Neurons react differently to incoming stimuli depending upon their previous history of stimulation. This property can be considered as a single-cell substrate for transient memory, or context-dependent information processing: depending upon the current context that the neuron "sees" through the subset of the network impinging on it in the immediate past, the same synaptic event can evoke a postsynaptic spike or just a subthreshold depolarization. We propose a formal definition of History-Dependent Excitability (HDE) as a measure of the propensity to firing in any moment in time, linking the subthreshold history-dependent dynamics with spike generation. This definition allows the quantitative assessment of the intrinsic memory for different single-neuron dynamics and input statistics. We illustrate the concept of HDE by considering two general dynamical mechanisms: the passive behavior of an Integrate and Fire (IF) neuron, and the inductive behavior of a Generalized Integrate and Fire (GIF) neuron with subthreshold damped oscillations. This framework allows us to characterize the sensitivity of different model neurons to the detailed temporal structure of incoming stimuli. While a neuron with intrinsic oscillations discriminates equally well between input trains with the same or different frequency, a passive neuron discriminates better between inputs with different frequencies. This suggests that passive neurons are better suited to rate-based computation, while neurons with subthreshold oscillations are advantageous in a temporal coding scheme. We also address the influence of intrinsic properties in single-cell processing as a function of input statistics, and show that intrinsic oscillations enhance discrimination sensitivity at high input rates. Finally, we discuss how the recognition of these cell-specific discrimination properties might further our understanding of neuronal network computations and their relationships to the distribution and functional connectivity of different neuronal types.

BACKGROUND

This is a methodological study investigating the online responses to a national debate over an important health and social problem in Russia. Russia is the largest Internet market in Europe, exceeding Germany in the absolute number of users. However, Russia is unusual in that the main search provider is not Google, but Yandex.

OBJECTIVE

This study had two main objectives. First, to validate Yandex search patterns against those provided by Google, and second, to test this method's adequacy for investigating online interest in a 2010 national debate over Russian illicit drug policy. We hoped to learn what search patterns and specific search terms could reveal about the relative importance and geographic distribution of interest in this debate.

METHODS

A national drug debate, centering on the anti-drug campaigner Egor Bychkov, was one of the main Russian domestic news events of 2010. Public interest in this episode was accompanied by increased Internet search. First, we measured the search patterns for 13 search terms related to the Bychkov episode and concurrent domestic events by extracting data from Google Insights for Search (GIFS) and Yandex WordStat (YaW). We conducted Spearman Rank Correlation of GIFS and YaW search data series. Second, we coded all 420 primary posts from Bychkov's personal blog between March 2010 and March 2012 to identify the main themes. Third, we compared GIFS and Yandex policies concerning the public release of search volume data. Finally, we established the relationship between salient drug issues and the Bychkov episode.

RESULTS

We found a consistent pattern of strong to moderate positive correlations between Google and Yandex for the terms "Egor Bychkov" (r(s) = 0.88, P < .001), "Bychkov" (r(s) = .78, P < .001) and "Khimki"(r(s) = 0.92, P < .001). Peak search volumes for the Bychkov episode were comparable to other prominent domestic political events during 2010. Monthly search counts were 146,689 for "Bychkov" and 48,084 for "Egor Bychkov", compared to 53,403 for "Khimki" in Yandex. We found Google potentially provides timely search results, whereas Yandex provides more accurate geographic localization. The correlation was moderate to strong between search terms representing the Bychkov episode and terms representing salient drug issues in Yandex-"illicit drug treatment" (r(s) = .90, P < .001), "illicit drugs" (r(s) = .76, P < .001), and "drug addiction" (r(s) = .74, P < .001). Google correlations were weaker or absent-"illicit drug treatment" (r(s) = .12, P = .58), "illicit drugs " (r(s) = -0.29, P = .17), and "drug addiction" (r(s) = .68, P < .001).

CONCLUSIONS

This study contributes to the methodological literature on the analysis of search patterns for public health. This paper investigated the relationship between Google and Yandex, and contributed to the broader methods literature by highlighting both the potential and limitations of these two search providers. We believe that Yandex Wordstat is a potentially valuable, and underused data source for researchers working on Russian-related illicit drug policy and other public health problems. The Russian Federation, with its large, geographically dispersed, and politically engaged online population presents unique opportunities for studying the evolving influence of the Internet on politics and policy, using low cost methods resilient against potential increases in censorship.

Neuronal-growth-inhibitory factor (GIF) is a metalloprotein specific to the central nervous system which has been linked to Alzheimer's disease. The high metal content, approximately seven metal atoms/protein molecule, and 70% sequence identity to mammalian metallothioneins (MT), including a preserved array of 20 cysteinyl residues, place GIF in the family of MT. In contrast to MT, native GIF isolated from human or bovine brain contains an unusual metal composition, viz. four Cu(I) and three Zn(II) per polypeptide chain. Cu and/or Zn K-edge X-ray absorption spectra have been recorded for native Cu, Zn-GIF, Zn-substituted GIF, and these metals bound to the 32-residue N-terminal domain, Cu4-, Cu6- or Zn3-GIF-(1-32) at 77 K. The results are consistent with the metals being bound to the protein by cysteinyl residues in every case. The Cu-S distance is approximately 2.25 A and the EXAFS is considered to be consistent with primarily trigonal coordination of the Cu(I); Cu...Cu backscattering is observed at approximately 2.67 A, indicative of the formation of Cu(x)(Scys)y clusters. Thus, the Cu(I) environment is similar to that observed in MT. This is also the case for Zn(II), with 4 S at approximately 2.34 A. However, in contrast to Zn-MT for Zn-substituted GIF and Zn3-GIF-(1-32), Zn...Zn backscattering is observed at approximately 3.28 A. The significance of these results are discussed with respect to the specific biological activity of GIF.

BACKGROUND

The differences between 2-way and 4-way angulation endoscopes for use in unsedated patients undergoing transnasal EGD have not been elucidated.

OBJECTIVE

Our purpose was to evaluate the feasibility and tolerance of 2- and 4-way angulation endoscopes for unsedated transnasal EGD in GI cancer screening of elderly people.

METHODS

A total of 291 patients were randomized to receive unsedated transnasal EGD with a 5.2-mm diameter 2-way angulation endoscope (GIF-N260, Olympus, Tokyo, Japan) (n = 146) or 5.5-mm diameter 4-way angulation endoscope (XGIF-XP240N2, Olympus) (n = 145). The transnasal insertion success rate and incidence of epistaxis were compared. The following parameters were evaluated: overall quality of the examination, ease of passing the endoscope through the pylorus, intubation of the second portion of the duodenum, ability to observe the entire upper GI tract and perform target biopsy, and examination time. Patient tolerance and acceptance were also assessed with regard to nasal pain, choking, gagging, abdominal discomfort, and overall pain and discomfort.

METHODS

Matsushita Health Care Center, Moriguchi, Japan.

METHODS

A total of 291 patients had unsedated transnasal EGD as part of a gastric cancer screening program.

RESULTS

Use of the pediatric 4-way angulation endoscope significantly shortened the examination time when biopsy was performed compared with the 2-way angulation instrument, whereas the examination time without biopsy was not significantly different. Other parameters were not significantly different between the 2 endoscopes.

CONCLUSIONS

For unsedated transnasal EGD with biopsy, the 5.5-mm 4-way angulation videoscope shortens examination time while providing easy transnasal insertion and improved patient tolerance.

OBJECTIVE

A prospective technical feasibility study of cap assisted ESD for 'curative intent' in patients with residual or local neoplastic recurrence following EMR. Primary end points were second stage R0 resection rate, safety and recurrence.

METHODS

Salvage ESD was performed using the Olympus GIF-XQ240 gastroscope and KD-630L insulation tipped knife. Thirty-day mortality, re-admission rates, complications and histological resection status were collected prospectively up to 9 months following index resection.

RESULTS

Thirty patients met eligibility criteria. Index R0 resection was achieved in 25/30 (83%) lesions. One patient underwent surgical excision with a second receiving a curative second stage dissection. Ninety-six per cent (29/30) patients were discharged within 24 h of the procedure with a 0% 30-day mortality and re-admission rate. Bleeding occurred in 5/30 (16%) treated successfully with endoluminal haemostasis. There were no perforations. Overall 'cure' rates at short-term follow-up [median 6/12 (range; 3-18)] was 96%.

CONCLUSIONS

This novel application of ESD for first line 'salvage' therapy in treating residual or locally recurrent neoplastic disease may be a safe, minimally invasive and cost effective alternative to direct surgical resection in a select patient cohort.

Immunohistochemical study on growth inhibitory factor (GIF) in rat brain has revealed that a glial cell layer on the surface of cerebral cortex and the cells surrounding Purkinje cells has been reported. In addition, neurons in gray matter were weakly immunostained for GIF. In situ hybridization using digoxigenin-labeled single-strand RNA probes also demonstrated that most of the neurons and small round cells, which were presumably astrocytes, expressed GIF mRNA in the cerebral cortex of rat brain. These findings indicate that GIF is produced in neurons as well as in astrocytes. The most prominent findings in this study are, a very strong reaction of GIF and GIF mRNA in the reactive astrocytes around the site of injury induced by stab wound or kainic acid injection. These results raised the possibility that GIF may act as an acute-phase protein in reactive astrocytes and have a role in tissue repair.

OBJECTIVE

Soluble mesothelin-related peptide (SMRP) is regarded as a biomarker of malignant pleural mesothelioma (MPM). Herein, we compared the diagnostic performances of SMRP in matched pleural effusion (PE-SMRP) and serum (S-SMRP).

METHODS

Diagnosis on pleural biopsies was performed for all patients including 43 with MPM, 23 with non-MPM pleural metastases (MTS) and 36 with benign (BNG) pleural diseases. SMRP was measured by a MesoMark ELISA (Cis-Bio International Gif/Yvette; France).

RESULTS

Using the receiver operating characteristic (ROC) analysis, 12.70 and 1.08 nM were detected as cut-off values to optimal discrimination for PE-SMRP and S-SMRP, respectively. PE-SMRP showed a better diagnostic accuracy than S-SMRP in MPM vs. MTS+BNG (area under the ROC curve=81.6 vs. 70.5; sensitivity=69.8% vs. 46.5%; specificity=88.1% vs. 84.7%; diagnostic odds ratio (DOR)=17.1 vs. 4.8). In S-SMRP-negative patients, PE-SMRP maintained an acceptable performance (Sensitivity=47.8%; DOR=8.3; p=0.001), whereas in PE-SMRP-negative patients, S-SMRP performed very poorly (Sensitivity=15.4%; DOR=1.2; p=0.858).

CONCLUSIONS

PE-SMRP detection has a superior diagnostic accuracy than S-SMRP detection in the diagnosis of MPM.

We investigated whether visual complexity of novel abstract patterns affects perceived duration. Previous research has reported that complex visual stimuli led to an underestimation of durations. However, to clarify the nature of the time estimation process, it is necessary to establish which component of image complexity, spatial or semantic, plays the critical role. Here we tested the impact of specific spatial properties. We used unfamiliar and abstract patterns made using black-and-white checkerboards in which the difference between stimuli was exclusively in configuration. Visual complexity was quantified by the GIF index based on a compression algorithm, which scanned the pattern in both horizontal and vertical directions. This metric correlated positively with subjective complexity (Experiment 1A). In the second study, we increased variability in the stimuli by changing the number of items across patterns while keeping overall size constant. A high positive correlation was found between objective and subjective complexity (r = 0.95) (Experiment 2A). In Experiments 1B and 2B, observers estimated pattern durations in seconds using a continuous scale. A multilevel linear analysis found that perceived duration was not predicted by visual complexity for either of the two sets of stimuli. These results provide new constraints to theories of time perception, hypothesizing that complexity leads to an underestimation of duration when it reduces attention to time.

OBJECTIVE

This study was done to determine whether the use of reference values obtained in children with idiopathic short stature (ISS) improved the clinical value of serum insulin-like growth factor I (IGF-1) as a tool for diagnosing GH deficiency (GHD) in prepubertal children.

METHODS

Serum IGF-1 was measured with a new IRMA kit (IGFI-RIA CT, Cis Bio, Gif sur Yvette, France) in 168 prepubertal normal children and in prepubertal children with ISS (n = 68), organic GHD due to a craniopharyngioma (oGHD, n = 15) and permanent idiopathic GHD (iGHD, n = 28).

RESULTS

IGF-1 was lower (P < 0.001) in iGHD than in either ISS or oGHD and was below the fifth percentile of the normal range in 29/68 ISS (43%), 8/15 oGHD (53%) and 28/28 (100%) iGHD patients. Three oGHD (20%) and two iGHD (7%) patients had a serum IGF-1 below the fifth percentile of the normal group but above the fifth percentile of the ISS group. Thus, a serum IGF-1 below the fifth percentile of the normal group distinguished between normal children and iGHD with 100% sensitivity, between normal and oGHD with 53% sensitivity and between normal and all GHD (idiopathic + organic) with 84% sensitivity; the overall specificity was only 57%. Conversely, a serum IGF-1 below the fifth percentile of the ISS population distinguished between ISS and iGHD with 93% sensitivity, between ISS and oGHD with 33% sensitivity and between ISS and all GHD with 72% sensitivity; the overall specificity was then 95%.

CONCLUSIONS

A serum IGF-1 within the normal range virtually excludes idiopathic GHD but does not rule out organic GHD, whereas an IGF-1 below the ISS range is strongly in favour of GHD, after exclusion of poor nutritional status and/or liver disease. An IGF-1 below the normal range but in the idiopathic short stature range gives no definitive conclusion even when it is associated with a low GH peak. Thus, whereas reference values obtained in normal children must be used to interpret serum IGF-1 in short prepubertal children, reference data obtained in idiopathic short stature children should also be taken into account.

Reproductive success of angiosperms relies on the precise development of the gynoecium and the anther, because their primary function is to bear and to nurture the embryo sac/female gametophyte and pollen, in which the egg and sperm cells, respectively, are generated. It has been known that the GRF-INTERACTING FACTOR (GIF) transcription co-activator family of Arabidopsis thaliana (Arabidopsis) consists of three members and acts as a positive regulator of cell proliferation. Here, we demonstrate that GIF proteins also play an essential role in development of reproductive organs and generation of the gamete cells. The gifgifgifgif triple mutant also displayed severe structural and functional defects in the anther, producing neither microsporangium nor pollen grains. Therefore, we propose that the GIF family of Arabidopsis is a novel and essential component required for the cell specification maintenance during reproductive organ development and, ultimately, for the reproductive competence.

Beginning about three years ago, the world of academic publishing has become infected by fake impact factors and misleading metrics that are launched by bogus companies. The misleading metrics and fake impact factors have damaged the prestige and reliability of scientific research and scholarly journals. This article presents the in-depth story of some of the main bogus impact factors, how they approached the academic world, and how the author identified them. Some names that they use are Universal Impact Factor (UIF), Global Impact Factor (GIF), and Citefactor, and there even is a fake Thomson Reuters Company.

It is known that local filtering-based edge preserving smoothing techniques suffer from halo artifacts. In this paper, a weighted guided image filter (WGIF) is introduced by incorporating an edge-aware weighting into an existing guided image filter (GIF) to address the problem. The WGIF inherits advantages of both global and local smoothing filters in the sense that: 1) the complexity of the WGIF is O(N) for an image with N pixels, which is same as the GIF and 2) the WGIF can avoid halo artifacts like the existing global smoothing filters. The WGIF is applied for single image detail enhancement, single image haze removal, and fusion of differently exposed images. Experimental results show that the resultant algorithms produce images with better visual quality and at the same time halo artifacts can be reduced/avoided from appearing in the final images with negligible increment on running times.

BACKGROUND

Patients with esophageal cancer often present with dysphagia and malnutrition. Obstructive symptoms may improve after radiotherapy and chemotherapy. Nutrition support via a nasogastric tube (NG) or gastrostomy is very important during treatment. The newly developed ultrathin endoscope (Olympus, GIF-N230, outer diameter: 6 mm) has a smaller diameter than the standard endoscope and can be introduced into the esophagus via the nasal cavity. This article reports on the use of an ultrathin endoscope for NG placement for patients with esophageal cancer who presented with dysphagia and failed traditional NG tube placement.

METHODS

A consecutive series of 40 patients with esophageal cancer were referred to our hospital from November 2001 to October 2002 for endoscopic placement of NG tubes due to failure of traditional methods of NG placement. An ultrathin endoscope was used to advance the guidewire into the stomach via the nasal cavity. After withdrawal of the scope, the NG tube was inserted over the guidewire under fluoroscopy.

METHODS

A total of 71 procedures were performed in 40 patients (37 males, 3 females), age 57 +/- 15 years (range, 37-91 y). Seventy procedures (99%) were successful in completing NG tube placement by using an ultrathin transnasal endoscope. Only one procedure failed because the esophageal lumen was completely occluded and the guidewire was not able to be passed through the obstructed site. The average duration that the NG tube was left in place was 49 +/- 35 days (range, 2-144 days). No procedure-related complications, such as bleeding or perforation, occurred.

CONCLUSIONS

Using ultrathin transnasal endoscopy to place an NG tube for esophageal cancer patients is effective and safe. It simplifies the procedures and increases the success rate.

The interaction of angular and linear stimuli produces a complex alignment of spatial orientation and the VOR. This phenomenon was studied by measuring three dimensional eye movements in 6 squirrel monkeys during centrifugation in the dark. The axis of eye rotation was always aligned with gravity and with the spinal axis of the upright monkeys. The erect monkeys were oriented such that they were either facing toward the direction of motion or were facing away from the motion. Angular velocity trapezoids were utilized as the motion stimuli with a ramp acceleration of 10 degrees/s2 to a constant velocity of 200 degrees/s. This yields a final centripetal acceleration of 1 g. The orientation of centripetal acceleration dramatically altered the VOR by changing the axis of eye rotation, the peak value of slow phase eye velocity, and the time constant of per-rotary decay. The axis of eye rotation always tended to align with gravito-inertial force, the peak value of slow phase eye velocity was greater when the monkey faced the motion than when it faced away from the motion, and the time constant of decay was smaller when the monkey faced the motion than when it faced away from the motion. These findings were statistically significant (p less than 0.05) and were consistent across all monkeys. The data also indicate that the VOR may be separated into two reflexes, a linear reflex and a rotational reflex. The linear reflex decays as the axis of eye rotation aligns with gravito-inertial force (GIF). These results indicate that GIF is resolved into two components: one representing an internal estimate of linear acceleration and one representing an internal estimate of gravity.

The glycosylation-inhibiting factor (GIF) was isolated from serum-free culture supernatants of the murine T-cell hybridoma, 231F1 cells, by using an immunosorbent coupled with the monoclonal anti-lipomodulin antibody. The isolated lymphokine is a 14-kDa protein with a pI of 5.5, as determined by SDS/PAGE and two-dimensional gel electrophoresis. Fractionation of a mixture of radiolabeled GIF with culture supernatant of the 231F1 cells on ion-exchange and reverse-phase columns and by gel filtration demonstrated homogeneity of the 14-kDa GIF and confirmed that the bioactivity of GIF and the antigenic determinant recognized by the monoclonal anti-GIF antibody are associated with the 14-kDa protein. The 125I-labeled 14-kDa protein binds to the murine T-cell hybridoma 12H5 cells, which have been used for bioassay of GIF, and the murine B-cell line A20.3 cells, but the binding of the protein to resting murine splenic lymphocytes was barely detectable. Under the same experimental conditions, binding of the 125I-labeled recombinant human lipocortin I to the 12H5 cells was not detectable. In contrast, the 125I-labeled lipocortin, but not the 14-kDa GIF, bound to phosphatidylserine vesicles. The results indicate that GIF does not belong to the anexin family.

Neuronal growth-inhibitory factor (GIF), a central-nervous-system-specific metallothionein-like protein, has been isolated by means of an improved isolation procedure from bovine brain. The native protein contains 4-5 Cu+ and 2-2.5 Zn2+, which results in an overall stoichiometry of 6-7 mol metal ions/mol protein. Native Cu, ZN-GIF and the Zn2+ -substituted and Cd2+-substituted metalloforms have been characterized by means of electronic-absorption, CD, magnetic-circular-dichroism (MCD) and low-temperature (77 K) Cu(I)-luminescence spectroscopy. Analysis of the metal-induced-charge-transfer transitions below 300 nm in the electronic-absorption and CD spectra of Cu, ZN-GIF revealed spectral features characteristic of metal-thiolate coordination. The presence of formally spin-forbidden 3d ->> 4s Cu(I)-cluster-centered transitions, above 300 nm in the corresponding CD and MCD spectra indicate the existence of a Cu(I) cluster. The 77-K luminescence spectrum of Cu, ZN-GIF revealed two emissive bands at approximately 420 nm and 570 nm, which were reported also for CU4 clusters in mammalian Cu8-metallothionein. By analogy with Cu8-metallothionein, we propose the presence of a Cu4 cluster with similar electronic structure in native GIF. However, the determined Cys/Cu+ ratio of approximately 2:1 in Cu, Zn-GIF is higher than the ratio found in mammalian Cu(I)-metallothionein forms (approximately 1.6:1 ), which implies that the coordination geometry of CU+-binding sites is different in the CU4 Cluster. The spectroscopic characterization of Zn2+-substituted and Cd2+-substituted GIF (6-7 metal ions/protein) showed CD and MCD features at positions identical to those reported for the well-characterized mammalian Zn7-metallothionein and Cd7-metallothionein. Therefore, it is inferred that the cluster organization in GIF with divalent metal ions is comparable to that found in mammalian metallothioneins. The effect of metal ions on the protein structure with regard to the biological function of GIF is discussed.

An important locus for Atopy (familial asthma, hay fever and eczema) has been localized to the 11q12-q13 region with the minimum recombination fraction around the CD20 gene. We have constructed a 2.8 megabase (Mb) Yeast Artificial Chromosome (YAC) contig of the candidate region using 15 STSs. A total of seven genes have been mapped within this interval in the order cen-OSBP-TCN1-GIF-Fc epsilon RI beta-CD20-CD5-PGA-q(ter) and can be covered by a minimum of eight YAC clones. Contig integrity was assayed with fluorescence in-situ hybridization (FISH) and the mapping of YAC ends on somatic cell and radiation hybrid panels. A long range restriction map of the contig has been constructed to establish the order of and distance between loci. Two promising candidates for the atopy locus, the beta subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI beta) and CD20, a molecule involved in B cell differentiation, have been placed within the contig.

The purpose of present study is to examine effect of binary lipid matrix (combination of lipids) on the entrapment and storage stability of repaglinide (RG) loaded solid lipid nanoparticles (SLN). Solid lipid nanoparticles were prepared by modified solvent injection method for oral delivery to improve the bioavailability of RG, an antidiabetic drug. The stearic acid and tristearin were used to form lipid core materials, and Pluronic-F68 was used as a stabilizer. Nanoparticles were characterized by evaluating their particle size, zeta potential, entrapment efficiency, drug loading, solid-state studies (differential scanning calorimetry, X-ray diffraction), in vitro drug release, particle surface (transmission electron microscopy analysis with electron diffraction pattern), stability study in gastrointestinal fluids (GIFs) and storage stability at 30 °C/65% RH for 3 months. The characterization of SLN suggested that binary lipid matrix based nanoparticles had better drug entrapment and loading, desired release characteristics, stable in GIFs and significantly higher storage stability compared with single lipid formulations. Pharmacodynamic (blood glucose, blood cholesterol, blood triglyceride levels) and pharmacokinetic (AUC, T(max), peak plasma concentrations, K, t(1/2), mean residence time and relative bioavailabilities) studies were performed for the selected formulations. These studies indicate that the formulation based on binary lipid matrix significantly improves the oral bioavailability of RG.

The effect of leukocyte antibodies detected under different conditions on the fate in vivo of granulocytes was studied using 111-indium-labeled granulocytes. Sera from patients were tested by granulocyte agglutination (GA), granulocytotoxicity (GC), granulocyte immunofluorescence (GIF), lymphocytotoxicity (LC), and antibody-dependent lymphocyte-mediated granulocytotoxicity. Granulocytes from donors to be studied were labeled with 111-indium and injected. Then the intravascular recovery and survival or tissue localization was determined in 93 studies. Antibodies detected by granulocyte agglutination were associated with a significant reduction in recovery (6.7% v 30.8% in controls; P less than .001) and t1/2 (0.3 hours v 5.6 hours in controls; P = .002). When all possible combinations of serum reactivity were considered, reactivity in the GA plus GIF assays had the best correlation with decreased recovery (R2 = .49; P less than .001) and t1/2 (R2 = .73; P less than .001). When the relationship between the strength of antibody reactivity and the recovery and t1/2 were analyzed, the best relationship was between the combination of LC and GIF with recovery (R2 = .62; P = .001). Because of the general availability of the HLA (LC) testing, the role of LC reactivity was investigated in other ways. There was a strong relationship between sera highly reactive by LC and those reactive by GIF. These highly reactive sera were also associated with reduced recovery and t1/2. The influence of specific HLA antigen mismatches was also studied. When donor and recipient were mismatched for the HLA-A2, B8, or BW44 antigens, there was a significant reduction in either recovery, t1/2, or both. Tissue localization was studied by body scans in patients with and without known sites of inflammation. Antibodies detected by a combination of GA and GIF caused abnormal pulmonary sequestration of granulocytes (three cases) and failure of granulocytes to localize at known sites of inflammation (three cases). HLA (LC) antibodies did not alter tissue localization despite the presence of the corresponding HLA antigens on granulocytes. It appears that GA, GIF, or a combination of these tests is the most effective predictor of altered in vivo fate of granulocytes. However, sera highly reactive by LC and GIF probably define a group of highly immunized patients in whom granulocyte recovery and t1/2 are also reduced. Mismatching for certain HLA antigens is also associated with reduced granulocyte recovery and survival. At present, GA, with or without the immunofluorescence assay, is the most effective predictor of altered in vivo granulocyte activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Human T cell hybridomas, which constitutively secrete glycosylation inhibiting factor (GIF), were constructed from PBL of an allergic individual who was sensitive to honey bee venom. PBMC of the patient were stimulated with either denatured or cyanogen bromide-treated bee venom phospholipase A2 (PLA2), and Ag-activated cells were propagated by IL-2 in the presence of human recombinant lipocortin I. T cells obtained in the cultures were fused with a HAT-sensitive mutant of the human lymphoblastoid cell line CEM. Approximately one-third of hybridoma clones constitutively secreted GIF. The GIF-producing hybridomas were CD3+ and bore TCR-alpha beta. GIF formed by unstimulated hybridomas lacked affinity for bee venom PLA2. Upon cross-linking of CD3, however, a majority of the GIF-producing hybridomas formed IgE-binding factors and GIF, the latter of which had affinity for bee venom PLA2. Both nonspecific GIF and Ag-binding GIF from the hybridomas bound to an immunosorbent coupled with the anti-lipomodulin mAb 141-B9. Using an affinity-purified GIF as an immunogen, we established mouse B cell hybridomas that secreted monoclonal anti-human GIF. In order to characterize human nonspecific GIF, one of the GIF-producing hybridomas was adapted to a serum-free medium, and culture supernatant was fractionated by DEAE-Sepharose column chromatography and by gel filtration. The majority of nonspecific GIF in the culture supernatant was recovered from DEAE-Sepharose by elution of the column with 10 mM Tris-HCl buffer, pH 8.0, containing 50 mM NaCl. Affinity-purification of GIF in the DEAE Sepharose fraction by using anti-GIF-coupled Affigel, and analysis of the purified GIF by SDS-PAGE revealed that human GIF is a single polypeptide chain of 14 to 15 kDa. Gel filtration of both crude and affinity-purified GIF preparations confirmed the molecular size of the cytokine.

BACKGROUND

From our early experience with NOTES, our group has acquired familiarity with transesophageal submucosal dissection and myotomy in swine model, which allowed us to perfect a model to perform purely endoscopic transesophageal myotomy (TEEM) for the treatment of achalasia and apply it into clinical practice. This study was designed to assess the safety, feasibility, and efficacy of TEEM in a series of patients with achalasia.

METHODS

Under institutional review board approval, patients were enrolled on our study, where TEEM was offered as an alternative to laparoscopic or robotic Heller myotomy. The inclusion criteria were patients with achalasia confirmed by esophageal manometry, between age 18 and 50 years, and ASA class 2 or lower. The exclusion criteria were pregnancy, prior esophageal surgery, immunosuppression, coagulopathies, and severe medical comorbidities. The procedures were performed under general anesthesia, with the patient in supine position on positive pressure ventilation. With a GIF-180 (Olympus, Tokyo, Japan) positioned at 10 cm above the GEJ, a mucosotomy was performed at the 2 o'clock position, and a submucosal space was developed caudally creating a controlled submucosal tunnel extending 2 cm distal to the GEJ. Upon completion of this tunnel the gastroesophageal lumen was inspected for mucosal integrity. The scope was then reinserted into the submucosal tunnel and using a triangle-tip knife, myotomy was performed starting at 5 cm above the GEJ and ending at 2 cm below the GEJ. During this process the circular muscle layer of the esophagus was carefully divided with preservation of the longitudinal layer. At the end of the procedure, the mucosal incision was closed longitudinally with endoscopic clips and surgical glue.

RESULTS

Five patients underwent TEEM, with no perioperative complication. All patients reported significant improvement of their dysphagia immediately after the procedure. On the first postoperative day, all barium swallows showed disappearance of the classical bird beak taper, rapid emptying of contrast into the stomach, and absence of leaks. All patients were discharged on the second postoperative day on liquid diet. Two patients reported transient heartburn, which were well controlled with medications. The average preoperative GERD-HRQL was 20, which improved to 11.3 at 7 days postoperative and 2 at 30 days postoperative. To date, three patients have already returned for their 6-month follow-up, reporting adequate swallowing and low LES pressures on esophageal manometry (their mean preoperative LES resting pressure was 36.46 mmHg and residual pressure was 43.16 mmHg, whereas the 6-month follow-up mean LES resting pressure was 10.06 mmHg and residual pressure was 0.43 mmHg).

CONCLUSIONS

TEEM seems to be safe, feasible, and effective for the treatment of patients with achalasia. Long-term data are still necessary for wide-spread utilization of this novel technique.

Metallothioneins (MTs) are metal binding proteins and have four isoforms. MT-3, known as growth inhibitory factor (GIF), exists mainly in the central nervous system. It regulates zinc levels and exhibits a neuroprotective effect in the various types of brain diseases. However, the reports demonstrate that the relation between MT-3 and psychiatric disorder is still unknown. In the present study, the authors carried out behavioral tests on MT-3 knock-out (KO) mice. The duration of the MT-3 KO mice's social interactions were significantly shorter than that of the wild-type (WT) mice. The acoustic startle response of the MT-3 KO mice showed diminished prepulse inhibition (PPI) at all prepulse intensities. However, the locomotor activity tests of the MT-3 KO mice displayed normal circadian rhythm, activity, and habituation to a novel environment. In the novel object recognition test, the MT-3 KO mice exhibited normal memory. These findings indicate that abnormalities of psychological behavior were observed in the MT-3 KO mice. Further experiments will be needed to clarify the involvement of MT-3 in higher brain function.

OBJECTIVE

To investigate both neoplastic and non-neoplastic lesions of the esophagus and to clarify the features of the surface cell morphology using a newly developed endocytoscope, the GIF-Y0002.

METHODS

The surface cell morphology was examined with toluidine blue staining, and histological features of 53 patients with 54 lesions, including 39 patients with esophageal squamous cell carcinoma (ESCC) and 14 patients with 15 non-neoplastic esophageal lesions, were compared. One endoscopist classified the lesions using type classification, and we consulted one pathologist to evaluate the endocytoscopy pictures with regard to neoplasia or non-neoplasia.

RESULTS

The overall sensitivity for ESCC of the findings by the endoscopist and pathologist based on GIF-Y0002 observation were 100.0% and 94.9%, respectively; while the specificity was 80.0% and 46.7%. For the 3 cases of low-grade intraepithelial neoplasia, 2 were diagnosed as Type 2 and one case as suspected neoplasia by the endoscopist while the pathologist considered 2 cases to be neoplastic. Among the 9 cases of esophagitis, the endoscopist diagnosed 2 cases as Type 2 or 3, which was suggestive of neoplasia, whereas the pathologist diagnosed 6 cases to be neoplastic.

CONCLUSIONS

The low percentage of specificity for the pathologist's diagnosis was considered to be attributed to the low magnification power of the GIF-Y0002. A further increase in the magnifying power of this instrument will be necessary to broaden its clinical applications.

Escherichia coli-derived recombinant human glycosylation inhibiting factor (rhGIF) contains three cysteine residues (Cys-57, -60, and -81). All SH groups in the cysteine residues are free, and the GIF molecule had no biologic activity. Carboxymethylation of the SH group of Cys-60 in the molecule resulted in the generation of bioactivity, although the activity of the carboxymethylated GIF was 10- to 20-fold less than that of suppressor T cell (Ts)-derived GIF. However, treatment of the inactive rhGIF with ethylmercurithiosalicylate or 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) resulted in the generation of derivatives whose bioactivity was comparable to that of the Ts-derived bioactive GIF. The activity of these derivatives was lost by treatment with DTT. Isolation and chemical analysis of the DTNB-treated GIF derivative revealed that binding the 5-thio-2-nitrobenzoic acid group with Cys-60 was responsible for the generation of the highly bioactive derivative. Inactive cytosolic GIF from mammalian cells could also be converted to bioactive derivative by treatment with the SH reagent, while Ts-derived bioactive GIF was inactivated by DTT. These results, together with an x-ray crystal structure of GIF molecules, strongly suggest that the generation of bioactivity of GIF in Ts cells is due to posttranslational modifications that result in conformational changes in the molecule.