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Abstract Objective: To conduct a systematic review of evidence supporting the safety profiles of frequently used oral H(1)-antihistamines (AHs) for the treatment of patients with histamine-release related allergic diseases, e.g. allergic rhinitis and urticaria, and to compare them to the safety profiles of other medications, mostly topical corticosteroids and leukotriene antagonists (LTRA). Research design and methods: Systematic search of the published literature (PubMed) and of the regulatory authorities databases (EMA and FDA) for oral AHs. Results: Similarly to histamine, antihistamines (AHs) have organ-specific efficacy and adverse effects. The peripheral H(1)-receptor (PrH1R) stimulation leads to allergic symptoms while the brain H(1)-receptor (BrH1R) blockade leads to somnolence, fatigue, increased appetite, decreased cognitive functions (impaired memory and learning), seizures, aggressive behaviour, etc. First-generation oral AHs (FGAHs) inhibit the effects of histamine not only peripherally but also in the brain, and additionally have potent antimuscarinic, anti-[alpha]-adrenergic and antiserotonin effects leading to symptoms such as visual disturbances (mydriasis, photophobia, and diplopia), dry mouth, tachycardia, constipation, urinary retention, agitation, and confusion. The somnolence caused by FGAHs interferes with the natural circadian sleep-wake cycle and therefore FGAHs are not suitable to be used as sleeping pills. Second-generation oral AHs (SGAHs) have proven better safety and tolerability profiles, much lower proportional impairment ratios, with at least similar if not better efficacy, than their predecessors. Only SGAHs, and especially those with a proven long-term (e.g., >=12 months) clinical safety, should be prescribed for young children. Evidence exist that intranasally applied medications, like intranasal antihistamines, have the potential to reach the brain and cause somnolence. Conclusions: Second-generation oral antihistamines are the preferred first-line treatment option for allergic rhinitis and urticaria. Patients taking SGAHs report relatively little and mild adverse events even after long-term continuous treatments. An antihistamine should ideally possess high selectivity for the H(1)-receptor, high PrH1R occupancy and low to no BrH1R occupancy. [ABSTRACT FROM AUTHOR]

Abstract: Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4α (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30–2.31) (P =0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study. [Copyright &y& Elsevier]

The article presents a research study on the role of histamine H1 receptors on cognition, behavioral, and neurochemical changes using H1 receptor gene knockout mice (H1KO). It states that the memories of mice were evaluated using object recognition, Barnes maze and fear conditioning tests. It states that sedative antihistamines induce cognitive decline in humans.

The histamine H1 receptor binding capacity of the amygdalas of amygdaloid kindled rats was studied. In the kindled nonstimulated amygdala, significant decreases in KD and Bmax values compared with those of control amygdala were found 1 week after the last kindled seizure. One month after the last kindled seizure, the decreased KD value was sustained in the kindled nonstimulated amygdala. This decreased Bmax value 1 week after the last kindled seizure in nonstimulated amygdala may partly and transiently contribute to kindled seizure susceptibility. The decreased KD value in nonstimulated amygdala observed until 1 month after the last kindled seizure indicates the long-lasting increment of binding affinity of the pyrilamine binding site of the histamine H1 receptor in the steady state of kindled seizure susceptibility. [ABSTRACT FROM AUTHOR]

Background and purpose Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy ( PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [18F] THK-5351, which we have recently developed. Methods Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [3H] THK-5351 and immunohistochemistry. Nine healthy controls, 13 patients with Alzheimer's disease and three patients with PSP participated in this PET study with [18F] THK-5351. To detect amyloid-β deposition, PET imaging with Pittsburgh compound B was also performed. Results Autoradiography in the brain sections of patients with PSP demonstrated [3H] THK-5351 binding to tau deposits with a high selectivity. Although patients with PSP exhibited no remarkable [18F] THK-5351 retention in the temporal cortex, significantly higher tracer retention was observed in the globus pallidus and midbrain. In contrast, amyloid imaging with Pittsburgh compound B showed no remarkable accumulation in the cerebral cortex of PSP. Conclusions We conclude that [18F] THK-5351 PET can potentially be used to detect the regional brain distribution of tau lesions in PSP, thereby facilitating the differential diagnosis of neurodegenerative disorders associated with tau protein. [ABSTRACT FROM AUTHOR]

Following the early prediction of the skyrmion lattice (SkL)-a periodic array of spin vortices-it has been observed recently in various magnetic crystals mostly with chiral structure. Although non-chiral but polar crystals with Cnv symmetry were identified as ideal SkL hosts in pioneering theoretical studies, this archetype of SkL has remained experimentally unexplored. Here, we report the discovery of a SkL in the polar magnetic semiconductor GaV4S8 with rhombohedral (C3v) symmetry and easy axis anisotropy. The SkL exists over an unusually broad temperature range compared with other bulk crystals and the orientation of the vortices is not controlled by the external magnetic field, but instead confined to the magnetic easy axis. Supporting theory attributes these unique features to a new Néel-type of SkL describable as a superposition of spin cycloids in contrast to the Bloch-type SkL in chiral magnets described in terms of spin helices. [ABSTRACT FROM AUTHOR]

The threshold voltage (VT) shift of hydrogenated amorphous silicon thin-film transistors (a-Si:H TFTs) by boron doping has been investigated. In TFTs with a uniformly doped structure (SiN/B-doped a-Si:H), VT shifts to a positive voltage by boron doping, while the field-effect mobility decreases markedly. By using a step-doped structure (SiN/undoped a-Si:H/B-doped a-Si:H), the degradation of the field-effect mobility by boron doping becomes less than that of a uniformly doped TFT with the same VT shift, and a VT shift of 3.5 V was obtained without degradation of the field-effect mobility. [ABSTRACT FROM AUTHOR]

Background and Purpose: Histamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin.Experimental Approach: The expression of histamine receptors in pancreatic beta cells was examined by RT-PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H₃ receptors in glucose-induced insulin secretion (GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H₃ receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting.Key Results: Histamine H₃ receptors were expressed in pancreatic beta cells. A selective H₃ receptor agonist, imetit, and a selective inverse H₃ receptor agonist, JNJ-5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ-5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element-binding protein (CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H₃ receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation.Conclusions and Implications: Histamine H₃ receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation. [ABSTRACT FROM AUTHOR]

Background and Purpose Histamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin. Experimental Approach The expression of histamine receptors in pancreatic beta cells was examined by RT- PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H3 receptors in glucose-induced insulin secretion ( GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H3 receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting. Key Results Histamine H3 receptors were expressed in pancreatic beta cells. A selective H3 receptor agonist, imetit, and a selective inverse H3 receptor agonist, JNJ-5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ-5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element-binding protein ( CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H3 receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation. Conclusions and Implications Histamine H3 receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Chiropractic spinal manipulation (CSM) is an alternative treatment for back pain. The autonomic nervous system is often involved in spinal dysfunction. Although studies on the effects of CSM have been performed, no chiropractic study has examined regional cerebral metabolism using positron emission tomography (PET). Objective: The aim of the present study was to investigate the effects of CSM on brain responses in terms of cerebral glucose metabolic changes measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Methods: Twelve male volunteers were recruited. Brain PET scanning was performed twice on each participant, at resting and after CSM. Questionnaires were used for subjective evaluations. A visual analogue scale (VAS) was rated by participants before and after chiropractic treatment, and muscle tone and salivary amylase were measured. Results: Increased glucose metabolism was observed in the inferior prefrontal cortex, anterior cingulated cortex, and middle temporal gyrus, and decreased glucose metabolism was found in the cerebellar vermis and visual association cortex, in the treatment condition (P < .001). Comparisons of questionnaires indicated a lower stress level and better quality of life in the treatment condition. A significantly lower VAS was noted after CSM. Cervical muscle tone and salivary amylase were decreased after CSM. Conclusion The results of this study suggest that CSM affects regional cerebral glucose metabolism related to sympathetic relaxation and pain reduction. [ABSTRACT FROM AUTHOR]

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials. [ABSTRACT FROM AUTHOR]

Aim: To determine early brain changes in the distribution of an amyloid positron emission tomography (PET) probe, 11C-labeled BF-227 or [11C]BF-227, in order to accurately predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Patients and Methods: Amyloid plaque burden was evaluated using [11C]BF-227 PET in AD, MCI and aged normal controls. A voxel-based analysis of [11C]BF-227 PET images was performed to characterize the culprit brain lesion in patients with MCI who were destined to progress to AD, referred to as MCI converters (MCI-C). In addition, binding characteristics of BF-227 to amyloid deposits were examined using postmortem AD brain samples. Results: Voxel-based statistical analyses of the BF-227 PET images clearly demonstrated an abnormal distribution of BF-227 mainly in the posterior association area in MCI-C and patients with AD. BF-227 uptake in the lateral temporal cortex was consistently observed in almost all MCI-C and patients with AD, and it distinguished MCI-C from MCI nonconverters. BF-227 binding strongly correlated with dense amyloid-β protein plaque density, but not with diffuse plaque density in the frontal cortex. Conclusion: BF-227 uptake in the lateral temporal cortex is a reliable indicator that can be used for predicting prognosis in patients with MCI. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The histopathological hallmark of multiple system atrophy is the appearance of intracellular inclusion bodies, named glial cytoplasmic inclusions, which are mainly composed of alpha-synuclein fibrils. In vivo visualization of alpha-synuclein deposition should be used for the diagnosis and assessment of therapy and severity of pathological progression in multiple system atrophy. Because 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole could stain alpha-synuclein-containing glial cytoplasmic inclusions in post-mortem brains, we compared the carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole positron emission tomography findings of eight multiple system atrophy cases to those of age-matched normal controls. The positron emission tomography data demonstrated high distribution volumes in the subcortical white matter (uncorrected P < 0.001), putamen and posterior cingulate cortex (uncorrected P < 0.005), globus pallidus, primary motor cortex and anterior cingulate cortex (uncorrected P < 0.01), and substantia nigra (uncorrected P < 0.05) in multiple system atrophy cases compared to the normal controls. They were coincident with glial cytoplasmic inclusion-rich brain areas in multiple system atrophy and thus, carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole positron emission tomography is a promising surrogate marker for monitoring intracellular alpha-synuclein deposition in living brains. [ABSTRACT FROM AUTHOR]

In a biological body, trace elements including metallic elements play important roles. Knowing their spatial distribution and amounts, we can find out some relations among a physiological role of the trace element in vivo, the function, and the disease appearance. In this study, we investigated a method to obtain elemental distributions in whole brain slice taken from mental disease model mice and control mice using in-air submilli-PIXE camera at Tohoku University. We administered 5-BrdU that was the analogue of the thymidine as a marker to detect a new born cell in especially the dentate gyrus of the hippocampus. We obtained the elemental distributions of the whole brain of subject and control mice. From elemental distributions of the brain of a mental disease model mouse, a brain contained light elements, such as P, S, Cl and K, which were uniformly distributed over the brain. Fe was accumulated in the specific area of brain. Elemental concentration of Fe was more than 10 times higher than that in the other. However, the accumulation of iron in brain slices was not observed in those of control mice. Zn is accumulated in the vicinity in hippocampus. Br was uniformly distributed over the brain. The submilli-PIXE camera will provide a powerful tool for this research. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Determining the gene that plays a key role in brain–gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. Methods: We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n =14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n =14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[15-O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. Results: Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg  to 40 mm Hg  than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p <0.0001). The increase in rCBF by colorectal distention of 20 mm Hg  compared with 0 mm Hg  was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p <0.0001). Conclusion: These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain. [Copyright &y& Elsevier]

To systematically evaluate genetic susceptibility to type 2 diabetes (T2D) in “candidate” regions on chromosomes 1q, 3q and 12q, we examined disease association by using a total of 2,083 SNPs in two-step screening; a screening panel comprised 473 cases and 285 controls and an extended (or combined) panel involved 658 cases and 474 controls. For the total interval screened (40.9 Mb), suggestive evidence of association was provided for several annotated gene loci. For example, in the MCF2L2 gene on 3q, a significant association (a nominal P value of 0.00009) was observed when logistic regression analysis was performed for three associated SNPs (rs684846, rs35069869 and rs35368790) that belonged to different LD groups. Also, in the SLC15A4 gene on 12q, rs3765108 showed a marginally significant association with an overall estimated odds ratio of 0.79 ( P = 0.001). No significant association was found for known candidate gene loci on 3q, such as ADIPOQ and IGF2BP2. Using the available samples, we have observed disease associations of SNPs derived from two novel gene loci in the Japanese population through high-density searches of diabetes susceptibility in three chromosomal regions. Independent replication will clarify the etiological relevance of these genomic loci to T2D. [ABSTRACT FROM AUTHOR]

Abstract: An animal PET scanner using CdTe detectors was developed for the purpose of biomedical study using mice and rats. A spatial resolution of 0.8mm FWHM within the central 20mm-diameter of the field of view (FOV) was obtained by small CdTe elements of 1.1mm×5.0mm×1.0mm. This spatial resolution is the first achievement of a practical semiconductor animal PET scanner. The determination of the depth of the γ interaction in the detector was carried out by the use of two detector layers. The FOV is 64mm in diameter and 26mm in axis. Fine [18F]FDG images of the heads of a mouse and a rat, where the cerebral cortex, the gray matter and the corpus striatum could be respectively distinguished, were successfully obtained. This work inspires the dawn of the high resolution semiconductor PET scanner age as the next generation. [Copyright &y& Elsevier]

Histamine has many physiological roles in the brain and periphery. Neuronal histamine is metabolized almost exclusively by histamine N-methyltransferase. Although several neurotransmitter systems such as dopamine and 5-hydroxytryptamine have their specific reuptake system in their neurons and glial cells, a specific histamine reuptake system into the corresponding nerve terminals or glial cells has not yet been clearly elucidated. We characterized the uptake of histamine into the P2 fractions of rat brain homogenized in 0.32 mol/l sucrose using in vitro uptake techniques. [3H]histamine uptake increased with the increment of added protein amount and elapsed time. [3H]histamine uptake was also temperature-dependent. The uptake of [3H]histamine into the P2 fractions occurs by two saturable processes, a high-affinity and a low-affinity, characterized by Km values of 0.16 and 1.2 μmol/l, respectively. Na+, Cl– and HCO3– ions were essential for the uptake of histamine in P2 fractions. [3H]histamine uptake was inhibited in the presence of several tricyclic antidepressants. In accordance with this, the endogenous release of histamine from brain slices evoked by 100 mmol/l K+ was augmented in the presence of 20 μmol/l imipramine. These results further support the existence of a specific histamine uptake system in the brain, although the precise molecular entities have not been identified until now. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We have developed an in-air on/off axis STIM for simultaneous density mapping with PIXE and RBS, which will be useful for damage-monitoring in cell analysis and for yield correction based on the thickness distribution of X-ray self-absorption in samples. The in-air on/off axis STIM system provides a mass concentration map in the cell analysis. In the system, a thin scattering foil is placed downstream of the sample and scattered protons are detected by a Si-PIN photodiode set at 30 degrees with respect to the beam axis. These components are set in a He-gas-filled chamber to reduce energy loss, scattering and sample damage. Using this system, areal density mapping is carried out for RBL-2H3 cells simultaneously with PIXE and RBS. Correction for self-absorption is performed and areal density map of elements is converted into a mass-concentration map using the measured matrix density. The areal density distribution of P corresponds to that of matrix and mass concentration of P is uniform in the cell region. On the other hand, Br is concentrated in the nucleus, even in the mass concentration map. The Br accumulation in the nucleus is first confirmed in mass concentration using the on/off axis STIM and PIXE system. The in-air on/off STIM system will be effective for monitoring changes in cell density during beam irradiation. [ABSTRACT FROM AUTHOR]

Brain-gut interaction is considered to be a major factor in the pathophysiology of irritable bowel syndrome. However, only limited information has been provided on the influence of gastrointestinal tract stimulation on the brain. Our aim in this study was to determine the specific regions of the brain that are responsible for visceral perception and emotion provoked by distention of the descending colon in humans. Fifteen healthy males aged 22 ± 1 participated in this study. Using a colonoscope, a balloon was inserted into the descending colon of each subject. After sham stimulation, the colon was randomly stimulated with bag pressures of 20 and 40 mmHg, and regional cerebral blood flow was measured by [15O] positron emission tomography. The subjects were asked to report visceral perception and emotion using an ordinate scale of 0–10. Colonic distention pressure dependently induced visceral perception and emotion, which significantly correlated with activation of specific regions of the brain including the prefrontal, anterior cingulate, parietal cortices, insula, pons, and the cerebellum. In conclusion, distention of the descending colon induces visceral perception and emotion. These changes significantly correlate with activation of specific regions in the brain including the limbic system and the association cortex, especially the prefrontal cortex. [ABSTRACT FROM AUTHOR]

Rat basophilic leukaemia cells (RBL-2H3) were analyzed by in air micro-PIXE analysis to investigate the relationship between the distribution of dements and histamine release in immune system RBL-2H3 cells were sensitized with monoclonal immunoglobuline E (IgE) and stimulated with antigen In the stimulated cells, it is understood that the level of Ca2+ increases in cytoplasm and then the degranulation or the release of chemical mediators occur. In this study, stimulated RBL-2H3 cells with antigen and control cells were analyzed. After the stimulation, the Na in the cells was increased. Moreover some stimulated cells showed the characteristic distribution of sulfur that is not accompany with the distribution of phosphorus. In the same measurement, the aggregations of Na, Ca, Fe, and Zn were observed. [ABSTRACT FROM AUTHOR]

The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons. [Copyright &y& Elsevier]

This paper discusses the effects of radiation damage to SiPMs on the performances of plastic scintillator counters with series-connected SiPM readout, focusing on timing measurements. The performances of a counter composed of a 120 × 40 × 5 mm 3 scintillator tile read out by two sets of six SiPMs from AdvanSiD connected in series attached on the short sides are presented, for different combinations of SiPMs at various levels of irradiation. Firstly, six SiPMs were equally irradiated with electrons from 90Sr sources up to a fluence of Φ e− ≈ 3 × 1 0 12 cm − 2 . The timing resolution of the counter gradually deteriorated by the increase in dark current. The dark current and the deterioration were reduced when the counter was cooled from 30 °C to 10 °C. Secondly, 33 SiPMs were irradiated with reactor neutrons. The fluence levels ranged from Φ eq ≈ 8. 7 × 1 0 8 cm − 2 to Φ eq ≈ 5. 5 × 1 0 13 cm − 2 . The characteristics of counters read out by series-connected SiPMs with non-uniform damage levels were investigated. The signal pulse height, the time response, and the timing resolution depend on the hit position in the counter when SiPMs' irradiation is not uniform. [ABSTRACT FROM AUTHOR]

We have developed a new laser-based time calibration system for highly segmented scintillator counters like the MEG II pixelated Timing Counter (pTC), consisting of 512 centimetre-scale scintillator counters read out by silicon photomultipliers (SiPMs). It is difficult to apply previous laser-based calibration methods for conventional metre-scale Time-Of-Flight detectors to the MEG II pTC from the implementation and the accuracy points of view. This paper presents a new laser-based time calibration system which can overcome such difficulties. A laser pulse is split into each scintillator counter via several optical components so that we can directly measure the time offset of each counter relative to the laser-emitted time. We carefully tested all the components and procedures prior to the actual operation. The laser system was installed into the pTC and thoroughly tested under the real experimental condition. The system showed good stability and being sensitive to any change of timing larger than ∼ 10 ps. Moreover, it showed an uncertainty of 48 ps in the determination of the time offsets, which meets our requirements. The new method provides an example of the implementation of a precise timing alignment for the new type of detectors enabled by the advance of SiPM technology. [ABSTRACT FROM AUTHOR]