Insulinoma induces a hyperinsulinemia-mediated decrease of GLUT2 and GLP1 receptor in normal pancreatic ß-cells.

There have been several clinical reports of transient postoperative hyperglycemia in patients with insulinoma, but the effect of insulinoma on normal ß-cells has not been investigated. We examined the glucose transporter 2 (GLUT2) and glucagon-like peptide 1 receptor (GLP1R) expression in normal pancreatic ß-cells of five patients with insulinoma and five patients with normal glucose tolerance (NGT) as controls. The positive rate of GLUT2-or GLP1R-positive islets in the nontumor area was calculated by the ratio with the analyzed islets. For functional in vitro analyses, q-PCR and Western blotting were performed after insulin loading on MIN6 cells. The expression rates of both GLUT2 and GLP1R were significantly lower in nontumor area islets of insulinoma patients than in patients with NGT (GLUT2: 31.6 ± 15.3% vs 95.9 ± 6.7%, p < 0.01, GLP1R: 66.8 ± 15.0% vs 96.7 ± 5.0%, p < 0.01). Exposure of MIN6 cells to high concentrations of insulin resulted in a significant decrease in GLUT2 protein for 12 h and GLP1R protein for 24 h (GLUT2; 1.00 ± 0.079 vs 0.81 ± 0.04. p = 0.02, GLP1R; 1.00 ± 0.10 vs 0.50 ± 0.24, p = 0.03) but not in those mRNAs. Our findings show that insulinoma is associated with the downregulation of GLUT2 and GLP1R expression in nontumor area islets. These phenomena may be caused by high levels of insulin.

Extending coherence time of macro-scale diamond magnetometer by dynamical decoupling with coplanar waveguide resonator.

Ultimate sensitivity for quantum magnetometry using nitrogen-vacancy (NV) centers in a diamond is limited by a number of NV centers and coherence time. Microwave irradiation with a high and homogeneous power density for a large detection volume is necessary to achieve a highly sensitive magnetometer. Here, we demonstrate a microwave resonator to enhance the power density of the microwave field and an optical system with a detection volume of 1.4 × 10-3 mm3. The strong microwave field enables us to achieve 48 ns Rabi oscillation which is sufficiently faster than the phase relaxation time of NV centers. This system combined with a decoupling pulse sequence, XY16, extends the spin coherence time (T 2) up to 27 times longer than that with a spin echo method. Consequently, we obtained an AC magnetic field sensitivity of 10.8 pt/ Hz using the dynamical decoupling pulse sequence.

Coupling between the photo-excited cyclic π system and the 4f electronic system in a lanthanide single molecule magnet.

A new type of electronic interaction which couples two angular momenta, i.e. the angular momentum of a localized 4f system (J) and an orbital angular momentum generated in a cyclic π conjugated system by irradiation with a circularly-polarized light, has been identified in a lanthanide single molecule magnet.

Characterisation of Kiss1r (Gpr54)-Expressing Neurones in the Arcuate Nucleus of the Female Rat Hypothalamus.

Kisspeptin is essential in reproduction and acts by stimulating neurones expressing gonadotrophin-releasing hormone (GnRH). Recent studies suggest that kisspeptin has multiple roles in the modulation of neuronal circuits in systems outside the hypothalamic-pituitary-gonadal axis. Our recent research using in situ hybridisation (ISH) clarified the histological distribution of Kiss1r (Gpr54)-expressing neurones in the rat brain that were presumed to be putative targets of kisspeptin. The arcuate nucleus (ARN) of the hypothalamus is one of the brain regions in which Kiss1r expression in non-GnRH neurones is prominent. However, the characteristics of Kiss1r-expressing neurones in the ARN remain unclear. The present study aimed to determine the neurochemical characteristics of Kiss1r-expressing neurones in the ARN using ISH and immunofluorescence. We revealed that the majority (approximately 63%) of Kiss1r-expressing neurones in the ARN were pro-opiomelanocortin (POMC) neurones, which have an anorexic effect in mammals. Additionally, a few Kiss1r-expressing neurones in the dorsal ARN are tuberoinfundibular dopamine (TIDA) neurones, which control milk production by inhibiting prolactin secretion from the anterior pituitary. TIDA neurones showed a relatively weak Kiss1r ISH signal compared to POMC neurones, as well as low co-expression of Kiss1r (approximately 15%). We also examined the expression of Kiss1r in neuropeptide Y and kisspeptin neurones, which are reported to arise from POMC-expressing progenitor cells during development. However, the vast majority of neuropeptide Y and kisspeptin neurones in the ARN did not express Kiss1r. These results suggest that kisspeptin may directly regulate energy homeostasis and milk production by modulating the activity of POMC and TIDA neurones, respectively. Our results provide an insight into the wide variety of roles that kisspeptin plays in homeostatic and neuroendocrine functions.

Increased Facet Fluid Predicts Dynamic Changes in the Dural Sac Size on Axial-Loaded MRI in Patients with Lumbar Spinal Canal Stenosis.

BACKGROUND AND PURPOSE: Axial-loaded MR imaging, which simulates the spinal canal in a standing position, demonstrates reductions of the dural sac cross-sectional area in patients with lumbar spinal canal stenosis. However, there has been no useful conventional MR imaging finding for predicting a reduction in the dural sac cross-sectional area on axial-loaded MR imaging. Previous studies have shown that increased facet fluid is associated with the spinal instability detected during positional changes. The purpose of this study was to analyze the correlations between facet fluid and dynamic changes in the dural sac cross-sectional area on axial-loaded MR imaging. MATERIALS AND METHODS: In 93 patients with lumbar spinal canal stenosis, the dural sac cross-sectional area was measured by using axial images of conventional and axial-loaded MR imaging. Changes in the dural sac cross-sectional area induced by axial loading were calculated. The correlation between the facet fluid width measured on conventional MR imaging and the change in dural sac cross-sectional area was analyzed. The change in the dural sac cross-sectional area was compared between the intervertebral levels with and without the facet fluid width that was over the cutoff value determined in this study. RESULTS: The dural sac cross-sectional area was significantly smaller on axial-loaded MR imaging than on conventional MR imaging. The facet fluid width significantly correlated with the change in the dural sac cross-sectional area (r = 0.73, P < .001). The change in the dural sac cross-sectional area at the intervertebral level with the facet fluid width over the cutoff value was significantly greater than that at the other level. CONCLUSIONS: The increased facet fluid on conventional MR imaging is highly predictive of the dynamic reduction of dural sac cross-sectional area detected on axial-loaded MR imaging in the clinical assessment of lumbar spinal canal stenosis.

Mapping of Kisspeptin Receptor mRNA in the Whole Rat Brain and its Co-Localisation with Oxytocin in the Paraventricular Nucleus.

The neuropeptide kisspeptin and its receptor play an essential role in reproduction as a potent modulator of the gonadotrophin-releasing hormone (GnRH) neurone. In addition to its reproductive function, kisspeptin signalling is also involved in extra-hypothalamic-pituitary-gonadal (HPG) axis systems, including oxytocin and arginine vasopressin (AVP) secretion. By contrast to the accumulating information for kisspeptin neurones and kisspeptin fibres, the histological distribution and function of the kisspeptin receptor in the rat brain remain poorly characterised. Using in situ hybridisation combined with immunofluorescence, the present study aimed to determine the whole brain map of Kiss1r mRNA (encoding the kisspeptin receptor), and to examine whether oxytocin or AVP neurones express Kiss1r. Neurones with strong Kiss1r expression were observed in several rostral brain areas, including the olfactory bulb, medial septum, diagonal band of Broca and throughout the preoptic area, with the most concentrated population being around 0.5 mm rostral to the bregma. Co-immunofluorescence staining revealed that, in these rostral brain areas, the vast majority of the Kiss1r-expressing neurones co-expressed GnRH. Moderate levels of Kiss1r mRNA were also noted in the rostral periventricular area, paraventricular nucleus (PVN), and throughout the arcuate nucleus. Relatively weak Kiss1r expression was observed in the supraoptic nucleus and supramammillary nuclei. Moderate to weak expression of Kiss1r was also observed in several regions in the midbrain, including the periaqueductal gray and dorsal raphe nucleus. We also examined whether oxytocin and AVP neurones in the PVN co-express Kiss1r. Immunofluorescence revealed the co-expression of Kiss1r in a subset of the oxytocin neurones but not in the AVP neurones in the PVN. The present study provides a fundamental anatomical basis for further examination of the kisspeptin signalling system in the extra-HPG axis, as well as in reproductive function.

Differential impacts of duration of untreated psychosis (DUP) on cognitive function in first-episode schizophrenia according to mode of onset.

BACKGROUND: The mode of onset and the course of schizophrenia illness exhibit substantial individual variations. Previous studies have pointed out that the mode of onset affects the duration of untreated psychosis (DUP) and clinical outcomes, such as cognitive and social functioning. This study attempted to clarify the association between the DUP and clinical features, taking the different modes of onset into consideration, in a prospective longitudinal study examining patients with first-episode schizophrenia. METHODS: This study was conducted in six areas of Japan. Patients with first-episode schizophrenia were followed for over 18 months. Cognitive function, psychopathology, and social functioning were assessed at baseline and at 6, 12, and 18-month follow-up points. RESULTS: We identified 168 patients and sufficient information was available to determine the DUP and the mode of onset for 156 patients (92.9%): 79 had an acute onset, and 77 had an insidious onset. The DUP was significantly associated with quality of life (QOL), social functioning, and cognitive function at most of the follow-up points in the insidious-onset group. The DUP and negative symptoms at baseline were significant predictors of cognitive function at the 18-month follow-up in the insidious-onset group. CONCLUSIONS: The present results further support the hypothesis that the DUP affects QOL, social functioning, and cognitive function over the course of illness, especially in patients with an insidious onset. Effective strategies for detecting and caring for individuals with insidious onset early during the course of schizophrenia will be essential for achieving a full patient recovery.

Tumour characteristics, treatment patterns and survival of patients aged 80 years or older with colorectal cancer.

AIM: This study aimed to clarify tumour characteristics and treatment patterns for patients with colorectal cancer aged 80 years or older and the impact of age on survival using a large-scale cancer registry database. METHOD: The database was used to identify 40 851 colorectal cancer patients who underwent surgery between 1995 and 2004. Patients were stratified into four age groups (< 50, 50-64, 65-79, ≥ 80 years). Demographics, tumour characteristics, treatment pattern and survival were compared between age groups. Additionally, the impact of lymph node dissection and adjuvant chemotherapy on survival was studied using the propensity score-matching method. RESULTS: In the over 80 age group, patients were more commonly female, with right colon cancer, multiple primary cancers, history of colorectal cancer, high serum carcinoembryonic antigen values, large tumour, undifferentiated histology, and more frequent pT3/pT4 tumours. In contrast, metastatic disease, central lymph node dissection and adjuvant chemotherapy were less frequent. Overall survival and cancer-specific survival decreased with increasing age for any stage. Multivariate analysis showed age to be an independent predictor of overall survival (hazard ratio 1.45, 95% CI 1.34-1.58, P < 0.001). In the propensity score-matched cohort, overall survival of the patients with central node dissection and having adjuvant chemotherapy was significantly better than for those without. This difference was not statistically significant in patients aged 80 and above. CONCLUSION: This study showed a significant difference in tumour characteristics and treatment patterns in patients aged 80 and above. Even after adjustment for clinicopathological factors, the difference in survival persisted and age was considered a robust prognostic factor.

Influence of intramedullary stress on cervical spondylotic myelopathy.

STUDY DESIGN: A cross-sectional analysis. OBJECTIVE: To examine whether intramedullary stress is related to the appearance of symptoms in cervical spondylotic myelopathy (CSM). SETTING: Japan. METHODS: Thirty-three consecutive patients with CSM and 30 consecutive patients without CSM were enrolled. A total of 99 disc levels from C3 to C6 in 33 patients with CSM were divided into two groups: 33 disc levels with high signal intensity (HSI) on T2-weighted magnetic resonance image (HSI group) and 66 disc levels without HSI (Non-HSI group). Ninety disc levels from C3 to C6 in patients without CSM were set up in a control group. Intramedullary stress value at each level was analyzed using the finite element method. Stress was compared among the three groups. A cutoff value of stress to present HSI was investigated from receiver operator characteristics (ROC) curve. RESULTS: In all the patients with CSM, the disc level with HSI presented the highest stress among the three disc levels evaluated. The stress was 3.16 ± 0.86 kPa (mean ± s.d.) in the HSI group, 1.81 ± 0.72 kPa in the Non-HSI group and 1.01 ± 0.37 kPa in the control group. The stress differed significantly among the three groups (P<0.0001). The qualified cutoff value derived from the ROC curve was 2.30 kPa (sensitivity 78.8%, specificity 91.9%). None of the disc levels in the control group exceeded 2.30 kPa. CONCLUSION: HSI was strongly associated with intramedullary stress. Threshold of intramedullary stress to present HSI that related closely to the symptoms of myelopathy was revealed.

Dynamic changes in the dural sac cross-sectional area on axial loaded MR imaging: is there a difference between degenerative spondylolisthesis and spinal stenosis?

BACKGROUND AND PURPOSE: Axial loaded MR imaging, which can simulate the spinal canal of patients in a standing position, demonstrates a significant reduction of the DCSA compared with conventional MR imaging and provides valuable imaging findings in the assessment of the lumbar spinal canal. The purpose of this study was to compare the DCSA on axial loaded MR imaging between patients with DS and SpS. MATERIALS AND METHODS: Eighty-eight consecutive patients were divided into DS and SpS groups. DCSA on conventional MR imaging and axial loaded MR imaging and changes in the DCSA induced by axial loading were compared between DS and SpS groups. The prevalence of a significant change (>15 mm(2)) in the DCSA was compared between the 2 groups. RESULTS: Axial loaded MR imaging demonstrated significantly smaller DCSA in the DS group (35 ± 22 mm(2)) than in the SpS group (50 ± 31 mm(2)), though conventional MR imaging did not show any differences between the 2 groups. The change in the DCSA induced by axial loading was significantly larger in the DS group (17 ± 12 mm(2)) compared with the SpS group (8 ± 8 mm(2)). The prevalence of a >15-mm(2) change in the DCSA was significantly higher in the DS group (62.5%) than in the SpS group (16.7%) (odds ratio, 8.33; 95% confidence interval, 3.09-22.50). CONCLUSIONS: Axial loaded MR imaging demonstrated significantly larger changes in the DCSA in patients with DS compared those with SpS. A significant change in the DCSA was more frequently observed in patients with DS. Axial loaded MR imaging may therefore be a more useful tool to decrease the risk of underestimating the spinal canal narrowing in patients with DS than in those with SpS.

Identification, localisation and functional implication of 26RFa orthologue peptide in the brain of zebra finch (Taeniopygia guttata).

Several neuropeptides with the C-terminal Arg-Phe-NH(2) (RFa) sequence have been identified in the hypothalamus of a variety of vertebrates. The present study was conducted to isolate novel RFa peptides from the zebra finch brain. Peptides were isolated by immunoaffinity purification using an antibody that recognises avian RFa peptides. The isolated peptide consisted of 25 amino acids with RFa at its C-terminus. The sequence was SGTLGNLAEEINGYNRRKGGFTFRFa. Alignment of the peptide with vertebrate 26RFa has revealed that the identified peptide is the zebra finch 26RFa. We also cloned the precursor cDNA encoding this peptide. Synteny analysis of the gene showed a high conservation of this gene among vertebrates. In addition, we cloned the cDNA encoding a putative 26RFa receptor, G protein-coupled receptor 103 (GPR103) in the zebra finch brain. GPR103 cDNA encoded a 432 amino acid protein that has seven transmembrane domains. In situ hybridisation analysis in the brain showed that the expression of 26RFa mRNA is confined to the anterior-medial hypothalamic area, ventromedial nucleus of the hypothalamus and the lateral hypothalamic area, the brain regions that are involved in the regulation of feeding behaviour, whereas GPR103 mRNA is distributed throughout the brain in addition to the hypothalamic nuclei. When administered centrally in free-feeding male zebra finches, 26RFa increased food intake 24 h after injection without body mass change. Diencephalic GPR103 mRNA expression was up-regulated by fasting for 10 h. Our data suggest that the hypothalamic 26RFa-its receptor system plays an important role in the central control of food intake and energy homeostasis in the zebra finch.

Melting of peridotite to 140 gigapascals.

Interrogating physical processes that occur within the lowermost mantle is a key to understanding Earth's evolution and present-day inner composition. Among such processes, partial melting has been proposed to explain mantle regions with ultralow seismic velocities near the core-mantle boundary, but experimental validation at the appropriate temperature and pressure regimes remains challenging. Using laser-heated diamond anvil cells, we constructed the solidus curve of a natural fertile peridotite between 36 and 140 gigapascals. Melting at core-mantle boundary pressures occurs at 4180 ± 150 kelvin, which is a value that matches estimated mantle geotherms. Molten regions may therefore exist at the base of the present-day mantle. Melting phase relations and element partitioning data also show that these liquids could host many incompatible elements at the base of the mantle.

The fabrication and single electron transport of Au nano-particles placed between Nb nanogap electrodes.

We have fabricated Nb nanogap electrodes using a combination of molecular lithography and electron beam lithography. Au nano-particles with anchor molecules were placed in the gap, the width of which could be controlled on a molecular scale (approximately 2 nm). Three different anchor molecules which connect the Au nano-particles and the electrodes were tested to investigate their contact resistance, and a local gate was fabricated underneath the Au nano-particles. The electrical transport measurements at liquid helium temperatures indicated single electron transistor (SET) characteristics with a charging energy of about approximately 5 meV, and a clear indication of the effect of superconducting electrodes was not observed, possibly due to the large tunnel resistance.

Clinical significance of intramedullary Gd-DTPA enhancement in cervical myelopathy.

STUDY DESIGN: Prospective multicenter study. OBJECTIVE: To clarify the significance of intramedullary Gd-DTPA enhancement in cervical myelopathy, the prevalence, morphologic features, clinical relevance and postoperative change were investigated. SETTING: Four hospitals in Japan. METHODS: A total of 683 patients with cervical myelopathy who underwent decompressive surgery were consecutively examined. T1, 2 and Gd-DTPA-enhanced MRI were taken before surgery. Fifty consecutive cases without intramedullary enhancement were allocated in the non-enhancement group. The following variables were investigated: prevalence of the enhancement, the morphologic feature, the relationship between the enhancement and T2 high-intensity areas, the change of the Japanese Orthopedic Association (JOA) score for cervical myelopathy and the change of the enhancement after surgery. RESULTS: Intramedullary enhancement was observed in 50 cases (7.3%). The enhancements were observed between the most severely compressed disc and the cranial half of the lower vertebral body. On axial images, they were observed at the posterior or posterolateral periphery of the spinal cord. Enhancement areas were observed within T2 high-intensity areas and smaller than them. The preoperative JOA score was 9.8+/-2.8 points in the enhancement group and 9.8+/-3.3 points in the non-enhancement group (NS). The postoperative JOA score was 12.7+/-2.9 points in the enhancement group and 14.2+/-2.4 in the non-enhancement group (P=0.006). Intramedullary enhancement disappeared in 60% of the patients 1 year after surgery. CONCLUSION: Intramedullary enhancement indicated not the severity of preoperative symptoms, but a sign of a worse prognosis.

Prognostic significance of peritoneal tumour cells identified at surgery for colorectal cancer.

BACKGROUND: The prognostic significance of intraperitoneal tumour cells (IPCs) in colorectal cancer is not clear. This study aimed to determine whether detection of IPCs could be used a prognostic marker for selecting patients at high risk of recurrence. METHODS: The study included 226 patients with colorectal cancer who underwent elective resection. Clinical variables, including the presence of IPCs, were analysed for their prognostic significance. RESULTS: Thirty-three patients (14.6 per cent) were positive for IPCs. Univariable analysis indicated that the presence of IPCs was a significant prognostic factor in patients with stage III colorectal cancer; the 5-year disease-specific survival rate was 14 per cent in IPC-positive patients versus 79 per cent in those without IPCs (P < 0.001). Multivariable analysis showed that IPC positivity was the most robust prognostic factor in stage III disease (hazard ratio 2.2; P = 0.003), whereas nodal category (N1 or N2) showed no significant association with prognosis. In addition, IPCs were associated with haematogenous recurrence (P = 0.004) rather than peritoneal or local recurrence (P = 0.077) in patients with stage III disease. CONCLUSION: The presence of IPCs is a significant prognostic factor in patients with stage III colorectal cancer.