Assessing the subjective visual vertical, SVV, in a static upright position is an easy clinical test in which a deviation of some 10 degrees from true vertical indicates an acute loss of unilateral (otolithic) vestibular function on the side to which the SVV is tilted. Because this deviation of the SVV is compensated during the following months, patients with chronic unilateral vestibular loss do no longer differ from normal subjects. This study presents an experimental set-up that allows for clear detection of compensated chronic loss of unilateral otolithic function by testing the SVV. 21 normals and 17 unilaterally vestibular deafferentiated (UVD) patients (vestibular neurectomies) were first rotated on a human centrifuge about an earth vertical yaw axis through the midsagittal plane of the head (240 degrees/s). This induced tilts of the gravito-inertial force (GIF) vectors, which differed at the two inner ears by 8 degrees. During constant velocity rotation, the subjects were moved in pseudo-randomized steps laterally up to 16 cm apart from the rotation axis, inducing roll tilts of the GIF vectors up to 16 degrees. Normal subjects set their SVV to pre-centrifugation values at positions with the midsagittal plane of their head close to the rotation axis, while chronic UVD patients indicated pre-centrifugation values during positions with the rotation axis 5.9 +/- 2.5 cm paramedian on the side of the intact ear. Tilts of the GIF vectors shifted the SVV with a gain of 0.70 in normals and only 0.32 in UVD patients. Roll gains for laterally directed GIF vectors relative to the intact inner ear did not differ from medially directed roll gains in the UVD patients. The roll gains observed in this experimental set-up were lower than those observed with static body tilts or during eccentric rotation with a larger radius, which might be at least partially due to conflicting stimulation between otolithic and extra-vestibular cues.

A 20-year-old male castrated domestic longhair cat was evaluated for assessment of its chronic kidney disease (CKD) and a non-healing ulcerated mass at the site of a previously placed and subsequently removed GIF tube. The cat had been diagnosed with CKD 10 years prior and two GIF tubes had been placed over a 5-year period, the second of which was associated with secondary infection. Biopsy of the non-healing ulcerated mass was consistent with grade 2 soft tissue sarcoma. At necropsy there was a discrete, serpentine, subcutaneous mass measuring approximately 8 mm in diameter that extended approximately 20 cm along the dorsum to the caudal thorax, following the path of the GIF tube, from the main intrascapular, ulcerated mass where the fluid port injection site was located. This is the first report of a fibrosarcoma arising at the site of a subcutaneous fluid port in a cat. Although the cat's owners were pleased with the 4 years of quality of life provided by this device, this complication should be considered when a decision to place ports for long-term management of disease is made.

Upon antigenic stimulation with OVA-pulsed syngeneic macrophages, the mouse T cell hybridoma 231F1 produced glycosylation inhibiting factor (GIF) having affinity for OVA and IgE-suppressive factors, whereas another T cell hybridoma, 12H5, cells produced OVA-binding glycosylation enhancing factor (GEF) and IgE-potentiating factor. The OVA-binding GIF from the 231F1 cells is an Ag-specific Ts cell factor, whereas OVA-binding GEF from the 12H5 cells is an Ag-specific augmenting factor. Both hybridomas express CD3 complex and functional TCR-alpha beta. Cross-linking of TCR-alpha beta or CD3 molecules on the hybridomas by anti-TCR-alpha beta mAb or anti-CD3 mAb and protein A resulted in the formation of the same factors as those obtained by the stimulation of the cells with OVA-pulsed syngeneic macrophages. It was also found that both the 231F1 cells and 12H5 cells formed IgE-binding factors upon incubation with H-2d and H-2b APC, respectively, with a synthetic peptide corresponding to residues 307-317 in the OVA molecules (P307-317). Six other synthetic peptides, including those containing the major immunogenic epitope, i.e., P323-339, failed to stimulate the hybridomas in the presence of APC. Indeed, all of the 10 T cell hybridoma clones, which could produce either OVA-binding GIF or OVA-binding GEF, responded to P307-317 and APC for the formation of IgE-binding factors. In contrast, GIF/GEF derived from six other hybridoma clones, whose TCR recognized P323-339 in the context of a MHC product, failed to bind to OVA-coupled Sepharose. The results indicate the correlation between the fine specificity of TCR and the affinity of GIF/GEF to the nominal Ag. The amino acid sequence of P307-317 suggested that TCR on the cell sources of Ag-binding factors are specific for an external structure of the Ag molecules.

Researchers' obligations to disclose genetic incidental findings (GIFs) have been widely debated, but there has been little empirical study of the engagement of institutional review boards (IRBs) with this issue.

This article presents data from the first extensive (n = 796) national survey of IRB professionals' understanding of, experience with, and beliefs surrounding GIFs.

Most respondents had dealt with questions about GIFs (74%), but only a minority (47%) felt prepared to address them. Although a majority believed that there is an obligation to disclose GIFs (78%), there is still not consensus about the supporting ethical principles. Respondents generally did not endorse the idea that researchers' additional time and effort (7%), and lack of resources (29%), were valid reasons for diminishing a putative obligation. Most (96%) supported a right not to know, but this view became less pronounced (63%) when framed in terms of specific case studies.

IRBs are actively engaged with GIFs but have not yet reached consensus. Respondents were uncomfortable with arguments that could be used to limit an obligation to return GIFs. This could indicate that IRBs are providing some of the impetus for the trend toward returning GIFs, although questions remain about the relative contribution of other stakeholders.Genet Med 18 7, 705-711.

BACKGROUND

Prostate cancer is a common and often deadly cancer. Decades of study have yet to identify genes that explain much familial prostate cancer. Traditional linkage analysis of pedigrees has yielded results that are rarely validated. We hypothesize that there are rare segregating variants responsible for high-risk prostate cancer pedigrees, but recognize that within-pedigree heterogeneity is responsible for significant noise that overwhelms signal. Here we introduce a method to identify homogeneous subsets of prostate cancer, based on cancer characteristics, which show the best evidence for an inherited contribution.

METHODS

We have modified an existing method, the Genealogical Index of Familiality (GIF) used to show evidence for significant familial clustering. The modification allows a test for excess familial clustering of a subset of prostate cancer cases when compared to all prostate cancer cases.

RESULTS

Consideration of the familial clustering of eight clinical subsets of prostate cancer cases compared to the expected familial clustering of all prostate cancer cases identified three subsets of prostate cancer cases with evidence for familial clustering significantly in excess of expected. These subsets include prostate cancer cases diagnosed before age 50 years, prostate cancer cases with body mass index (BMI) greater than or equal to 30, and prostate cancer cases for whom prostate cancer contributed to death.

CONCLUSIONS

This analysis identified several subsets of prostate cancer cases that cluster significantly more than expected when compared to all prostate cancer familial clustering. A focus on high-risk prostate cancer cases or pedigrees with these characteristics will reduce noise and could allow identification of the rare predisposition genes or variants responsible.

BACKGROUND

Ileal pouch strictures that are visually inaccessible by an endoscope may be balloon-dilated by exchange guide wire across the stricture with the aid of fluoroscopy. We present a technique of wire-guided balloon dilation without fluoroscopy to navigate strictures in the ileal pouch.

METHODS

A 50-year-old Caucasian female presented with a 24-year history of ulcerative colitis (UC) with restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) for 7 years. She developed Crohn's disease (CD) of the pouch with multiple strictures at the afferent limb of the pouch and a pouch-vaginal fistula. On pouchoscopy, the patient had two strictures at the distal neoterminal ileum, at 10 cm and 15 cm proximal to the pouch inlet. In retrospect, the distal stricture was angulated and 1 cm in length, and the proximal one was ulcerated and pinhole in size, which prevented the passage of an endoscope (9.8-mm single-channel, GIF-H180; Olympus Optical, Tokyo, Japan). The stricture number and locations were confirmed by retrograde water-soluble contrast X-ray. There was great difficulty in negotiating the strictures with balloon dilation and hence concern that blind passage of the balloon into the strictures might induce mucosal trauma or perforation. A controlled radial expansion (CRE) wire-guided balloon dilation catheter (CRE TM Single-Use Wire Guided Balloon Dilator; Boston Scientific Microvasive, Natick, MA) was introduced through the scope. Wire exchange technique was applied with help of our endoscopy nurse (A.O.). The guide wire was passed through the strictures without any resistance under endoscopy view. Subsequently, the balloon was introduced across the strictures, and both were successfully dilated to 16 mm (Videos 1 and 2).

RESULTS

The procedure and postprocedure course were uneventful, and patient reported great symptomatic relief.

CONCLUSIONS

Endoscopic guide-wire balloon dilation without fluoroscopic guidance appears to be feasible for CD-related strictures in experienced hands.

The glycosylation inhibiting factor (GIF) was detected in EGTA extracts of the OVA-specific Ts cell hybridoma, 231F1 cells and 71B4 cells, which constitutively secrete GIF. The lymphokine in both culture supernatants and EGTA extracts failed to bind to OVA-Sepharose. Association of GIF with the plasma membrane was confirmed by surface labeling of the 231F1 cells with 125I. The major species of GIF in the extract was 14.4-kDa peptide as determined by SDS-PAGE, and was identical to that detected in culture supernatants. Pretreatment of the cells with monoclonal anti-GIF switched the cells from the formation of unglycosylated IgE-BF to the formation of glycosylated IgE-BF, indicating that the membrane-associated GIF is involved in the determination of the nature of IgE-binding factor during their biosynthesis. When the hybridoma was stimulated with OVA-pulsed APC, EGTA extracts of the cells contained GIF having affinity for OVA. The binding of the OVA-binding GIF in the EGTA extracts to OVA-Sepharose was inhibited by a synthetic peptide, which corresponds to amino acid residues 307-317 in the OVA molecule and represents the epitope recognized by TCR on the cells. The OVA-binding GIF in the extracts bound to the monoclonal anti-TCR-alpha chain, H-28-710 and the mAb 14-12, which is specific for the Ag-binding chain of effector type suppressor factor, and suppressed the in vivo antibody response of BDF1 mice to DNP-OVA in a carrier-specific manner. Evidence was obtained that indicated that the Ag-binding chain was associated with nonspecific GIF chain on the cell surface of the Ag-stimulated cells.

Optical microscopy, electron microscopy and microspectrophotometry were used to characterize pigments in the eyes of planktonic larvae of two species of the lysiosquilloid stomatopod Pullosquilla, P. litoralis and P. thomassini, which live sympatrically in French Polynesia. In contrast to the adult retina, which contains a diverse assortment of visual pigments in the main rhabdoms, the principal photoreceptors throughout the larval eyes of both species were found to contain a single rhodopsin with an absorption maximum (max) close to 446 nm. The expression of this visual pigment may survive metamorphosis, since several adult rhodopsins occur at a similar spectral position. The retinas of these planktonic larvae also contain a novel yellow photostable pigment, which is arrayed in a regular pattern at the distal margin of the larval retina. The absorption spectrum of this pigment is well matched to the larval rhodopsin, suggesting that it acts to screen the rhabdoms from stray light. By replacing opaque, black screening pigment, the transparent yellow pigment may act together with a blue iridescent layer in the larval retina to reduce the visual contrast of the larval eye against downwelling and sidewelling light, while simultaneously acting as a retinal screen.

Fibre-optic endoscopy of the upper gastro-intestinal tract has been successfully performed in 55 patients (60 examinations) with one complication related to general anaesthesia. Fifty-six of these examinations were performed under general anaesthesia in children ranging from 1 to 14 years. Four examinations were done without an anaesthetic. The instruments used were the Olympus GIF-K (forward oblique gastroscope) in the older children and the GIF-P2 (end-viewing paediatric gastroscope) in the younger patients. Indications for examination included gastro-intestinal bleeding, confirmation or exclusion of peptic ulceration as suspected on barium studies, persistent and recurrent vomiting, chronic abdominal pain, and the evaluation of gastro-oesophageal reflux. The need for careful selection of patients is emphasized since general anaesthesia is considered essential in the majority of chidren.

Since our previous experiments suggested that glycosylation-inhibiting factor (GIF) is a phosphorylated derivative of a phospholipase inhibitory protein, we determined whether other well-known phospholipase inhibitors may have similar biological activities. The results showed that phospholipase A2 (PLA2) inhibitors, such as recombinant human lipocortin I and ONO-RS-082, could switch T cell hybridoma 12H5 cells from the formation of glycosylated IgE-binding factors (IgE-BF) to the formation of unglycosylated IgE-BF, whereas neomycin, a phospholipase C inhibitor, failed to affect the nature of IgE-BF formed by the cells. The minimum concentrations of lipocortin I and ONO-RS-082 required for switching the 12H5 cells to the formation of unglycosylated IgE-BF were comparable to or less than IC50 of the inhibitors for PLA2. The ability of partially purified GIF to switch the 12H5 cells to the formation of unglycosylated IgE-BF was markedly enhanced by treatment of the preparation with alkaline phosphatase. It was also found that lipocortin I and ONO-RS-082, but not neomycin, facilitated the generation of GIF-producing T cells. When spleen cells of ovalbumin (OVA)-primed BDF1 mice were stimulated with homologous antigen and the activated T cells were propagated by recombinant IL-2 in the presence of GIF, lipocortin I, or ONO-RS-082, T cells obtained in the cultures constitutively produced their own GIF. Antigenic stimulation of the T cells induced the formation of unglycosylated IgE-BF and GIF with an affinity for OVA.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

Success of emergency endoscopy in upper GI-hemorrhage for diagnostics and treatment is limited by masses of blood clots, food or both. Using standard endoscopes supported by adjuvant techniques bleeding source can be defined in 90 to 95%. These procedures are often time consuming. Only bleeding sources which are defined can be treated. This is difficult in cases of ongoing hemorrhage. Circulatory shock may occur as well as aspiration of gastric contents. For these reasons we developed the new wide-channel endoscope.

METHODS

This endoscope (GIF-XT-30, Olympus, Tokyo) has two channels, one with a diameter of 6 mm and a jet channel with 1 mm. The outer diameter at the distal end is 13.7 mm. A three-way stopcock for suction and water input is connected to the 6 mm channel.

RESULTS

We achieved complete evacuation of stomach contents in 122 of 123 patients (= 23% of all emergency patients in this series) with upper GI-bleeding, in whom complete gastric cleaning and identification of the bleeding source had proved impossible using standard endoscopes. Gastric emptying using the big channel endoscope was possible within 5 minutes in all successful cases. Optimal conditions for therapeutic procedures were therefore provided.

CONCLUSIONS

The possibilities of this instrument enable a more aggressive technique of moving fixed coagula from ulcers to localize the vessel that is to be treated. Even in cases of provoked severe Forrest I A hemorrhage permanent visual control can be achieved. It is an indispensable tool for major endoscopic centers in emergency situations.

The neuroprotective effects and mechanism of action of GIF-0173, a Delta12-prostaglandin J analogue, were investigated in the early phase of cerebral ischemia. GIF-0173 was administered intravenously immediately following middle cerebral artery occlusion (MCAO) in photochemically induced thrombosis model of rat. Neurological scores and infarct sizes were examined at 24 h after MCAO. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry for 1 h after MCAO. In cultured cortical neurons obtained from 1-day-old rats, the effects of GIF-0173 on the excitotoxicity induced by glutamate were examined. Morphological changes, neuronal death, and changes in intracellular calcium concentration ([Ca(2+)](i)) were also examined. GIF-0173 improved neurological scores and reduced the infarct size in a dose-dependent manner following MCAO. But GIF-0173 did not improve CBF after MCAO. GIF-0173 also prevented glutamate-induced neuronal death and acute cellular swelling in primary cultures in a dose-dependent manner, indicating that it inhibited neuronal necrosis. GIF-0173 dose-dependently suppressed the glutamate-induced increase in [Ca(2+)](i), but could not inhibit NMDA-induced calcium influx. The effects of GIF-0173 against glutamate-induced [Ca(2+)](i) increase were reversed by addition of non-specific prostaglandin D (PGD(2)) receptor antagonist and were comparable to the effects of PGD(2) DP1 receptor agonist, which prevented [Ca(2+)](i) increase and neuronal death. We conclude that GIF-0173 reduces cerebral infarction and protects cultured neurons against glutamate-induced excitotoxicity by inhibiting [Ca(2+)](i) increase through DP1 receptor activation.

Parkinson's disease is characterized by degeneration of dopaminergic neurones in the substantia nigra. Chronic manganese poisoning shares many features of Parkinson's disease, and also induces extrapyramidal syndromes that resemble those of Parkinson's disease due to dopamine depletion in the central nervous system. This study was undertaken to develop novel neuroprotective drugs via the identification of compounds that inhibit manganese-induced apoptosis. Here, we report that (arylthio)cyclopentenone derivatives, which are synthetic analogs of cyclopentenone prostaglandins, prevent manganese-induced apoptosis in PC12 cells. A highly sensitive assay of caspase-3/7 activity was used for screening newly synthesized prostaglandin analogs. The results showed that some cyclopentenone derivatives (GIF-0642, GIF-0643, GIF-0644, GIF-0745, and GIF-0747) inhibit manganese-induced caspase-3/7 activation in a concentration-dependent manner. Effective compounds all have an arylthio group, indicating that this structure plays an important role in the anti-apoptotic effects of (arylthio)cyclopentenone derivatives. The anti-apoptotic effects of these compounds were confirmed by verifying their ability to inhibit the DNA fragmentation and caspase-9 activation induced by manganese. Furthermore, GIF-0747 prevented manganese-induced cytochrome c release from mitochondria. These results suggest that (arylthio)cyclopentenone derivatives may be good candidates for treating neurodegenerative diseases.

Metallothioneins (MTs) area family of low molecular weight proteins characterized by a high cysteine (about 30%) and heavy metal (Zn2+, Cu+) content. In rodents, there are four known MT isoforms, named MT-I to MT-IV. MT-I and MT-II are two widely expressed isoforms, while MT-III and MT-IV (isoforms recently discovered) have a more restricted expression, normally in the brain and in the keratinizing epithelia, respectively. Since all MT isoforms share a substantial homogeneity regarding their heavy metal binding properties, it seems feasible that they could also share physiological functions. However, the different pattern of expression suggest that the different MT isoforms could in addition have specific roles. Indeed, MT-III (or GIF) was initially discovered as a protein with apparent neuromodulatory effects, which were not shared by the normal counterparts MT-I and MT-II. To gain insight on the putative importance of these three MT isoforms in the brain, it is important to characterize their regulation in normal and pathophysiological states. In this review we summarize the major factors known to affect brain MT regulation.

Metallothionein (MT) domains of different origins, exhibiting distinct, highly conserved cysteine positions, show differences in metal-cysteine coordination and reactivity. Lobster MT, which includes two Cd3S9 beta domains, was chosen as a basic model to study the structure-function relationship among the clusters. The possible influence of (1) the position of the cysteine residues and (2) the steric and electrostatic effects of neighboring amino acids on the folding and stability of MT clusters have been examined with the native lobster beta C and beta N domains, each having nine cysteines and binding three M2+ ions, and a modified domain beta C->>N, in which the cysteines of the C-terminal domain are relocated so they are spaced as in the N-terminal domain. Each has been synthesized and characterized by UV, CD, 113Cd NMR, and 1H NMR spectroscopies. The synthetic native domains (Cd3 beta C and Cd3 beta N) displayed spectroscopic properties, metal-binding affinities, and kinetic reactivity similar to those of the holo protein. In contrast, the modified Cd3 beta C->>N domain was unusually reactive and, in the presence of Chelex, a metal-ion chelating resin, was converted to a Cd5(beta C->>N)2 dimer. These differences in structure and reactivity demonstrate that the requirements for formation of a stable type-B, Cd3S9, beta cluster are more stringent than simply the sequential positions of the cysteines along the peptide chain and include specific interactions with neighboring amino acids. Molecular mechanics calculations suggest that changes of even a single amino acid in lobster Cd3 beta N toward lobster Cd3 beta C->>N or in mammalian MT1 or MT2 toward Cd3 beta-MT3 (GIF) can destabilize their structures.

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor is a member of the serotonin 5-HT(2) subfamily of G-protein-coupled receptors signaling predominantly via the phospholipase C (PLC) pathway. Stimulation of phosphoinositide (PI) hydrolysis upon 5-HT(2C) receptor activation is traditionally assessed by measuring inositol monophosphate (IP(1)) using time-consuming and labor-intensive anion exchange radioactive assays. In this study, we have developed and optimized a cellular IP(1) assay using homogeneous time-resolved fluorescence (HTRF), a fluorescence resonance energy transfer (FRET)-based technology (Cisbio; Gif sur Yvette, France). The measurement is simple to carry out without the cumbersome steps associated with radioactive assays and may therefore be used as an alternative tool to evaluate PI hydrolysis activated by 5-HT(2C) agonists. In Chinese hamster ovary (CHO) cells stably expressing 5-HT(2C) receptors, characterization of 5-HT(2C) agonists with the HTRF platform revealed a rank order of potency (EC(50), nM) comparable to that from intracellular calcium mobilization studies measured by the fluorometric imaging plate reader (FLIPR). A similar rank order of potency was seen with conventional radioactive PI assay with the exception of 5-HT. Lastly, the new assay data correlated better with agonist-induced calcium responses in FLIPR (R(2) = 0.78) than with values determined by radioactive IP(1) method (R(2) = 0.64). Our study shows that the HTRF FRET-based assay detects IP(1) with good sensitivity and may be streamlined for high-throughput (HTS) applications.

Thirty heifers were randomly sampled at five ages from each of the Hereford, Charolais, and Simmental herds at the U.S. Meat Animal Research Center to estimate association of fasting heat production (FHP) with body composition. Replicated measures of respiratory exchange were obtained for six heifers per breed at ages 2 d, 3 mo, 7 mo, 10 mo, and 14 mo using open-circuit calorimetry. Regression adjustment of FHP/live weight.75 to zero activity (AFHP) reduced the mean by 12% and variance among periods for the same animal by 42%. Daily AFHP (kcal/kg.75) was highest at 2 d (122), lowest at 10 mo (92) (P less than .01), and intermediate (103 to 106) at other ages and averaged 109, 106, and 102 for Charolais, Simmental and Hereford over all ages (P less than .05). Pooled within-age correlations of AFHP were .77 with weight of carcass (CAR) nonfat or water and .75 with live and empty body weight (EBW) but were only .13 with fat weight. Prediction of AFHP within age groups was most accurate from multiple regression on the nonfat weight in visceral organs and blood (VOB), gastrointestinal tract (GIF), head, hide, and shanks (HHS), and CAR fractions (R2 = 61%, error SD = 21.5), from regression on nonfat in CAR alone (60%, 21.6), or from regression on chemical components in each of the four fractions (59%, 22.0), relative to EBW (55%, 22.9) or its four chemical components (58%, 22.3). Partial regressions were largest for water or nonfat (P less than .01) and were negligible for fat. Importance in predicting AFHP was two to eight times greater for nonfat in CAR than in other fractions because CAR was 60 to 65% of EBW. Lean mass is clearly a major predictor of nutrient requirement that is useful to evaluate effects of body composition on the efficiency of beef production.

OBJECTIVE

To analyse and discuss the use and the safety profile of individual antiepileptic drugs (AEDs) in Italy.

METHODS

The AED safety data referred to the period January 1988-June 2005 and were obtained from the database of the Italian Interregional Group of Pharmacovigilance (GIF). This database collects all spontaneous reports of suspected adverse drug reactions (ADRs) from six Italian regions which are the main contributors to the Italian spontaneous reporting system. Individual AED consumption data (defined daily dose/1,000 inhabitants per day) in the GIF area and in the whole of Italy referred to the period January 2003-June 2005 and were derived from drug sales data (Institute for Medical Statistics Health).

RESULTS

Phenobarbital was the most frequently used AED in the GIF area (4.26 DDD/1,000 inhabitants per day) followed by carbamazepine (1.97), valproic acid (1.33) and gabapentin (1.10). AED consumption in the whole of Italy showed a similar pattern. Gabapentin was the most frequently used AED among newer AEDs. In the GIF database 37,906 reports (up to June 2005) were present; 666 of them (1.76%) were associated with at least one AED (Anatomical Therapeutic Chemical code N03A). The AED with the highest number of reports was carbamazepine (208 reports) followed by phenobarbital (98), gabapentin (80), phenytoin (56), valproic acid (55), lamotrigine (51), oxcarbazepine (43) and vigabatrin (35). Use and toxicity profile were evaluated only for AEDs associated with at least 30 reports. Skin reactions were the most frequently reported ADRs, followed by haematological, general condition, hepatic, neurological and gastrointestinal adverse reactions. Phenobarbital, lamotrigine, carbamazepine and phenytoin had the highest percentage of skin reactions (69, 67, 60 and 54%, respectively). Many haematological reactions were reported for each AED; the highest percentage was related to valproic acid (25%). Vigabatrin was associated with the highest percentage of reactions related to hearing, vision and other senses (97%). Phenytoin and valproic acid had the highest percentage of hepatic reactions (30 and 20%), whereas gabapentin of nervous system, psychiatric, gastrointestinal and urinary reactions (26, 21, 21 and 14%, respectively) and phenobarbital of musculoskeletal reactions (13%).

CONCLUSIONS

In Italy antiepileptic drug therapy appears to be still dominated by traditional drugs. Our analysis showed a different safety profile related to each AED. Some of the drug-adverse reaction associations discussed are not included in the Italian drug leaflets or have not been reported before in the literature.

A non-destructive method for scanning electron microscopy allows individual developing flower surfaces to be imaged sequentially. Kinematic analysis, the quantitative characterization of expansion behavior, can be applied to consecutive images of the same primordium. The individual cell, delimited as a polygon by its anticlinal walls, is the unit of analysis. Growth in two dimensions is characterized by a right-angle cross giving the maximal and minimal rates of extension relative to a known side of the cell. Methods have been developed here to make the analysis rapid and the results easy to portray. Data were obtained for the flower primordium of Anagallis arvensis L. from its origin as a smooth dome through the development of five small stamens and an incipient gynoecium. The outermost sepal whorl arises synchronously as a fivefold undulation. This maneuver is closely coupled to the formation of five stamen buttresses alternating with the small sepals (petals form later). The most characteristic kinematics occur as the stamen buttresses expand rapidly at their tips. The sides of the buttresses, and the regions between them, show highly directed extension following the five radii of the flower. These unique expansions are associated with the origin of the filament as a stalked structure and also correlate with the future bilateral symmetry of the anther. The region interior to the stamens grows slowly as circumferentially oriented anticlinal divisions initiate a radial cell-file pattern for the gynoecium. The developmental sequence has many features of "feed-forward" where the previous structure is important for the generation of structure to come (e.g. stamens alternate precisely with sepals). Some of these features fit plausible biomechanical explanations for morphogenesis.We wish to thank Mr. N. Rasmussen, Department of Biology, Stanford University, for providing Fig. 1A, B. Use of the SEM facility of Professor G. Goffinet, Institute of Zoology, University of Liège, is greatly appreciated. We thank Dr. R. Jacques, C.N.R.S., Le Phytotron, Gif-sur-Yvette, France, for providing the experimental material, and Mr. Philippe Ongena and Dr. Suresh Tiwari for expert photography. Support was from grants from the U.S. Department of Agriculture and National Science Foundation and as well as from the Fonds National de la Recherche Scientifique, Fonds de la Recherche Fondamentale et Collective and the "Action de Recherche Concertée" of Belgium.

We have used adult rat peripheral nerve avulsion models to evaluate the effects of neuroprotective molecules on motoneuron degeneration. The right facial nerves of adult Fischer 344 male rats were avulsed and adenoviral vectors encoding glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta2 (TGFbeta2), and growth inhibitory factor (GIF) were injected into the facial canal. The treatment with the vectors significantly prevented the loss of lesioned facial motoneurons, improved choline acetyltransferase (ChAT) immunoreactivity and suppressed the induction of nitric oxide synthase activity in these neurons. In separate experiments, animals were orally administered a solution of a neuroprotective compound T-588 after avulsion. Both free oral administration and oral tube administration of T-588 improved the survival of injured motoneurons and ameliorated their ChAT immunoreactivity. These results indicate that the gene transfer of GDNF, BDNF, TGFbeta2, and GIF and oral administration of T-588 may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.

Several genome-wide association studies (GWAS) have identified a strong association between serum vitamin B12 and fucosyltransferase 2 (FUT2), a gene associated with susceptibility to Helicobacter pylori infection. Hazra et al. conducted a meta-analysis of three GWAS and found three additional loci in MUT, CUBN and TCN1. Other GWAS conducted in Italy and China confirmed the association for FUT2 gene. Alpha-2-fucosyltransferase (FUT2) catalyzes fucose addition to form H-type antigens in exocrine secretions. FUT2 non-secretor variant produces no secretion of H-type antigens and is associated with high-plasma vitamin B12 levels. This association was explained by the influence of FUT2 on H. pylori, which is a risk factor of gastritis, a main cause of vitamin B12 impaired absorption. However, we recently showed that H. pylori serology had no influence on FUT2 association with vitamin B12, in a large sample population, suggesting the involvement of an alternative mechanism. GIF is another gene associated with plasma levels of vitamin B12 and gastric intrinsic factor (GIF) is a fucosylated protein needed for B12 absorption. Inherited GIF deficiency produces B12 deficiency unrelated with gastritis. We report 2 families with heterozygous GIF mutation, 290T>C, M97T, with decreased binding affinity of GIF for vitamin B12 and one family with heterozygous GIF mutation 435_437delGAA, K145_N146delinsN and no B12 binding activity of mutated GIF. All cases with vitamin B12 deficit carried the FUT2 rs601338 secretor variant. Ulex europeus binding to GIF was influenced by FUT2 genotypes and GIF concentration was lower, in gastric juice from control subjects with the secretor genotype. GIFGIF mutations by impairing GIF secretion, independently from H. pylori-related gastritis.

OBJECTIVE

Drug-induced gastropathy was common in developing countries in which drug consumption was heavy. The aim of this study is to evaluate the difference in the distribution of clinical features and endoscopic findings between elderly and non-elderly and to determine the risk factors of drug-induced gastrointestinal mucosal damage in elderly.

METHODS

Four hundred and fifty patients with gastrointestinal mucosal damages were recruited from the outpatient clinic or emergency room. All patients were confirmed by endoscopic examination with Olympus Videoscope QX-200 or GIF-p20. Patient's clinical symptoms, endoscopic findings and risk factors were collected. Data was analyzed by chi 2 test and expressed as Odds ratio.

RESULTS

The age distribution of gastropathy was predominant at 60-69 years old, and the case number gradually declined as age increased or decreased, respectively. The clinical presentation of asymptomatic bleeding was significantly higher in the elderly than in the non-elderly, while epigastric pain combined with dyspepsia or bleeding was not different between elderly and non-elderly groups. The endoscopic findings of gastric ulcer and erosions were significantly predominant in the elderly group, while no difference was found for duodenal ulcer between these 2 groups. Non-steroidal anti-inflammatory drugs were the popular drug which lead to gastropathy in both elderly and non-elderly groups. Drugs, especially steroids, history of arthritis or peptic ulcer, and alcohol consumption were found to be the risk factors associated with increased risk of gastropathy in the elderly. Stress was also significantly associated with increased risk of gastropathy in the non-elderly. There was no significant difference in smoking habit and use of other drugs between these 2 groups.

CONCLUSIONS

The clinical features of symptoms, endoscopic findings and risk factors of gastropathy varied significantly between the elderly and the non-elderly. Drug-induced gastropathy, especially steroid treatment for arthritis, was a significant risk factor in the elderly. Program for assessment and management of these elderly patients under treatment is important.

Intestinal occlusion is defined as an independent predictive factor of intra-abdominal hypertension (IAH) which represents an independent predictor of mortality. Baggot in 1951 classified patients operated with intestinal occlusion as being at risk for IAH ("abdominal blow-out"), recommending them for open abdomen surgery proposed by Ogilvie. Abdominal surgery provokes IAH in 44.7% of cases with mortality which, in emergency, triples with respect to elective surgery (21.9% vs 6.8%). In particular, IAH is present in 61.2% of ileus and bowel distension and is responsible for 52% of mortality (54.8% in cases with intra-abdominal infection). These patients present with an increasing intra-abdominal pressure (IAP) which, over 20-25 mmHg, triggers an Abdominal Compartment Syndrome (ACS) with altered functions in some organs arriving at Multiple Organ Dysfunction Syndrome (MODS). The intestine normally covers 58% of abdominal volume but when there is ileus distension, intestinal pneumatosis develops (third space) which can occupy up to 90% of the entire cavity. At this moment, Gastro Intestinal Failure (GIF) can appear, which is a specific independent risk factor of mortality, motor of "Organ Failure". The pathophysiological evolution has many factors in 45% of cases: intestinal pneumatosis is associated with mucosal and serous edema, capillary leakage with an increase in extra-cellular volume and peritoneal fluid collections (fourth space). The successive loss of the mucous barrier permits a bacterial translocation which includes bacteria, toxins, pro-inflammatory factors and oxygen free radicals facilitating the passage from an intra-abdominal to inter-systemic vicious cyrcle. IAH provokes the raising of the diaphragm, and vascular and visceral compressions which induce hypertension in the various spaces with compartmental characteristics. These trigger hypertension in the renal, hepatic, pelvic, thoracic, cardiac, intracranial, orbital and lower extremity areas, giving a critical clinical condition of Polycompartment Syndrome. The monitoring of Abdominal Perfusion Pressure (APP) is more correct than the measurement of IAP because it reveals hydrodynamic alterations in the abdominal compartment. The APP (MAP-IAP) depends on arterial flow, venous outflow and capacity of the abdominal compartments response to increased internal volumes. The medical therapy used to decrease IAH and to contrast ACS is intestinal decompression with gastric and rectal tube; colonic endoscopic detention; correction of electrolytic abnormalities and prokinetic agents. Surgery, besides being decompressive and resolutive, must prevent a recurrence of ACS through the "tension-free closure" procedure.

Glycosylation enhancing factor (GEF) from rat T cells is a kallikrein-like enzyme and enhances the assembly of N-linked oligosaccharides to IgE binding factors during their biosynthesis, whereas another T cell factor, i.e., glycosylation inhibiting factor (GIF), is a fragment of phosphorylated lipomodulin (i.e., phospholipase inhibitor), which when dephosphorylated inhibits phospholipase and the glycosylation process. The two T cell factors compete with each other when they are added to normal mesenteric lymph node cells during the formation of IgE binding factors. The addition of GEF to T cell hybridoma 23A4 cell switches the cells from the formation of unglycosylated IgE binding factor to the formation of N-glycosylated IgE binding factor. However, GEF neither inactivated GIF nor inhibited the formation of GIF by the T cell hybridoma. Stimulation of the T cell hybridoma with either affinity-purified GEF or bradykinin resulted in the release of GIF from the cells. GIF released by GEF stimulation had a m.w. of approximately 15,000 and bound to monoclonal antibody against lipomodulin. GEF and bradykinin also induced normal mesenteric lymph node cells to release GIF. Incorporation of 14C-arachidonic acid into 23A4 cells, followed by stimulation of the cells with GEF, resulted in the release of 14C-arachidonate. The results suggest that lipomodulin, a phospholipase inhibitory protein, is present in lymphocytes, and indicate that GEF and bradykinin induce the activation of phospholipase by stimulating cells to release lipomodulin.