-79, and ≤ 65 years old, respectively. The median progression-free survival (PFS) and overall survival (OS) of the ≥ 80, 66-79, and ≤ 65 years old groups were 19.1, 26.3, and 54.3 months, and 31.9, 54.8, and 83.8 months, respectively. Patients ≥ 80 but not ≤ 79 years old with ECOG performance score (PS) ≥ 3 and/or Charlson comorbidity index (CCI) ≥ 5 showed significantly shorter survival. ECOG PS and CCI predicted the treatment outcome of patients ≥ 80 but did not predict ≤ 79 years old.

An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity.

Cholinergic modulation of cortex powerfully influences information processing and brain states, causing robust desynchronization of local field potentials and strong decorrelation of responses between neurons. We found that intracortical cholinergic inputs to mouse visual cortex specifically and differentially drive a defined cortical microcircuit: they facilitate somatostatin-expressing (SOM) inhibitory neurons that in turn inhibit parvalbumin-expressing inhibitory neurons and pyramidal neurons. Selective optogenetic inhibition of SOM responses blocked desynchronization and decorrelation, demonstrating that direct cholinergic activation of SOM neurons is necessary for this phenomenon. Optogenetic inhibition of vasoactive intestinal peptide-expressing neurons did not block desynchronization, despite these neurons being activated at high levels of cholinergic drive. Direct optogenetic SOM activation, independent of cholinergic modulation, was sufficient to induce desynchronization. Together, these findings demonstrate a mechanistic basis for temporal structure in cortical populations and the crucial role of neuromodulatory drive in specific inhibitory-excitatory circuits in actively shaping the dynamics of neuronal activity.

Spatial Attention and Temporal Expectation Under Timed Uncertainty Predictably Modulate Neuronal Responses in Monkey V1.

The brain uses attention and expectation as flexible devices for optimizing behavioral responses associated with expected but unpredictably timed events. The neural bases of attention and expectation are thought to engage higher cognitive loci; however, their influence at the level of primary visual cortex (V1) remains unknown. Here, we asked whether single-neuron responses in monkey V1 were influenced by an attention task of unpredictable duration. Monkeys covertly attended to a spot that remained unchanged for a fixed period and then abruptly disappeared at variable times, prompting a lever release for reward. We show that monkeys responded progressively faster and performed better as the trial duration increased. Neural responses also followed monkey's task engagement-there was an early, but short duration, response facilitation, followed by a late but sustained increase during the time monkeys expected the attention spot to disappear. This late attentional modulation was significantly and negatively correlated with the reaction time and was well explained by a modified hazard function. Such bimodal, time-dependent changes were, however, absent in a task that did not require explicit attentional engagement. Thus, V1 neurons carry reliable signals of attention and temporal expectation that correlate with predictable influences on monkeys' behavioral responses.

oligoclonal bands in patients with multiple myeloma: its emergence per se could not be translated to improved survival.

The emergence of oligoclonal bands (OB) has been reported in patients with multiple myeloma (MM) after stem cell transplantation (SCT) or successful chemotherapy. However, their clinical relevance remains unclear. We reviewed the clinical records of MM patients from January 2006 to May 2014. Treatment response was evaluated by International Working Group (IMWG) criteria. Serum immunofixation tests were performed at least every 3 months if the patient achieved more than very good partial response (VGPR). Free light chain (FLC) and minimal residual disease measurement by multicolor flow cytometry (MFC) were performed to evaluate the response to treatment. Among the 163 patients included in the study, 40 developed OB. Detection rates of OB in patients with complete response (CR), VGPR and partial response (PR) or less were 51.8, 36.3 and 0%, respectively. Patients with OB showed better progression-free survival (PFS) and overall survival (OS) rates than those without OB (P = 0.028 and P < 0.001, respectively). However, if the patients were limited to ≥VGPR or CR, development of OB did not affect PFS (P = 0.621 and P = 0.646, respectively) or OS (P = 0.189 and P = 0.766, respectively). OB was observed in 60% of patients after SCT, and in 36.6% of patients with more than VGPR without SCT (P < 0.001). Patients with OB tended to have less minimal residual disease than those without OB (P = 0.054) and its presence may affect the stringent CR criteria. In conclusion, the emergence of OB was seen exclusively in patients with favorable responses, but its emergence per se could not be translated to improved survival.

Vagal enhancement linking abnormal blood pressure response and subendocardial ischemia in hypertrophic cardiomyopathy.

An abnormal blood pressure response to exercise has been reported to be associated with left ventricular subendocardial ischemia in patients with hypertrophic cardiomyopathy (HCM), but the underlying mechanism remains unclear. We report a case of HCM with an abnormal blood pressure response and subendocardial ischemia, in which the analysis of heart rate variability revealed exercise-induced vagal enhancement. The present case highlights the possible mechanism linking abnormal blood pressure response and left ventricular subendocardial ischemia in patients with HCM.

Serial Myocardial Imaging after a Single Dose of Thallium-201.

Although thallium-201 exercise scintigraphy has been established for the detection of myocardial ischemia and viability, little is known regarding the myocardial thallium-201 kinetics during angioplasty. Herein, we report a 77-year-old man with angina pectoris, in whom serial myocardial imaging after a single dose of thallium-201 was helpful in identifying not only the culprit lesion and myocardial viability, but also the dynamic changes in myocardial perfusion during angioplasty. Thallium-201 images after exercise showed a perfusion defect in the inferior wall, with a trivial redistribution 3 hours after the exercise and a marked improvement 24 hours later. Coronary angiography, performed 27 hours after exercise scintigraphy, showed severe stenosis in the right coronary artery. Guidewire crossing of the lesion interrupted the antegrade flow, which was restored after balloon dilation and stent implantation. Thallium-201 images, 2 hours after angioplasty (i.e., 30 hours after exercise), showed a decreased tracer uptake in the inferior wall, which improved the next day (i.e., 48 hours after exercise). Cardiac biomarkers were negative in the clinical course.