In Japan, cisplatin/5-fluorouracil 80/800 (cisplatin 80 mg/m2, 5-fluorouracil 800 mg/m2) is widely used to treat recurrent/metastatic squamous cell carcinoma of the head and neck, whereas cisplatin/5-fluorouracil 100/1000 (1000 mg/m2/24 h by continuous intravenous infusion on Days 1-4 plus cisplatin 100 mg/m2 on Day 1 in 3-week cycles) is the standard treatment in Europe and North America.
We have developed a Stress-free Therapy(®) device wherein "Pinpoint Plantar Long-wavelength Infrared Light Irradiation (PP-LILI)" increases peripheral-deep body temperature and blood flow volume and stabilizes blood pressure as well as significantly reduces stress hormones such as adrenocorticotrophic hormone and cortisol without using drugs. Moreover, we have found this therapy to significantly improve blood glucose and insulin resistance in patients with type 2 diabetes. Based on this background of clinical efficacy, we validated changes in cerebral blood flow in patients with metabolic cardiovascular disease and examined the efficacy of Stress-free Therapy(®) on cerebral blood flow as compared to that in healthy control subjects and placebo-treated patients.
Noncompaction of the left ventricular myocardium (NCLV) is a rare congenital cardiomyopathy resulting from an arrest in normal endomyocardial embryogenesis, and has been known as a disease of infants. However, some cases of NCLV in adults have been recently reported. We experienced an adultNCLV case repeating heart failure, and controlled it by surgery. The patient was 75-year-old man with NCLV and he had repeated heart failure and hospitalization. His heart failure had been barely controll by infusion of human atrial natriuretic peptide (hANP). Coronary angiography revealed double vesseldisease( #2 100%, #6 90).We performed coronary artery bypass grafting(CABG) with intraoperative cardiac resynchronization therapy. The heart failure was dramatically improved and the patient was discharged on foot 32 days after operation. However, careful observation of cardiac function is vital because of the possibility of progression to heart failure of NCLV.
Noncompetitive N-methyl-d-aspartate receptor antagonists such as phencyclidine and MK-801 are known to impair cognitive function in rodents and humans, and serve as a useful tool to study the cellular basis for pathogenesis of schizophrenia cognitive symptoms. In the present study, we tested in rats the effect of MK-801 on ventral hippocampus (HPC)-medial prefrontal cortex (mPFC) synaptic transmission and the performance in 2 cognitive tasks. We found that single injection of MK-801 (0.1 mg/kg) induced gradual and long-lasting increases of the HPC-mPFC response, which shares the common expression mechanisms with long-term potentiation (LTP). But unlike LTP, its induction required no enhanced or synchronized synaptic inputs, suggesting aberrant characteristics. In parallel, rats injected with MK-801 showed impairments of mPFC-dependent cognitive flexibility and HPC-mPFC pathway-dependent spatial working memory. The effects of MK-801 on HPC-mPFC responses and spatial working memory decayed in parallel within 24 h. Moreover, the therapeutically important subtype 2/3 metabotropic glutamate receptor agonist LY379268, which blocked MK-801-induced potentiation, ameliorated the MK-801-induced impairment of spatial working memory. Our results show a novel form of use-independent long-lasting potentiation in HPC-mPFC pathway induced by MK-801, which is associated with impairment of HPC-mPFC projection-dependent cognitive function.
Long-term memory in the prefrontal cortex is a necessary component of adaptive executive control and is strongly modulated by dopamine. However, the functional significance of this dopaminergic modulation remains elusive. In vitro experimental results on dopamine-dependent shaping of prefrontal long-term plasticity often appear inconsistent and, altogether, draw a complicated picture. It is also generally difficult to relate these findings to in vivo observations given strong differences between the two experimental conditions. This study presents a unified view of the functional role of dopamine in the prefrontal cortex by framing it within the Bienenstock-Cooper-Munro theory of cortical plasticity. We investigate dopaminergic modulation of long-term plasticity through a multicompartment Hodgkin-Huxley model of a prefrontal pyramidal neuron. Long-term synaptic plasticity in the model is governed by a calcium- and dopamine-dependent learning rule, in which dopamine exerts its action via D1 and D2 dopamine receptors in a concentration-dependent manner. Our results support a novel function of dopamine in the prefrontal cortex, namely that it controls the synaptic modification threshold between long-term depression and potentiation in pyramidal neurons. The proposed theoretical framework explains a wide range of experimental results and provides a link between in vitro and in vivo studies of dopaminergic plasticity modulation. It also suggests that dopamine may constitute a new player in metaplastic and homeostatic processes in the prefrontal cortex.
A 50-year-old man was admitted because of enlargement in diameter of the descending thoracoabdominal aorta. Seven years previously, he had undergone Bentall operation and graft replacement of the aortic arch due to an acute dissecting aneurysm, and he had also received graft replacement of the descending aorta due to a rupture of dissecting aneurysm 2 years before. The surgical stress of conventional repair under left lateral thoracotomy and laparotomy was considered to be excessive, and the 3-dimensional computed tomography (3D-CT) image revealed the reconstruction of intercostals artery was difficult. Hence, extra-anatomic bypasses were created to perfuse the visceral and renal vessels, and endovascular thoracic stent-grafts were deployed into the false lumen, because of the severe narrowing of the true lumen( hybrid-procedure). The postoperative course was uneventful and the patient was discharged on postoperative 30 days. Hybrid-procedure of aortic aneurysm is feasible, and may be an alternative to standard open procedures in high-risk patients and emergency cases.
Schizophrenia affects about 1% of the world population and is a major socio-economical problem in ours societies. Cognitive symptoms are particularly resistant to current treatments and are believed to be closely related to an altered function of prefrontal cortex (PFC). Particularly, abnormalities in the plasticity processes in the PFC are a candidate mechanism underlying cognitive symptoms, and the recent evidences in patients are in line with this hypothesis. Animal pharmacological models of cognitive symptoms, notably with non-competitive NMDA receptor antagonists such as MK-801, are commonly used to investigate the underlying cellular and molecular mechanisms of schizophrenia. However, it is still unknown whether in these animal models, impairments in plasticity of PFC neurons are present. In this article, we briefly summarize the current knowledge on the effect of non-competitive NMDA receptor antagonist MK-801 on medial PFC (mPFC) neuronal activity and then introduce a form of plasticity found after acute exposure to MK-801, which was accompanied by cognitive deficits. These observations suggest a potential correlation between cognitive deficits and the aberrant plasticity in the mPFC in the animal model of schizophrenia.
The present study elucidated whether early life stress alters the extracellular signal-regulated kinase (ERK) pathway that underlies fear retrieval and fear extinction based on a contextual fear conditioning paradigm, using a juvenile stress model. Levels of phospho-ERK (pERK), the active form of ERK, increased after fear retrieval in the hippocampal CA1 region but not in the medial prefrontal cortex (mPFC). ERK activation in the CA1 following fear retrieval was not observed in adult rats who received aversive footshock (FS) stimuli during the second postnatal period (2wFS), which exhibited low levels of freezing. In fear extinction, pERK levels in the CA1 were increased by repeated extinction trials, but they were not altered after extinction retrieval. In contrast, pERK levels in the mPFC did not change during extinction training, but were enhanced after extinction retrieval. These findings were compatible in part with electrophysiological data showing that synaptic transmission in the CA1 field and mPFC was enhanced during extinction training and extinction retrieval, respectively. ERK activation in the CA1 and mPFC associated with extinction processes did not occur in rats that received FS stimuli during the third postnatal period (3wFS), which exhibited sustained freezing behavior. The repressed ERK signaling and extinction deficit observed in the 3wFS group were ameliorated by treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine. These findings suggest that early postnatal stress induced the downregulation of ERK signaling in distinct brain regions through region-specific regulation, which may lead to increased behavioral abnormalities or emotional vulnerabilities in adulthood.
This work presents a computational model of dopamine (DA) influence on long-term potentiation (LTP) and long-term depression (LTD) in the prefrontal cortex. Distinct properties of the model are a DA-concentration-dependent switch from depression to potentiation during induction of plasticity, and an inverted-U-shaped dependence of protein synthesis on the level of background DA. Protein synthesis is responsible for the maintenance of LTP/LTD in the model. Our simulations suggest that in vitro experimental data on prefrontal plasticity, induced by high-frequency stimulation, may be accounted for by a single synaptic mechanism that is slowly (on the timescale of minutes) activated in the presence of DA in a concentration-dependent manner. The activation value determines the direction of plasticity during induction, while it also modulates the magnitude of plasticity during maintenance. More generally, our results support the hypothesis that phasic release of endogenous DA is necessary for the maintenance of long-term changes in synaptic efficacy, while the concentration of tonic DA determines the direction and magnitude of these changes in the PFC.
Mutation status of the KRAS gene in tumors has been shown to be a predictive biomarker of response to anti-epidermal growth factor receptor antibody therapy in patients with metastatic colorectal cancer. This retrospective analysis examined the association between efficacy and safety of the fully human anti-epidermal growth factor receptor antibody panitumumab and KRAS mutation status in Japanese metastatic colorectal cancer patients using data from two clinical trials with adherence to good clinical practices.
Bartonella henselae, the causative agent of cat scratch disease, is increasingly recognized as a cause of culture-negative endocarditis. This report describes the first Japanese case, which was diagnosed after a prolonged culture of the excised aortic valve. High IgG and IgM titers to B. henselae pointed to a subacute course of the disease.
Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients.
The neuromodulator noradrenaline (NA) is released in almost all brain areas in a highly diffused manner. Its action is slow, as it acts through G protein-coupled receptors, but its wide release in the brain makes NA a crucial regulator for various fundamental brain functions such as arousal, attention and memory processes . To understand how NA acts in the brain to promote such diverse actions, it is necessary to dissect the cellular actions of NA at the level of single neurons as well as at the level of neuronal networks. In the present article, we will provide a compact review of the main literatures concerning the NA actions on neuroplasticity processes. Depending on which subtype of adrenoceptor is activated, NA differently affects intrinsic membrane properties of postsynaptic neurons and synaptic plasticity. For example, beta-adrenoceptor activation is mainly related to the potentiation of synaptic responses and learning and memory processes. alpha2-adrenoceptor activation may contribute to a high-order information processing such as executive function, but currently the direction of synaptic plasticity modification by alpha2-adrenoceptors has not been clearly determined. The activation of alpha1-adrenoceptors appears to mainly induce synaptic depression in the brain. But its physiological roles are still unclear: while its activation has been described as beneficial for cognitive functions, it may also exert detrimental effects in some brain structures such as the prefrontal cortex.
Prefrontal cortex (PFC) mediates an assortment of cognitive functions including working memory, behavioral flexibility, attention, and future planning. Unlike the hippocampus, where induction of synaptic plasticity in the network is well-documented in relation to long-term memory, cognitive functions mediated by the PFC have been thought to be independent of long-lasting neuronal adaptation of the network. Nonetheless, accumulating evidence suggests that prefrontal cortical neurons possess the cellular machinery of synaptic plasticity and exhibit lasting changes of neural activity associated with various cognitive processes. Moreover, deficits in the mechanisms of synaptic plasticity induction in the PFC might be involved in the pathophysiology of psychiatric and neurological disorders such as schizophrenia, drug addiction, mood disorders, and Alzheimers disease.
In rat prefrontal cortex (PFC), long-term depression induced by low-frequency single stimuli has never been studied. Combined with the well-documented involvement of dopamine transporters (DATs) in the regulation of PFC-dependent cognitive processes, it is important to test whether this form of plasticity can be modulated by DAT activity in the PFC. Here, we show first that prolonged 3-Hz stimuli successfully induced synaptic depression in rat PFC slices whose induction depended on endogenous stimulation of D1-like and D2-like receptors and the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This depression was found to be significantly impaired by selective inhibition of the DAT by GBR12909 (1-200 nM) or GBR12935 (100 nM). The excess amount of extracellular dopamine caused by DAT inhibition acted critically on D1-like receptors to impair depression. Furthermore, this impairment by GBR12 909 was cancelled by the allosteric-positive mGluR5 modulator CDPPB, the drug known to reverse hyperdopaminergia-induced abnormal PFC activity, and the associated cognitive disturbances. Finally, these induction, impairment, and restoration of synaptic depression were correlated by an inverted-U shape manner with the phosphorylation level of ERK1/2. We suggest that abnormal increases of the extracellular dopamine level by DAT inhibition impair synaptic depression in the PFC through over-stimulation of D1-like receptors.
Early life adverse events can lead to structural and functional impairments in the prefrontal cortex (PFC). Here, we investigated whether maternal deprivation (MD) alters PFC-dependent executive functions, neurons and astrocytes number and synaptic plasticity in adult male Long-Evans rats. The deprivation protocol consisted of a daily separation of newborn Long-Evans pups from their mothers and littermates 3h/day postnatal day 1-14. Cognitive performances were assessed in adulthood using the temporal order memory task (TMT) and the attentional set-shifting task (ASST) that principally implicates the PFC and the Morris water maze task (WMT) that does not essentially rely on the PFC. The neurons and astrocytes of the prelimbic (PrL) area of the medial PFC (mPFC) were immunolabelled respectively with anti-NeuN and anti-GFAP antibodies and quantified by stereology. The field potentials evoked by electrical stimulation of ventral hippocampus (ventral HPC) were recorded in vivo in the PrL area. In adulthood, MD produced cognitive deficits in two PFC-dependent tasks, the TMT and ASST, but not in the WMT. In parallel, MD induced in the prelimbic area of the medial PFC an upregulation of long-term potentiation (LTP), without any change in the number of neurons and astrocytes. We provide evidence that MD leads in adults to an alteration of the cognitive abilities dependent on the PFC, and to an exaggerated synaptic plasticity in this region. We suggest that this latter phenomenon may contribute to the impairments in the cognitive tasks.
Recent studies focus on the functional significance of a novel form of synaptic plasticity, low-frequency stimulation (LFS)-induced synaptic potentiation in the hippocampal CA1 area. In the present study, we elucidated dynamic changes in synaptic function in the CA1 field during extinction processes associated with context-dependent fear memory in freely moving rats, with a focus on LFS-induced synaptic plasticity. Synaptic transmission in the CA1 field was transiently depressed during each extinction trial, but synaptic efficacy was gradually enhanced by repeated extinction trials, accompanied by decreases in freezing. On the day following the extinction training, synaptic transmission did not show further changes during extinction retrieval, suggesting that the hippocampal synaptic transmission that underlies extinction processes changes in a phase-dependent manner. The synaptic potentiation produced by extinction training was mimicked by synaptic changes induced by LFS (0.5 Hz) in the group that previously received footshock conditioning. Furthermore, the expression of freezing during re-exposure to footshock box was significantly reduced in the LFS application group in a manner similar to the extinction group. These results suggest that LFS-induced synaptic plasticity may be associated with the extinction processes that underlie context-dependent fear memory. This hypothesis was supported by the fact that synaptic potentiation induced by extinction training did not occur in a juvenile stress model that exhibited extinction deficits. Given the similarity between these electrophysiological and behavioral data, LFS-induced synaptic plasticity may be related to extinction learning, with some aspects of neuronal oscillations, during the acquisition and/or consolidation of extinction memory.
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