A Case of End-stage Renal Disease in Which Diazoxide was Effective in Treating Hypoglycemia Caused by Late Dumping Syndrome after Gastrectomy.

We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with ESRD. A 50-year-old man with end-stage renal disease (ESRD) and a history of gastrectomy underwent hemodialysis. Although he was administered voglibose to treat recurrent reactive hypoglycemia caused by late dumping syndrome, he had difficulty continuing treatment because of gastrointestinal side effects. When he began diazoxide treatment, the reactive hypoglycemia improved. The dose was gradually increased with no apparent side effects, and the hypoglycemic attacks disappeared one year after the start of treatment.

Assembly of four modules onto a tetraazide platform by consecutive 1,2,3-triazole formations.

Efficient consecutive 1,2,3-triazole formations using multiazide platforms are disclosed. On the basis of unique clickability of the 1-adamantyl azido group, a four-step synthesis of tetrakis(triazole)s was achieved from a tetraazide platform molecule. This method was applied to a convergent synthesis of tetrafunctionalized probes in a modular synthetic manner.

A facile preparation of functional cycloalkynes via an azide-to-cycloalkyne switching approach.

A facile method for preparing various functional cycloalkynes, including proteins incorporated with a cycloalkyne moiety, from the corresponding azides is developed. Treatment of diynes bearing strained and terminal alkyne moieties with a copper salt enabled terminal alkyne-selective click conjugation with azides, whereas a more azidophilic strained alkyne moiety was transiently protected from the click reaction via complexation with copper.

Staudinger reaction using 2,6-dichlorophenyl azide derivatives for robust aza-ylide formation applicable to bioconjugation in living cells.

Efficient formation of water- and air-stable aza-ylides has been achieved using the Staudinger reaction between electron-deficient aromatic azides such as 2,6-dichlorophenyl azide and triarylphosphines. The reaction proceeds rapidly and has been successfully applied to chemical modification of proteins in living cells.

Quantification of receptor activation by oxytocin and vasopressin in endocytosis-coupled bioluminescence reduction assay using nanoKAZ.

Oxytocin (OXT) and arginine vasopressin (AVP) are structurally similar neuropeptide hormones that function as neurotransmitters in the brain, and have opposite key roles in social behaviors. These peptides bind to their G protein-coupled receptors (OXTR and AVPRs), inducing calcium ion-dependent signaling pathways and endocytosis of these receptors. Because selective agonists and antagonists for these receptors have been developed as therapeutic and diagnostic agents for diseases such as psychiatric disorders, facile methods are in demand for the evaluation of selectivity between these receptors. In this study, we developed a quantitative assay for OXT- and AVP-induced endocytosis of their receptors. The mutated Oplophorus luciferase, nanoKAZ, was fused to OXTR and AVPRs to enable rapid quantification of agonist-induced endocytosis by bioluminescence reduction. Agonist stimulation significantly decreases bioluminescence of nanoKAZ-fused receptors in living cells. Using this system, we evaluated clinically used OXTR antagonist atosiban and a reported pyrazinyltriazole derivative, hereby designated as PF13. Atosiban acted as an antagonist of AVPR1a, as well as an agonist for AVPR1b, whereas PF13 antagonized OXTR more selectively than atosiban, as reported previously. This paper shows a strategy for quantification of agonist-induced endocytosis of OXTR and AVPRs, and confirms its potent utility in the evaluation of agonists and antagonists.

Periostin and its interacting proteins in the construction of extracellular architectures.

Periostin is a matricellular protein that is composed of a multi-domain structure with an amino-terminal EMI domain, a tandem repeat of four FAS 1 domains, and a carboxyl-terminal domain. These distinct domains have been demonstrated to bind to many proteins including extracellular matrix proteins (Collagen type I and V, fibronectin, tenascin, and laminin), matricellular proteins (CCN3 and ßig-h3), and enzymes that catalyze covalent crosslinking between extracellular matrix proteins (lysyl oxidase and BMP-1). Adjacent binding sites on periostin have been suggested to put the interacting proteins in close proximity, promoting intermolecular interactions between each protein, and leading to their assembly into extracellular architectures. These extracellular architectures determine the mechanochemical properties of connective tissues, in which periostin plays an important role in physiological homeostasis and disease progression. In this review, we introduce the proteins that interact with periostin, and discuss how the multi-domain structure of periostin functions as a scaffold for the assembly of interacting proteins, and how it underlies construction of highly sophisticated extracellular architectures.

Periostin is required for matricellular localization of CCN3 in periodontal ligament of mice.

CCN3 is a matricellular protein that belongs to the CCN family. CCN3 consists of 4 domains: insulin-like growth factor-binding protein-like domain (IGFBP), von Willebrand type C-like domain (VWC), thrombospondin type 1-like domain (TSP1), and the C-terminal domain (CT) having a cysteine knot motif. Periostin is a secretory protein that binds to extracellular matrix proteins such as fibronectin and collagen. In this study, we found that CCN3 interacted with periostin. Immunoprecipitation analysis revealed that the TSP1-CT interacted with the 4 repeats of the Fas 1 domain of periostin. Immunofluorescence analysis showed co-localization of CCN3 and periostin in the periodontal ligament of mice. In addition, targeted disruption of the periostin gene in mice decreased the matricellular localization of CCN3 in the periodontal ligament. Thus, these results indicate that periostin was required for the matricellular localization of CCN3 in the periodontal ligament, suggesting that periostin mediated an interaction between CCN3 and the extracellular matrix.

Insulin Autoimmune Syndrome Accompanied by Multiple Myeloma.

In 1981, a 48-year old man was diagnosed with insulin autoimmune syndrome. In 2005, he experienced a substantial increase in his monoclonal insulin antibody levels; in 2006 and 2007, serum monoclonal gammopathy and an 11% marrow plasmacyte ratio were confirmed. In 2012, asymptomatic multiple myeloma was diagnosed based on an increased γ-globulin fraction and serum M-protein (IgG) levels. The insulin antibody binding rate was 75.4% in 2005 and 78.8% in 2012. In 2012, he was hospitalized for ileus and died. Autopsy identified multiple myeloma and no endocrinological tumors in the pancreas.

Recent progress toward measles elimination in Hokkaido, Japan, during 2011-2012.

Laboratory diagnoses for measles were performed in a total of 97 cases in Hokkaido, Japan, during 2011-2012. Two patients were confirmed to be positive for measles virus (MV), both of whom lived in the Iburi district of Hokkaido. Molecular analysis of the nucleotide sequences of the nucleoprotein (N) gene revealed that these 2 strains had high homology with each other and belonged to the genotype D8. The onset interval of these cases and epidemiological data suggested that MV transmission had occurred between them and then terminated. Phylogenetic analysis of the N gene revealed that the strains identified in Hokkaido were classified into a cluster that contained many genotype D8 strains that were detected within a large area of Japan. Eventually, 9 cases were officially reported as measles. However, other than the abovementioned 2 cases, no genetic information regarding MV was obtained. In future, further active surveillance combined with the genetic investigation should be required in all suspected measles cases to verify the elimination status.

Prognostic significance of reversion-inducing cysteine-rich protein with Kazal motifs expression in resected pathologic stage IIIA N2 non-small-cell lung cancer.

BACKGROUND: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a novel membrane-anchored matrix metalloproteinase inhibitor, and experimental studies have shown that RECK can suppress tumor progression through angiogenesis inhibition. We have already revealed that enhanced RECK expression is significantly correlated with a favorable prognosis in non-small-cell lung cancer (NSCLC). In this study, further analyses focused on pN2 disease were conducted to assess the clinical significance of RECK expression. METHODS: A total of 118 patients with completely resected pathologic stage IIIA N2 NSCLC were retrospectively examined. RECK expression in the primary tumor, along with involved N2 nodes, was examined immunohistochemically. RESULTS: RECK expression in the primary tumor was strong in 53 patients (44.9%) and was weak in the other 65 patients. The 5-year survival rate of patients with RECK-strong tumor (42.9%) was significantly higher than that of patients with RECK-weak tumor (23.1%; P = .017). Reduced RECK expression significantly correlated with a poor prognosis for patients with a single N2 node involved (P = .019), but not for patients with multiple N2 nodes involved (P = .440). A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (P = .031). RECK expression in involved N2 nodes was significantly higher than in primary tumors (P < .001). CONCLUSIONS: RECK status was a novel prognostic factor in pathologic stage IIIA N2 NSCLC.

Magnetic field strength increase yields significantly greater contrast-to-noise ratio increase: Measured using BOLD contrast in the primary visual area.

RATIONALE AND OBJECTIVE: The advantage of a higher static magnetic field for functional MRI has been advocated; however, the observed advantage varies. The aim of this study was to evaluate the effect of increasing static magnetic field strength on the task-related increase in blood oxygenation level-dependent (BOLD) signal and residual noise with visual stimuli of different frequencies, which may enable better comparisons of results of different MRI scanners. MATERIALS AND METHODS: Eight right-handed healthy volunteers were presented checkerboard stimuli flickering at 5 different frequencies up to 8 Hz. Field strengths of 3 T or 1.5 T were used to measure frequency-dependent signal changes in the primary visual area. Regression analysis was performed for the signal increase and the "noise," which was defined by the root mean of squares of the residual signal fluctuation. These values were compared and their relationship was analyzed. Imaging parameters were identical except for the use of a 25% shorter echo time using 3 T. RESULTS: The frequency-dependent increase in BOLD signal using 3 T was twice that using 1.5 T. In contrast, the ratio of noise values that reflect time-course signal fluctuation (3 T/1.5 T) was only 0.88. There was large individual variance in these values, but the slope and noise values were linearly related using either field strength. The contrast-to-noise ratio using 3 T was 2.3 times higher than that using 1.5 T. CONCLUSION: There was a greater-than-linear increase in the contrast-to-noise ratio compared with the increase of field strength, demonstrating an advantage of using higher field strengths in fMRI studies.

Assessing the impact of the September 11 terrorist attacks on U.S. airline demand.

This paper assesses the impact of the September 11 terrorist attacks and its after-effects on U.S. airline demand. Using monthly time-series data from 1986 to 2003, we find that September 11 resulted in both a negative transitory shock of over 30% and an ongoing negative demand shock amounting to roughly 7.4% of pre-September 11 demand. This ongoing demand shock has yet to dissipate (as of November 2003) and cannot be explained by economic, seasonal, or other factors.

Pit-fall sign on computed tomography predicts pleural involvement and poor prognosis in non-small cell lung cancer.

Pleural involvement by a peripheral non-small cell lung cancer (NSCLC) is an important prognostic factor, but the accurate preoperative evaluation is sometimes difficult. We have already identified a feature on computed tomography (CT) that suggests a possible pleural involvement (pit-fall sign, i.e. multiple linear strands between the nodule and chest wall and/or inter-lobar fissure), and the clinical impact was assessed in the present study. A total of 103 consecutive peripheral NSCLC patients were prospectively examined, and the sensitivity, specificity, and accuracy of pit-fall sign in the diagnosis of pleural involvement were 83.3, 76.1, and 78.6%, respectively. The 5-year survival rate of pit-fall sign-positive patients was 46.5%, which was significantly lower than that of pit-fall sign-negative patients (68.9%; P = 0.044), and the prognostic significance was confirmed by a multivariate analysis. In conclusion, the pit-fall sign on preoperative CT suggests a possible pleural involvement correlated with a poor prognosis.

Skip mediastinal nodal metastases in non-small cell lung cancer.

OBJECTIVE: To reveal the incidence and clinical significance of mediastinal nodal metastases without N1-station nodal metastases ('skip-N2 metastases') in non-small cell lung cancer (NSCLC). METHODS: A total of 450 NSCLC patients who underwent tumor resection with a systemic mediastinal nodal dissection were retrospectively reviewed. p53 status and proliferative activity represented as proliferative index (PI) were also examined immunohistochemically. RESULTS: Skip-N2 metastases were documented in 49 (13%) patients of all 450 patients; among 334 patients without N1-nodal involvement, 18% patients had skip-N2 metastases. The postoperative survival of skip-N2 patients was almost same as that for patients with metastases to both N1 and N2 nodes. Skip-N2 metastases were significantly more frequent in male patients and squamous cell carcinoma patients. In addition, the mean PI for tumor with skip-N2 metastases was significantly higher than that for any other pathologic nodal (pN)-status diseases. Combined with histologic type and PI, the incidences of skip-N2 metastases for adenocarcinoma showing lower PI were only 5% (7/137) of all patients and 7% (7/94) of patients without N1-nodal involvement. CONCLUSIONS: N1 nodal status is not a useful predictor of N2 nodal status in NSCLC, because skip-N2 metastases were documented in 18% patients showing no N1-nodal involvement. However, N1 node-guided dissection might be performed in patients with adenocarcinoma showing lower PI, because the incidence of skip-N2 metastases was extremely low.

Prognostic factors in resected pathologic (p-) stage IIIA-N2, non-small-cell lung cancer.

BACKGROUND: Postoperative prognosis for patients with pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) is poor, and significant factors that influence the prognosis remain unclear. METHODS: A total of 99 patients who underwent complete resection for p-stage IIIA-N2 NSCLC without any preoperative therapy were retrospectively reviewed. Biological features such as tumor angiogenesis (intratumoral microvessel density [IMVD]), proliferative activity (proliferative index [PI]), and p53 status were also evaluated immunohistochemically. RESULTS: Univariate analysis revealed that the number of involved N2 stations was a significant prognostic factor; 5-year survival rates for a tumor with metastases in single N2 stations, tumor with metastases in two N2 stations, and tumor with metastases in 3 or more N2 stations were 41.6%, 35.3%, and 0.0%, respectively (P =.041) In addition, the 5-year survival rate for cN0-1 disease was significantly higher than that for cN2 disease (41.9% and 25.5%, respectively; P =.048) Tumor angiogenesis and proliferative activity were the most significant prognostic factors; 5-year survival rates for lower-IMDV tumor and higher-IMVD tumor were 53.6% and 15.9%, respectively (P =.002), and those for lower-PI tumor and higher-PI tumor were 47.0% and 20.4%, respectively (P =.019) There was no difference in the postoperative survival between tumor showing aberrant p53 expression and tumor showing no aberrant p53 expression. These results were confirmed by a multivariate analysis. CONCLUSIONS: P-stage IIIA-N2 NSCLC cases represented a mixture of heterogeneous prognostic subgroups, and the number of involved N2 stations, cN status, PI, and IMVD were significant predictors of the survival.

[Clinical results of LINAC-based stereotactic radiosurgery for pituitary adenoma].

PURPOSE: We retrospectively evaluated our clinical results of stereotactic radiosurgery (SRS) for pituitary adenoma. MATERIALS AND METHODS: Between 1995 and 2000, 13 patients were treated with SRS for pituitary adenoma. In all cases, the tumors had already been surgically resected. The adenomas were functional in 5 and non-functional in 8 patients. The median follow-up period was 30 months. SRS was performed with the use of a dedicated stereotactic 10-MV linear accelerator (LINAC). The median dose to the tumor margin was 15 Gy. The dose to the optic apparatus was limited to less than 8 Gy. RESULTS: MR images of 12 patients revealed tumor CR in one case and PR in 9 cases; in the remaining two patients, tumor size decreased by less than 50%. There was no recognizable regrowth of any of the tumors. In two of four GH-secreting adenomas, hormonal overproduction normalized, while the other two showed reduced hormonal production. One PRL-secreting adenoma did not respond. Reduction of visual acuity and field was seen in one patient. This patient also had a brain infarction. None of the patients developed brain radionecrosis or radiation-induced hypopituitarism. CONCLUSION: Although further studies based on greater numbers of cases and longer follow-up periods are needed, our results suggest that SRS seems to be a safe, effective treatment for pituitary adenoma.

Validation of the dual-table autoradiographic method to quantify two sequential rCBFs in a single SPET session with N-isopropyl-[123I] p-iodoamphetamine.

We evaluated an autoradiographic (ARG) method to calculate regional cerebral blood flow (rCBF) sequentially before and after an acetazolamide (ACZ) challenge in a single session of single-photon emission tomography (SPET) with two injections of N-isopropyl-[(123)I] p-iodoamphetamine (IMP). The method uses a table look-up method with a fixed distribution volume (Vd) and a standard input function of IMP. To calculate rCBF after an ACZ challenge, two look-up tables (a dual-table) are used to reflect the effect of radioactivity in the brain from the first dose of IMP. We performed simulation studies to evaluate errors attributable to (a) a change in rCBF induced by an ACZ challenge during the scan and (b) a fixed Vd value that might be different from an individual one, along with the effect of (c) scan length. Thirty-three patients were studied by dynamic SPET with two injections of IMP and frequent arterial blood sampling, and the data were analysed using the dual-table ARG method. Twenty-four of the 33 patients received an injection of ACZ 10 min before the second dose of IMP. We generated a standard input function by averaging individual input functions. The optimal method to calibrate a standard input function was determined so that the SD of differences between rCBF calculated by using a calibrated standard input function (F(SIF)) and that calculated by using an individual input function (F(IIF)) was minimised. Reliability of the method was evaluated by comparing F(SIF) with gold standard rCBF (F(REF)) obtained by two-compartment model analysis of dynamic SPET data and an individual input function with a non-linear least squares fitting method. Errors caused by (a) were less than 4% for a first rCBF ranging between 20 and 60 ml 100 g(-1) min(-1) and an rCBF change of between -25% and 50%. Errors caused by (b) were relatively large compared with those caused by (a), and were affected by (c) with an increasing error in a longer scan. In the patient study with a proposed scan protocol of 25 min for the first and 15 min for the second measurement, the error attributable to the standard input function was smaller when calibrated with a continuously drawn arterial blood sample (random error of 3.8% for continuous 10-min arterial blood sampling after the second dose of IMP) than with a single arterial blood sample (random error of 9.0% at 5 min after the second dose of IMP). Systematic and random errors of F(SIF) compared with F(REF) were 0.0% and 6.3%, respectively. The dual-table ARG method can be reliably used to quantify rCBF before and after an ACZ challenge with a 40-min scan protocol and continuous arterial blood sampling for several minutes.

Age-dependent change in metabolic response to photic stimulation of the primary visual cortex in infants: functional magnetic resonance imaging study.

The blood oxygen level-dependent (BOLD) response to photic stimulation in the primary visual cortex (V1) reverses from positive to negative around 8 weeks of age. This phenomenon may be caused by increased oxygen consumption during stimulation as the result of a rapid increase of synaptic density at this age. To test this hypothesis, we applied existing mathematic models of BOLD signals to the experimental data from infants. When the stimulus-related increments of cerebral blood flow and cerebral blood volume were fixed at 60% and 20%, respectively, the mean estimated increment of the cerebral metabolic rate of oxygen of the V1 in the elder infant group (57.1% +/- 8.8%) was twice as large as that in the younger infant group (32.2% +/- 4.7%), which corresponds to the reported difference in synaptic density. The present data confirmed that a change in oxygen consumption could explain a transition from a positive to a negative BOLD response.