The IgE synthesis is regulated by T cell derived IgE-binding factors in an isotype-specific manner. The IgE-potentiating and IgE-suppressive factors may share common structural genes; therefore, a common polypeptide chain and their biologic activities are determined by posttranslational glycosylation processes. Under the physiological conditions, the carbohydrate moieties in the IgE-binding factors formed by a subset of T cells are determined by the ratio between two T cell factors, i.e., glycosylation-enhancing factors and glycosylation-inhibiting factors (GIF), in their environment. GIF is an immunosuppressive lymphokine. Repeated injections of this lymphokine into antigen-primed mice facilitated the generation of antigen-specific suppressor T cells and suppressed both IgE and IgG antibody responses. This effect of GIF was reproduced in vitro. Activation of antigen-specific T cells by antigen-pulsed macrophages, followed by propagation of the antigen-activated T cells by interleukin 2 in the presence of GIF resulted in the generation of suppressor T cells which produced antigen-specific GIF upon antigenic stimulation. Some of the T cell hybridomas constructed from the antigen-specific suppressor T cells formed antigen-specific GIF upon antigenic stimulation. The antigen-specific GIF formed by the T cell hybridoma share several common properties with antigen-specific suppressive factor and suppressed the antibody response of syngeneic mice in a carrier-specific manner. The results obtained with mouse lymphocytes suggest a maneuver to suppress the IgE antibody formation to an allergen in atopic patients.

BACKGROUND

Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors ('statins'), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1-3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population.

OBJECTIVE

In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature.

METHODS

The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal 'fluvastatin and hepatic reactions'.

RESULTS

At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage.

CONCLUSIONS

In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk.

Congenital intrinsic factor (IF) deficiency is a disorder characterized by megaloblastic anemia due to the absence of gastric IF (GIF, GenBank NM_005142) and GIF antibodies, with probable autosomal recessive inheritance. Most of the reported patients are isolated cases without genetic studies of the parents or siblings. Complete exonic sequences were determined from the PCR products generated from genomic DNA of five affected individuals. All probands had the identical variant (g.68A>G) in the second position of the fifth codon in the coding sequence of the gene that introduces a restriction enzyme site for Msp I and predicts a change in the mature protein from glutamine(5) (CAG) to arginine(5) (CGG). Three subjects were homozygous for this base exchange and two subjects were heterozygous, one of which was apparently a compound heterozygote at positions 1 and 2 of the fifth codon ([g.67C>G] + [g.68A>G]). The other patient, heterozygous for position 2, had one heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at base pair g.68 (A>G) and expressed in COS-7 cells. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF. The allelic frequency of g.68A>G was 0.067 and 0.038 in two control populations. This sequence aberration is not the cause of the phenotype, but is associated with the genotype of congenital IF deficiency and could serve as a marker for inheritance of this disorder.

OBJECTIVE

Vitamin B12 (B12) deficiency after Roux-en-Y gastric bypass (RYGB) is highly prevalent and may contribute to postoperative complications. Decreased production of intrinsic factor owing to gastric fundus removal is thought to have a major role, but other components of B12 metabolism may also be affected. We evaluated changes in the expression levels of multiple B12 pathway-encoding genes in gastrointestinal (GI) tissues to evaluate the potential roles in contributing to post-RYGB B12 deficiency.

METHODS

During double-balloon enteroscopy, serial GI biopsies were collected from 20 obese women (age, 46.9±6.2 years; body mass index, 46.5±5.3 kg/m2) with adult-onset type 2 diabetes (fasting plasma glucose ≥126 mg/dl; hemoglobin A1c≥6.5%) before and, at the same site, 3 months after RYGB. Gene expression levels were assessed by the Affymetrix Human GeneChip 1.0 ST microarray. Findings were validated by real-time quantitative PCR (RT-qPCR).

RESULTS

Gene expression levels with significant changes (P≤0.05) included: transcobalamin I (TCN1) in remnant (-1.914-fold) and excluded (-1.985-fold) gastric regions; gastric intrinsic factor (GIF) in duodenum (-0.725-fold); and cubilin (CUBN) in duodenum (+0.982-fold), jejunum (+1.311-fold), and ileum (+0.685-fold). Validation by RT-qPCR confirmed (P≤0.05) observed changes for TCN1 in the remnant gastric region (-0.132-fold) and CUBN in jejunum (+2.833-fold).

CONCLUSIONS

RYGB affects multiple pathway-encoding genes that may be associated with postoperative B12 deficiency. Decreased TCN1 levels seem to be the main contributing factor. Increased CUBN levels suggest an adaptive genetic reprogramming of intestinal tissue aiming to compensate for impaired intestinal B12 delivery.

The dimeric [M(2)(OAc)(5)(py)(2)&mgr;-(OH(2))]Et(4)N complexes, I (M = Mn, Fe, Co), have been isolated from pyridine solutions of M(II)(OAc)(2).xH(2)O and Et(4)N(OAc).4H(2)O. The X-ray structures of I (M = Mn, Fe, Co) have been determined and show the metal ions asymmetrically bridged by two acetate ligands and a water molecule. One of the metal ions is bound by a pyridine ligand and two monodentate acetate ligands that are hydrogen bonded to the bridging water molecule. The second metal ion is bound to a bidentate acetate ligand and a pyridine ligand. Recrystallization of I from acetonitrile leads to the reorganization of I and isolation of the M(3)(OAc)(8)(Et(4)N)(2) complexes, II (M = Mn, Fe, Co). The X-ray structure of II (M = Mn, Co) has been determined and shows the three metal ions connected by four bridging acetate ligands in a &mgr;(1), &mgr;(2) mode and two acetate ligands in the &mgr;(1),eta(1) mode, with a bidentate acetate ligand on each of the external metal ions completing the distorted octahedral geometry. Air oxidation of I-Fe in propionitrile leads to the formation of the mixed-valence [Fe(3)&mgr;(3)-(O)(OAc)(7)(OH(2))]Et(4)N(III). The X-ray structure of III has been determined and resembles the core of the basic acetate complexes; however, it has five bridging acetate ligands. The Mössbauer spectrum of III shows two quadrupole doublets in a 1:2 ratio with delta(Fe) = 1.29(1) and 0.48 mm/s; DeltaE(q) = 1.89 and 0.71 mm/s. The oxidation of I-Fe by H(2)O(2)/O(2) in pyridine solution in the presence of Cl(-) ligands affords Fe(4)&mgr;(3)-(O)(2)(OAc)(6)(py)(4)Cl(2) (IV). The X-ray structure of IV shows a rhombic {Fe(III)(4)(&mgr;(3)-O)(2)} core previously found in iron and manganese chemistry. The reaction of ferrocenium ion with I-Fe under basic conditions in dichloromethane solution led to the formation of the familiar mixed-valence Fe(3)&mgr;(3)-(O)(OAc)(6)(py)(3) complex (V) with the basic acetate structure. Complexes I-Fe, II-Fe, III, and IV catalyze the reaction of O(2) with adamantane under GiF conditions to give adamantanols and adamantanone. The similarity of the results in comparison to similar studies previously reported for iron/carboxylate complexes are noted and discussed.

We successfully used argon plasma coagulation (APC) to treat two cases of dialysis patients with hemorrhagic gastric angiodysplasia. Gastric angiodysplasia is recognized as an important cause of gastrointestinal bleeding. Angiodysplastic lesion confined to the gastric antrum was first described in 1953 and named gastric antral vascular ectasia (GAVE). The condition is characterized as submucosal capillary dilatation and fibromuscular hyperplasia. The typical finding of GAVE is the so-called watermelon stomach, attributable to vasodilatation. In case 1, a 69-year-old man was introduced continuous ambulatory peritoneal dialysis (CAPD) in July 1997 because of chronic renal failure due to nephrosclerosis. He was hospitalized for severe anemia in December 1997. Gastrointestinal fiberscopy (GIF) showed oozing in the antrum, and gastritis and esophagitis with sliding hernia. Famotidine was started and recombinant human erythropoietin (rHuEPO) was used for anemia. However, the severe anemia did not improve. The patient was hospitalized again for severe anemia and hematemesis. Another GIF showed typical watermelon stomach, which corresponded with GAVE. An APC was performed without complications. Three months later, the anemia was improved, and the dose of rHuEPO was reduced. In case 2, a 57-year-old woman was introduced to hemodialysis in 1998 for uremia due to nephrosclerosis. In October 2000, she was hospitalized for rHuEPO-resistant anemia. A GIF showed oozing in the antrum with diffuse vasodilation in the antrum; GAVE was diagnosed. An APC was carried out without complications. Three months later, anemia was improved. Recently, gastric angiodysplasia was reported to be an important complication in dialysis patients and was recognized as an important cause of rHuEPO-resistant anemia. Argon plasma coagulation is an effective treatment for gastric angiodysplasia in patients on dialysis.

Human umbilical cord (UC) and cord blood (CB) provide attractive sources of mesenchymal stem cells (MSCs) for cell therapy. Both UCMSCs and CBMSCs have been demonstrated to play prominent roles in clinical therapy. However, little is known about their functional differences in clinical application. Our transcriptome analysis uncovered high activity of insulin secretion related signaling pathways for CBMSCs and cell adhesion related signaling pathways for UCMSCs. Expression of a large number of immune related signaling pathways also showed the difference in both cells, implying their distinct immune modulatory functions. As the therapeutic effects of MSCs mainly dependent on the cytokines and growth factors produced by transplanted MSCs, we further compared the cytokine profiles of UCMSCs and CBMSCs using antibody array. By evaluating the expression of 106 cytokines, we found both MSCs abundantly secreted TSP-1, TSG-14, TIMP-1, IL-8, IL-6, CXCL1, GIF and IGFBP3. However, the expression of CCL2 in UCMSCs showed significantly higher than CBMSCs. IGFBP1 and IGFBP2 were secreted by CBMSCs with higher abundance than UCMSCs. Overall, these results suggest that UCMSCs and CBMSCs preserve different functional potentials, which have to be carefully considered before clinical treatment.

Growth-regulating factor (GRF) interacting factors (GIFs) are involved in several developmental processes in Arabidopsis. We previously showed that upregulation of OsGIF1 expression improves rice grain size. However, whether OsGIF1 is involved in other developmental processes remains unclear. Here, we report pleiotropic effects of OsGIF1 on rice organ size regulation. Overexpression and functional knock-out via a CRISPR/Cas9 strategy revealed that OsGIF1 not only positively regulates the sizes of rice leaf, stem, and grain but also influences rice reproduction. Expression profiles based on both qRT-PCR and GUS (β-glucuronidase) histochemical staining suggested that OsGIF1 is differentially expressed across various rice tissues, consistent with its roles in regulating the development of multiple rice organs. Additionally, we found that OsGIF1-GFP localized preferentially in the nucleus, which supports its proposed role as a transcriptional cofactor. Further histological analysis suggested that OsGIF1 affected rice organ size possibly by regulating cell size. Our results suggest that OsGIF1 plays important roles in vegetative and reproductive developmental processes, with important implications for rice breeding.

Here, we report a case of a pancreatobiliary (PB) fistula caused by an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The PB fistula was suspected after endoscopic retrograde cholangiopancreatography (ERCP) and diagnosed after direct visualization with a direct peroral cholangioscopy and pancreatoscopy by using an ultra-slim endoscope. No previous reports exist on the precise diagnosis of a PB fistula with direct peroral cholangioscopy and pancreatoscopy. In our case report, a 69-year-old man underwent an ERCP because of a pancreatic head mass and biliary tract obstruction. During ERCP, a fistula between the common bile duct (CBD) and main pancreatic duct (MPD) was suspected. After endoscopic sphincterotomy, we examined both the CBD and MPD with an ultra-slim videoendoscope (GIF-N260; Olympus Optical Co, Tokyo, Japan) under direct visualization and biopsy of the mass. The analysis of the biopsy specimen confirmed this mass to be an IPMN of the pancreas. When we examined the CBD, one fistula with copious mucin secretion was identified at the distal CBD. In conclusion, direct peroral cholangioscopy and pancreatoscopy using the ultra-slim endoscope is an efficient tool for diagnosis of PB fistula and pancreatic IPMN.

<AbstractText>The basal forebrain is a subcortical structure that plays an important role in learning, attention, and memory. Despite the known subcortical involvement in frontotemporal dementia (FTD), there is little research into the role of the basal forebrain in this disease. We aimed to investigate differences in basal forebrain volumes between clinical, genetic, and pathological diagnoses of FTD.</AbstractText><AbstractText>356 patients with FTD were recruited from the UCL Dementia Research Centre and matched on age and gender with 83 cognitively normal controls. All subjects had a T1-weighted MR scan suitable for analysis. Basal forebrain volumes were calculated using the Geodesic Information Flow (<em>GIF</em>) parcellation method and were compared between clinical (148 bvFTD, 82 svPPA, 103 nfvPPA, 14 PPA-NOS, 9 FTD-MND), genetic (24 MAPT, 15 GRN, 26 C9orf72) and pathological groups (28 tau, 3 FUS, 35 TDP-43) and controls. A subanalysis was also performed comparing pathological subgroups of tau (11 Pick's disease, 6 FTDP-17, 7 CBD, 4 PSP) and TDP-43 (12 type A, 2 type B, 21 type C).</AbstractText><AbstractText>All clinical subtypes of FTD showed significantly smaller volumes than controls (p ≤ 0.010, ANCOVA), with svPPA (10% volumetric difference) and bvFTD (9%) displaying the smallest volumes. Reduced basal forebrain volumes were also seen in MAPT mutations (18%, p < 0.0005) and in individuals with pathologically confirmed FTDP-17 (17%), Pick's disease (12%), and TDP-43 type C (8%) (p < 0.001).</AbstractText><AbstractText>Involvement of the basal forebrain is a common feature in FTD, although the extent of volume reduction differs between clinical, genetic, and pathological diagnoses. Tauopathies, particularly those with MAPT mutations, had the smallest volumes. However, atrophy was also seen in those with TDP-43 type C pathology (most of whom have svPPA clinically). This suggests that the basal forebrain is vulnerable to multiple types of FTD-associated protein inclusions.</AbstractText>

In patients with wide-open bilio-digestive anastomoses peroral cholangioscopy using the pediatric endoscope GIF-P2 is easily performed. The common bile duct is visualised down to the papilla and up to the distributaries of the hepatic ducts. The instrumentation channel allows mobilisation of incarcerated concretions, extraction of food particles (cholangiophytiasis) and guided biopsy of pathological findings. The experience in 12 patients with this method is promising.

CyAnimator (http://apps.cytoscape.org/apps/cyanimator) is a Cytoscape app that provides a tool for simple animations of Cytoscape networks. The tool allows you to take a series of snapshots (CyAnimator calls them frames) of Cytoscape networks. For example, the first frame might be of a network shown from a "zoomed out" viewpoint and the second frame might focus on a specific group of nodes. Once these two frames are captured by the tool, it can animate between them by interpolating the changes in location, zoom, node color, node size, edge thickness, presence or absence of annotations, etc. The animations may be saved as a series of individual frames, animated GIFs, MP4 movies, or H.264/MOV movies. CyAnimator is available from within the Cytoscape App Manager or from the Cytoscape app store.

BACKGROUND

Maneuvering in vehicles exposes occupants to low frequency forces (< 1 Hz) which can provoke motion sickness.

OBJECTIVE

Aligning with the tilting inertial resultant (gravity + imposed horizontal acceleration: gravito-inertial force (GIF)) may reduce motion sickness when tilting is either 'active' (self-initiated; Experiment 1) or 'passive' (suspension machinery; Experiment 2).

METHODS

Exp 1: Twelve seated subjects were exposed to continuous horizontal translational oscillation through the body x-axis (3.1 m x S(-2) peak acceleration, 0.20 Hz) while making head tilts which were either aligned or misaligned (180 degrees out of phase) with respect to GIF. The two sessions were one week apart at the same time of day, counterbalanced for order. Head tilts were controlled by tracking a moving LED display and head trajectory was verified by accelerometry. Motion continued until moderate nausea was achieved (motion endpoint) or until a 30 min cut-off. Exp 2: A different group of 12 subjects were exposed to continuous horizontal translational sinusoidal oscillation through the body x-axis (2.0 m x S(-2) peak acceleration, 0.176 Hz) while seated in a cab which was tilted by suspension machinery around the y-axis of the ears so that GIF was aligned or misaligned (180 degrees out of phase) with the body z-axis.

RESULTS

Exp 1: Mean +/- SD time to motion endpoint was significantly longer for aligned (19.2 +/- 12.0 min) than for misaligned (17.8 +/- 13.0 min; p < 0.05, two-tail). Exp 2: Mean +/- SD time to motion endpoint was significantly shorter for aligned (21.8 +/- 10.9 min) than for misaligned (28.3 +/- 5.8 min; p < 0.01, two-tail).

CONCLUSIONS

Whether or not compensatory tilting protects against (Exp 1) or contributes to (Exp 2) motion sickness may be influenced by whether the tilting is under the active control of the person (e.g., car driver) or under external control (e.g., passenger in a high-speed tilting train).

We investigated the biological roles of the Arabidopsis (Arabidopsis thaliana) GROWTH-REGULATING FACTOR (GRF) and GRF-INTERACTING FACTOR (GIF) transcriptional complex in the development of gynoecia and anthers. There are nine GRFs and three GIFs in Arabidopsis, and seven GRFs are posttranscriptionally silenced by microRNA396 (miR396). We found that overexpression of MIR396 in the gif1 gif2 double mutant background (gif1 gif2 35S:MIR396) resulted in neither ovary nor pollen. Histological and molecular marker-based analyses revealed that the mutant gynoecial primordia failed to develop carpel margin meristems and mature flowers lacked the ovary, consisting only of the stigma, style, and replum-like tissues. The mutant anther primordia were not able to form the pluripotent archesporial cells that produce pollen mother cells and microsporangia. Multiple combinations of GRF mutations also displayed the same phenotypes, indicating that the GRF-GIF duo is required for the formation of those meristematic and pluripotent cells. Most GRF proteins are localized and abundant in those cells. We also found that the weak gynoecial defects of pinoid-3 (pid-3) mutants were remarkably exacerbated by gif1 gif2 double mutations and 35S:MIR396, so that none of the gynoecia produced by gif1 gif2 pid-3 and 35S:MIR396 pid-3 developed ovaries at all. Moreover, gif1 gif2 double mutations and 35S:MIR396 also acted synergistically with 1-N-naphthylphthalamic acid in forming aberrant gynoecia. The results altogether suggest that the GRF-GIF duo regulates the meristematic and pluripotent competence of carpel margin meristems and the archesporial cell lineage and that this regulation is implemented in association with auxin action, ultimately conferring reproductive competence on Arabidopsis.

Over a period of 9 months we treated 50 patients with upper gastrointestinal bleeding from a peptic ulcer with a visible vessel. Their mean age was 58.8 years. Almost all cases had massive bleeding and required an average of 1930 +/- 2174 ml (S. D.) of blood. Twenty-eight cases were in shock when treated. The lowest mean hemoglobin was 8.2 +/- 2.2 gm/dl (S. D.). We treated them with the Olympus GIF-1T10 and the heat probe unit. A total of 825 +/- 735 joules (S. D. ) were applied to each bleeder. Forty-nine cases (98%) stopped bleeding after initial treatment. Seven cases (14.3%) rebled within one week post-treatment. We tried heat probe therapy again in 6 of the cases that rebled, and achieved hemostasis in four of them. Ultimately, only four failures were seen in our study. The success rate was 92% (46/50). We conclude that thermocoagulation with the heat probe may in the near future replace surgery in the majority of cases of hemorrhage from a peptic ulcer with a visible vessel in its base.

We performed a mass survey using a thin forward-viewing gastroscope (Olympus GIF-P2) as a secondary examination of 449 persons from 3457 employees who had undergone the first step of the screening with photofluorography. Comparing these results with those obtained in the mass survey of 1976 and 1977, in which the lateral-viewing gastrocamera, GT-PA2, was employed for the second step of the screening in 372 of 3548 persons examined, we arrived at the following conclusions: (1) the thin forward-viewing gastroscope for mass survey permits accurate diagnosis not only of gastric lesions but also of bulbar lesions; (2) there was no significant difference between the two mass surveys in the rate of discovery of gastric lesions, but gastric ulcer scars were detected at higher rate when using the gastrocamera; and (3) few lesions were noted in cases with an incompletely filled bulb; gastric erosions, especially prepyloric, were noted with bulbar deformity.

High-altitude polycythemia (HAPC) inducing gastric mucosal lesion (GML) is still out of control and molecular mechanisms remain widely unknown. To address the issues, endoscopy and histopathological analyses were performed. Meanwhile, microarray-based transcriptome profiling was conducted in the gastric mucosa from 3 pairs of healthy subjects and HAPC-induced GML patients. HAPC caused morphological changes and pathological damages of the gastric mucosa of GML patients. A total of 10304 differentially expressed genes (DEGs) were identified, including 4941 up-regulated and 5363 down-regulated DEGs in gastric mucosa of GML patients compared with healthy controls (fold change ≥2, P<0.01 and FDR <0.01). Particularly, apolipoprotein genes APOA4 and APOC3 were 1473-fold and 1468-fold up-regulated in GML patients compared with the controls. In contrast, gastric intrinsic factor (GIF) was 1102-fold down-regulated in GML patients compared with the controls. APOA4 (chr11:116691770-116691711), APOC3 (chr11:116703530-116703589) and GIF (chr11:59603362-59603303) genes are all located on chromosome 11. APOA4 and APOC3 act as an inhibitor of gastric acid secretion while gastric acid promotes ulceration. GIF deficiency activates a program of acute anemia, which may antagonize polycythemia while polycythemia raises the risk of GML. Therefore, the present findings reveal that HAPC-induced GML inspires the protection responses by up-regulating APOA4 and APOC3, and down-regulating GIF. These results may offer the basic information for the treatment of HAPC-induced gastric lesion in the future.

A mathematical model is presented for the production of a growth inhibitory factor (GIF) within a multicell spheroid. The model is based on the assumption that the GIF diffuses within the spheroid in a nonlinear spatially dependent manner. This is in contrast with previous models, in which the nonlinearity was assumed in the production term. The results of the new model are compared with those of previous models and with experimental data.

Growth inhibitory factor (GIF) is a small (7 kDa), heat-stable, acidic, hydrophilic metallothionein (MT)-like protein. GIF inhibits the neurotrophic activity in Alzheimer's disease (AD) brain extracts on neonatal rat cortical neurons in culture. GIF has been shown to be drastically reduced and down-regulated in AD brains. In neurodegenerative diseases in humans, GIF expression levels are reduced whereas GFAP expression levels are markedly induced in reactive astrocytes. Both GIF and GIF mRNA are present at high levels in reactive astrocytes following acute experimental brain injury. In chronological observations the level of GIF was found to increase more slowly and remain elevated for longer periods than that of glial fibrillary acidic protein (GFAP). These differential patterns and distribution of GIF and GFAP seem to be important in understanding the mechanism of brain tissue repair. The most important point concerning GIF in AD is not simply the decrease in the level of expression throughout the brain, but the drastic decrease in the level of expression in reactive astrocytes around senile plaques in AD. Although what makes the level of GIF decrease drastically in reactive astrocytes in AD is still unknown, supplements of GIF may be effective for AD, based on a review of current evidence. The processes of tissue repair following acute brain injury are considered to be different from those in AD from the viewpoint of reactive astrocytes.

OBJECTIVE

To present a software suitable for publication of medical images on the World Wide Web and compatible with both the DICOM and other popular formats like GIF and JPEG.

METHODS

DICOM viewer is a Java applet, written in Java 1.0. The tool offers the capability to publish medical images, to modify brightness and contrast (windowing) and to magnify the picture (magnification lens). Information related to the image is available for consultation only for DICOM images.

RESULTS

The viewer was tested with many DICOM files, generated by our PACS or downloaded from Internet. It works well with the DICOM 3.0 file format, but correct functioning is not granted for previous releases. The software was compatible with all the most popular Web browsers (MS Internet Explorer 3.0 or newer, Netscape Navigator 4.5 or newer, Sun and HotJava) and it works well in Windows, Sun Solaris. Macintosh, Windows CE. A 512 kb image (a standard MR image) requires about 5 seconds to be shown on an Intel Pentium II PC with 32 Mbyte RAM connected on a 10 Mbit/s Ethernet network. About 3 seconds are needed to download the file and about 2 seconds to display the image. Windowing and zooming are quick enough.

CONCLUSIONS

The applet allows to publish DICOM medical images directly on the World Wide Web, without converting them into another graphical format. Moreover, it supplies some image processing tools common in the radiological environment. The viewer characteristics make it suitable for preparing teaching radiology sites or clinical files on the Web. The viewer's performance is somewhat poor, particularly on the Internet. Better performances are achieved on local area network (intranet). To improve performance, we will introduce file compression and rewrite the software in Java 1.1. The software is available from the author free of charge.

Growth inhibitory factor (GIF) has been identified as a new metallothionein-like protein, the level of which is decreased in the Alzheimer's disease brain. GIF and glial fibrillary acidic protein (GFAP) have been reported to be expressed in reactive astrocytes in the rat brain following stab wounds. Moreover, strong expression of GIF mRNA in reactive astrocytes after ventricular injection of kainic acid has been demonstrated. To clarify the biological functions of GIF and GFAP in repair of the CNS, we examined changes in their relative levels to sham control using a Western blotting technique in the rat left hemisphere following occlusion of the left middle cerebral artery, for 28 days after surgery. The GIF relative level declined to 56% of the sham-operated control value on day 7. Thereafter the GIF relative level increased and returned to the normal relative level by days 21-28. The GFAP relative level increased from day 3 and reached a maximum of 120% of the sham-operated control value on days 14-21. While GIF and GFAP were both detected in reactive astrocytes, an increase in the GFAP relative level occurred prior to an increase in GIF relative level following the ischemia. The patterns of changes in relative expression levels of GIF and GFAP were quite similar to those in our previous studies on effects of cerebral stab wounds in rats, although the changes were more rapid in the previous studies. GIF and GFAP appear to play different roles in the repair of the CNS. The present results also indicated that GIF could play an important role in CNS repair after cerebral ischemia and provide new insights into the mechanism of gliosis investigated mainly from the viewpoint of GFAP.

Gastric cancer is one of the most common and lethal type of cancer worldwide. Infection with Helicobacter pylori (H. pylori) is recognized as the major cause of gastric cancer. However, it remains unclear the mechanism by which Helicobacter infection leads to gastric cancer. Furthermore, the underlying molecular events involved during the progression of Helicobacter infection to gastric malignancy are not well understood. In previous studies, we demonstrated that that H. felis-infected Myd88 -/- mice exhibited dramatic pathology and an accelerated progression to gastric dysplasia; however, the MyD88 downstream gene targets responsible for this pathology have not been described. This study was designed to identify MyD88-dependent genes involved in the progression towards gastric cancer during the course of Helicobacter infection.

Wild type (WT) and Myd88 deficient mice (Myd88 -/-) were infected with H. felis for 25 and 47 weeks and global transcriptome analysis performed on gastric tissue using MouseWG-6 v2 expression BeadChips microarrays. Function and pathway enrichment analyses of statistically significant, differential expressed genes (p < 0.05) were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tools.

Helicobacter infection affected the transcriptional profile of more genes in Myd88 -/- mice compared to WT mice. Infection of Myd88 -/- mice resulted in the differential expression of 1,989 genes at 25 weeks (1031 up and 958 downregulated). At 47 weeks post-H.felis infection, 2,162 (1140 up and 1022 downregulated) were differentially expressed. The most significant differentially upregulated gene during Helicobacter infection in Myd88 -/- mice was chitinase-like 4 (chil4), which is involved in tissue remodeling and wound healing. Other highly upregulated genes in H. felis-infected Myd88 -/- mice included, Indoleamine 2,3-Dioxygenase 1 (Ido1), Guanylate binding protein 2 (Gbp2), ubiquitin D (Ubd), β 2 -Microglobulin (B2m), CD74 antigen (Cd74), which have been reported to promote cancer progression by enhancing angiogenesis, proliferation, migration, metastasis, invasion, and tumorigenecity. For downregulated genes, the highly expressed genes included, ATPase H+/K+ transporting, alpha subunit (Atp4a), Atp4b, Mucin 5 AC (Muc5ac), Apolipoprotein A-1 (Apoa1), and gastric intrinsic factor (Gif), whose optimal function is important in maintaining gastric hemostasis and lower expression has been associated with increased risk of gastric carcinogenesis.

These results provide a global transcriptional gene profile during the development and progression of Helicobacter-induced gastric cancer. The data show that our mouse model system is useful for identifying genes involved in gastric cancer progression.

OBJECTIVE

To determine whether tidal expiratory airflow patterns change with increasing airways obstruction in patients with cystic fibrosis.

METHODS

An observational study.

METHODS

Lung function laboratory.

METHODS

Sixty-four children and young adults with cystic fibrosis.

METHODS

After measuring FEV(1) and airways resistance using body plethysmography, each subject was seated and asked to mouth breathe through a pneumotachograph for 2 min. The collected data were analyzed, and three expiratory airflow pattern-sensitive indexes were computed. The first index was derived from the ratio of the time to reach peak expiratory flow to the total expiratory time (tPTEF/tE). The second index, Trs, was an estimate of the time constant of the passive portion of expiration. The third index, f1.gif" BORDER="0">, describes the slope of the whole post-peak expiratory flow pattern after scaling.

RESULTS

Compared with FEV(1), the index tPTEF/tE was a poor indicator of airways obstruction (r(2) = 0.15, p = 0.002). Trs showed a strong relationship with the severity of airways obstruction (r(2) = 0.46, p < 0.001). Using f1.gif" BORDER="0">, the postexpiratory profile could be categorized into three shapes, and provided a good indicator of airways obstruction when linear and concave-shaped profiles occurred (r(2) = 0.42, p < 0.001). Convex-shaped flow profiles had to be treated separately and were indicative of normal lung function.

CONCLUSIONS

In a cross-sectional study of patients with cystic fibrosis, increase in airways resistance above normal is reflected by quantifiable changes in the expiratory airflow pattern.