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Inflammatory bowel disease (IBD) is uncommon in children younger than 2 years of age. The criteria for differentiating IBD from other diseases with similar clinical presentation is unclear. We describe 16 patients who, between 1984 and 2004, received a histological diagnosis of IBD during the first two years of life. Six patients presented with histological Crohn's disease, eight with ulcerative colitis and two with indeterminate colitis. The median age at diagnosis was 125 days (range 1 day to 18 months) and the medium follow up was 89 months (range 65 days to 20 years). The disease appeared to be very severe: four children (25%) underwent total parenteral nutrition (TPN), two received colectomy (12.5%) and three patients died. Many of the patients required an aggressive, multidrug, immunosuppressive approach (azathioprine [AZA], Infliximab, thalidomide, cyclosporine A). One child presented with a hypogammaglobulinaemia without any specific immunodeficiency, while in the other patients, Wiskott-Aldrich syndrome (WAS) (4 cases) and chronic granulomatous disease (CGD) (2 cases) were identified. In 6/16 cases, allergic colitis was first considered; these cases initially underwent cow's milk protein-free diet as the only therapy before IBD was finally diagnosed. In conclusion, early IBD has a severe prognosis and often needs an aggressive therapeutic approach. Furthermore, an improper diagnosis of allergic colitis might cause an important diagnostic delay. Some severe immunodeficiencies, such as WAS and CGD, may represent a problem in terms of differential diagnosis and might be wrongly diagnosed as very early onset IBD.

Background: In patients with cardiac syndrome X (CSX) who present with refractory angina episodes, spinal cord stimulation (SCS) has beneficial effects. The mechanisms of SCS, however, remain speculative. We assessed the effects of SCS on cardiac sympathetic function in these patients., Methods and Results: We studied 11 CSX patients treated by SCS for refractory angina (mean age, 60 +/- 9 years; 5 men and 6 women), both during SCS therapy (SCS-ON) and after withdrawal of SCS therapy (SCS-OFF), using a randomized crossover design. Planar and single photon emission computed tomography iodine 123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy and technetium 99m sestamibi (MIBI) bicycle exercise stress testing were performed at the end of each period. Compared with 10 healthy control subjects, CSX patients showed a lower heart-mediastinum ratio for MIBG uptake (2.19 +/- 0.3 vs 1.69 +/- 0.3, P = .001) and a higher cardiac MIBG uptake score (4.0 +/- 2.5 vs 19.7 +/- 27, P = .08). There were no differences in CSX patients during the SCS-ON and SCS-OFF phases of the study in heart-mediastinum ratio (1.74 +/- 0.3 vs 1.69 +/- 0.3, P = .13), cardiac washout rate of MIBG (42.9% +/- 14% vs 43.3% +/- 14%, P = .08), or MIBG defect score (18.7 +/- 25 vs 19.7 +/- 27, P = .22). Reversible perfusion defects during the SCS-OFF phase were detected in 8 patients; an improvement in perfusion defects was observed in 2 patients (25%) during the SCS-ON phase., Conclusions: Our data confirm the presence of abnormal cardiac adrenergic nerve function in CSX patients. SCS was unable to result in significant improvement of cardiac MIBG uptake abnormalities, suggesting that its therapeutic effects are unlikely to be mediated by modulation of cardiac adrenergic nerve activity.

Purpose: Somatostatin receptor scintigraphy with [(111)In]-diethylene triamine pentaacetate acid (DTPA)-octreotide is an accurate method for detecting neuroendocrine tumours (NETs) but often does not provide clear anatomical localisation of lesions. The aim of this study was to assess the clinical usefulness of anatomical-functional image fusion., Materials and Methods: Fifty-four patients with known or suspected NET were included in the study. Planar and single-photon-emission computed tomography (SPECT) imaging was performed using a dual-head gamma camera equipped with an integrated X-ray transmission system, and the images were first interpreted alone by two nuclear medicine physicians and then compared with SPECT/CT fusion images together with a radiologist. The improvement provided by SPECT/CT in the interpretation of SPECT data alone and any modification in patient management were recorded., Results: Fusion images improved SPECT interpretation in 23 cases, providing precise anatomical localisation of increased tracer uptake in 20 cases and disease exclusion in sites of physiological uptake in 5. In 10 patients, SPECT/CT allowed definition of the functional significance of lesions detected by diagnostic CT. SPECT/CT data modified clinical management in 14 cases by changing the diagnostic approach in 8 and the therapeutic modality in 6., Conclusions: Our study demonstrates that image fusion is clearly superior to SPECT alone, allowing precise localisation of lesions and reducing false-positive results.

Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, nevertheless we discovered a potent and selective modulator of the expression of microsomal prostaglandin E synthase 1 (mPGES-1), an enzyme highly involved in the inflammatory response, which represents an interesting target for the development of a new class of anti-inflammatory agents. In this paper we report the synthesis of a further collection of nine analogues, having the same scaffold of PM, the gamma-hydroxybutenolide, and bearing, as side chain, more complex aromatic portions, in substitution of the sesterterpene moiety. Their pharmacological behavior against PLA(2) enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and mPGES-1 enzymes is also described.

The natural cyclopeptide FR235222 is a potent HDAC inhibitor displaying relevant multiple anticancer effects and is considered an attractive lead compound for the generation of new and more effective antitumor therapeutics. Recently, we have synthesized a small collection of FR235222 simplified analogues which showed interesting biological activities. These results encouraged us to further explore the structural determinants responsible for the activity of this class of HDAC inhibitors in order to gain guidelines for the rational design of new derivatives with putative higher affinity for this target. In the present paper, we report the results obtained, docking these ligands in the binding pocket of HDLP, an HDAC homologue.

Germline mutations in the gene encoding the tumour suppressor E-cadherin (CDH1) are the underlying genetic defect responsible for hereditary diffuse gastric cancer (HDGC). A remarkably high percentage ( approximately 80%) of CDH1 mutations in HDGC patients and carriers generate premature termination codons (PTCs). Here, we examined whether CDH1 transcripts harbouring PTCs are downregulated by nonsense-mediated decay (NMD), an RNA surveillance pathway that degrades PTC-bearing transcripts. Using an allele-specific expression (ASE) assay to differentiate between mutated and wild-type CDH1 alleles, we found that PTC-bearing CDH1 mRNAs are strongly downregulated in normal gastric tissue from several CDH1 mutation carriers. We show that NMD is responsible for this robust downregulation, as CDH1 transcripts harbouring PTCs in the KATO-III gastric tumour cell line were upregulated in response to protein synthesis inhibitors or depletion of the NMD factors UPF1 and eIF4AIII. Analysis of HDGC patients harbouring CDH1 alleles with PTCs at a wide variety of different positions indicates an association of their predicted ability to induce NMD and an earlier age of onset of gastric cancer. This suggests that NMD may be detrimental for HDGC patients and therefore NMD is a potentially useful therapeutic target for CDH1 mutation carriers.

In the recent years, we focused our attention on the cyclodepsipeptide Jaspamide 1, an interesting marine metabolite, possessing a potent inhibitory activity against breast and prostate cancer, as a consequence of its ability to disrupt actin cytoskeleton dynamics. Although its biological profile has been well determined, many mechanistic details are still missing in terms of molecular target identification. For this reason, we decided to synthetically modify the natural metabolite, obtaining small arrays of unnatural variants useful to illuminate the structural requirements essential for the activity. Here, we report the synthesis of seven new Jaspamide analogues 2-8, containing, as the parent compound, a beta-amino acid in the cyclopeptide backbone. Their biological profile is also described.

FR235222, a novel histone deacetylase inhibitor (HDACi), at 50nM caused accumulation of acetylated histone H4, inhibition of cell proliferation and G1 cycle arrest accompanied by increase of p21 and down-regulation of cyclin E in human promyelocytic leukaemia U937 cells. The compound was also able to increase the protein and mRNA levels of annexin A1 (ANXA1) without effects on apoptosis. Similar effects were observed in human chronic myelogenous leukaemia K562 cells and human T cell leukaemia Jurkat cells. Cycle arrest and ANXA1 expression, without significant effects on apoptosis, were also induced by different HDACi like suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). FR235222 at 0.5 microM stimulated apoptosis of all leukaemia cell lines associated to an increased expression of the full-length (37kDa) protein and the appearance of a 33kDa N-terminal cleavage product in both cytosol and membrane. These results suggest that ANXA1 expression may mediate cycle arrest induced by low doses FR235222, whereas apoptosis induced by high doses FR235222 is associated to ANXA1 processing.

Various structurally modified analogues of FR235222 (1), a natural tetrapeptide inhibitor of mammalian histone deacetylases, were prepared in a convergent approach. The design of the compounds was aimed to investigate the effect of structural modifications of the tetrapeptide core involved in enzyme binding in order to overcome some synthetic difficulties connected with the natural product 1. The modifications introduced could also help identify key structural features involved in the mechanism of action of these compounds. The prepared molecules were subjected to in vitro pharmacological tests, and their potency was tested on cultured cells. Two of the components of the array were found to be more potent than the parent compound 1 and almost as efficient as trichostatin A (TSA). These results demonstrate that it is possible to synthesize highly active cyclic tetrapeptides using commercially available amino acids (with the exception of 2-amino-8-oxodecanoic acid, Ahoda). The nature of the residue in the second position of the cyclic peptide and the stereochemistry of the Ahoda tail are important for the inhibitory activity of this class of cyclic tetrapeptide analogues.

Thermal modifications induced in corneal stroma were investigated with the use of fluorescence microscopy. Tissue samples were heated in a water bath at temperatures in the 35-90 degrees C range. Fluorescence images of the structural modifications induced were acquired after staining with Indocyanine Green (ICG). Discrete Fourier Transform (DFT) and entropy analyses of each image made it possible to characterize the thermally-induced phase transitions in the stroma, and to indicate a threshold value for high thermal damage. The procedure could be proposed as the basis for a real-time controlling system for surgical techniques based on induced thermal effects.

As a part of our drug discovery effort, recently we clarified the molecular basis of phospholipase A2 (PLA2) inactivation by petrosaspongiolide M (PM), an interesting metabolite belonging to a marine sesterterpene family, containing in its structural architecture a gamma-hydroxybutenolide moiety and showing potent anti-inflammatory activity. In the attempt to expand structural diversity as well as to simplify crucial synthetic features of the parent compound, we decided to develop a selected library based on the densely functionalized gamma-hydroxybutenolide scaffold. The synthesized products were tested for their ability to inhibit PLA2 enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), two key enzymes highly involved in the inflammatory event, in order to discover new promising anti-inflammatory agents with better pharmacological profiles. This led us to the discovery of a promising inhibitor (4e) of prostanoid production acting by in vitro and in vivo selective modulation of microsomal prostaglandin E synthase 1 expression.

Purpose: To correlate ictal hyperperfusion single-photon emission computed tomography (SPECT) area during provoked seizures to the epileptogenic zone (EZ), as defined by depth recordings in adult drug-resistant patients., Methods: We included in the study eight drug-resistant epilepsy patients, subjected to both noninvasive and invasive (stereo-electroencephalography, SEEG) presurgical evaluation in the Epilepsy Surgery Center of the Catholic University in Rome, from 2001 to 2003. All patients were subjected to interictal and provoked ictal SPECT scans during scalp video-EEG monitoring. The ictal hyperperfusion area assessed by visual image analysis and, when possible, by statistical parametric mapping (SPM), was compared with the EZ, as assessed by SEEG, to define whether they colocalized., Results: For each provoked seizure, we obtained a SPECT hyperperfusion area. In five patients, the SPECT hyperperfusion area was included in the EZ as assessed by SEEG. The effectiveness of provoked SPECT was confirmed by comparison with SEEG data, SPM analysis (four patients), and spontaneous ictal SPECT (two patients). Our data were obtained in adult drug-resistant epilepsy patients whose EZ was either located in or extended to extratemporal regions in all but two patients., Conclusions: Provoked ictal SPECT confirmed its efficacy and accuracy in the presurgical evaluation because of the colocalization to the EZ. Although the low number of patients precluded any statistical correlation with the surgical outcome, it is worth pointing out that the five patients in whom the hyperperfusion area was included in the EZ showed very satisfactory results.

[reaction: see text] We report a regioselective entry to 3-bromo- and 4-bromo-5-hydroxy-5H-furan-2-ones by photooxidation of 3-bromofuran with a singlet oxygen in the presence of a suitable base. By this procedure, a variety of 3-substituted gamma-hydroxybutenolides have become for the first time easily accessible. Strategies employing these highly functionalized building blocks for the preparation of focused libraries of natural-like molecules are also discussed.

P-bodies are specialized cytoplasmic compartments where translational repression and mRNA turnover may occur. Findings in this issue of Cell provide evidence that P-bodies are sites of "mRNA purgatory." Bhattacharyya et al. (2006) reveal that normal mRNA can be released from P-bodies and translated into protein in response to stress. Meanwhile, Sheth and Parker (2006) report that aberrant mRNAs are targeted to P-bodies to undergo rapid decay.

[reaction: see text] Differently substituted 2-amino-8-oxodecanoic acids (Aodas), present in naturally occurring inhibitors of hystone deacetylase (HDAC), have been prepared using a convergent approach. The configuration in position 2 was derived from enantiomerically pure allylglycine or glutamic acid, whereas the stereochemistry of the substituent in position 9 derived from lactic acid or glyceraldehyde derivatives. Starting from allylglycine, (S)-Aodas, protected at the nitrogen as Boc or Fmoc, were obtained in four steps in about 30% overall yield. These products have been used to prepare a simplified analogue of a natural cyclic tetrapeptide HDAC inhibitor by SPPS.

Chromatin remodeling is a fundamental phenomenon in the life of eukaryotic cells, bearing implications to numerous physiological and pathological phenomena. This review outlines the chemistry of natural and synthetic agents endowed with the ability to interfere with such biological function, with a particular emphasis on histone deacetylase (HDAC) inhibitors. Other aspects covered in this article comprise structure activity relationships (SAR) and modes of action at molecular level, including the description of crystal structures of enzyme-inhibitor complexes.

Procedural sedation is generally recommended for children requiring repeated painful diagnostic or therapeutic procedures. A child with leukemia undergoes an average of 20 procedures such as lumbar puncture and bone marrow aspiration through the course of illness. No data are currently available about the psychological impact of repeated sedations on children. The objective of this study was to evaluate the attitudes of patients with leukemia toward repeated deep sedations using propofol. A questionnaire addressing sedation-related distress was given to 30 children with leukemia. Procedure-related distress was evaluated using the Amended Observational Scale of Behavioural Distress. Another questionnaire concerning the same issues was given to an historical group of 39 children who had undergone painful procedures without sedation in previous years. Fear and distress were significantly reduced in the sedation group compared with the historical one. Fear of sedation was reported by 17% of children of this group. Distressed behavior was observed in 27%. In conclusion, sedation-related distress was observed in a subgroup of patients; in these cases, specific strategies could be considered to reduce sedation-related distress.

Recently, we described the synthesis and the biological evaluation of three modified analogues of jaspamide (1), a natural cyclodepsipeptide possessing a potent antitumor activity as a consequence of its ability to interfere with actin cytoskeleton. To obtain additional information on the potential pharmacophoric core of the target molecule, which is of fundamental importance to discover new and more effective anticancer products, we decided to explore the biological effects of further structural modifications carried out on the parent molecule. The synthesis and the chemical characterization of six jaspamide analogues (2-7) are reported and their conformational and biological properties are described.

The case of a 72-year-old patient affected by myasthenia gravis under pyridostigmine therapy, admitted to the hospital for the onset of oppressive thoracic pain associated with mild enzyme increase, electrocardiographic and echocardiographic disorders, is discussed. Dypiridamole/gated SPECT perfusion scintigraphy at rest evidenced reduced coronary reserve at the level of the lateral wall with apical akinesia and normokinesia of mediobasal left ventricle. On coronarography, coronary arteries were free of significant stenoses and left ventricular apical akinesia. The diagnostic approach to ischemic cardiomyopathy with the correct sequence of performed diagnostic imaging led to the presumptive identification of a rare syndrome.

The case of a newborn infant of 40 days of age with persistent jaundice and blood chemistry values suggestive of cholestasis is discussed. Liver and bile duct US documented missed visualization of the gallbladder. In the suspicion of biliary atresia, hepatobiliary scintigraphy was performed; it showed preserved hepatocyte function, missed visualization of the gallbladder and absence of intestinal bile flow which confirmed the diagnostic hypothesis. Based on possible diagnostic alternatives, signs perceived and interpreted, are analyzed.

The case of a patient with dysphonia and ingravescent dysphagia, associated with crises of lipothymia "ab ingestis" is discussed. ENT examination with videolaryngoscopy evidenced a swelling of the posterior hypopharyngeal wall. X-ray study of the upper digestive tract was discontinued for inhalation. The scintigraphic study of swalling documented marked alteration of the oropharyngeal phase with phenomena of post-deglutitory aspiration. CT of the cervical vertebral column documented anterior diffuse vertebral hyperostosis of C3-C6: this finding was suggestive of Forestier disease.

Three analogues of the natural bioactive cyclodepsipeptide jaspamide (3-5) were efficiently synthesized using a combination of solid and solution phase techniques. The preliminary design of the molecules has involved the rational substitution and/or simplification of the most critical structural features of the lead compound. The synthetic products were subjected to pharmacological assays, and the conformational properties were investigated by MM (molecular mechanics) and MD (molecular dynamics) calculations, to describe the potential pharmacophoric core responsible for the observed activities.

Aims: To determine coeliac disease prevalence by an anti-transglutaminase antibody assay in a large paediatric population; to evaluate acceptance of the screening programme, dietary compliance, and long term health effects., Methods: Cross-sectional survey of 3188 schoolchildren (aged 6-12) and prospective follow up of diagnosed cases. Main outcome measures were: prevalence of coeliac disease defined by intestinal biopsy or positivity to both human tissue transglutaminase and anti-endomysium antibodies in HLA DQ2-8 positive subjects; percentage of children whose families accepted screening; dietary compliance as defined by negativity for anti-transglutaminase antibodies; and presence of clinical or laboratory abnormalities at 24 month follow up., Results: The families of 3188/3665 children gave their consent (87%). Thirty biopsy proven coeliacs were identified (prevalence 1:106). Three other children testing positive for both coeliac related autoantibodies and HLA DQ2-8 but refusing biopsy were considered as having coeliac disease (prevalence 1:96). Of 33 cases, 12 had coeliac related symptoms. The 30 biopsy proven coeliacs followed a gluten-free diet. Of 28 subjects completing 18-24 months follow up, 20 (71.4%) were negative for anti-transglutaminase antibodies, while eight were slightly positive; symptoms resolved in all 12 symptomatic children., Conclusions: Prevalence of coeliac disease is high in Italian schoolchildren. Two thirds of cases were asymptomatic. Acceptance of the programme was good, as was dietary compliance. Given the high prevalence and possible complications of untreated coeliac disease, the availability of a valid screening method, and evidence of willingness to comply with dietary treatment population mass screening deserves careful consideration.

The crystal structure of a ternary complex of the alcohol dehydrogenase from the archaeon Sulfolobus solfataricus (SsADH) has been determined at 2.3 A. The asymmetric unit contains a dimer with a NADH and a 2-ethoxyethanol molecule bound to each subunit. The comparison with the apo structure of the enzyme reveals that this medium chain ADH undergoes a substantial conformational change in the apo-holo transition, accompanied by loop movements at the domain interface. The extent of domain closure is similar to that observed for the classical horse liver ADH, although some differences are found which can be related to the different oligomeric states of the enzymes. Compared to its apo form, the SsADH ternary complex shows a change in the ligation state of the active site zinc ion which is no longer bound to Glu69, providing additional evidence of the dynamic role played by the conserved glutamate residue in ADHs. In addition, the structure presented here allows the identification of the substrate site and hence of the residues that are important in the binding of both the substrate and the coenzyme.

In recent years there has been an increase in the use of ACE inhibitors in the paediatric population. We describe a case of hyperchloraemic metabolic acidosis with hypoaldosteronism in a 4-year-old boy with nephrotic syndrome who was receiving ACE inhibitors.

The Soft Tissue Sarcomas shows consisting mortality that grazes 50%. Commonly the histologic type, the largeness of the tumor and the degree of malignity, are considered prognostic factors influencing the survival of patients affected from such tumor. The aim of our study is to characterize the new prognostic factors influencing the local recidives and metastatic dissemination. We have analysed 17 possible clinical and histologic prognostic factors in 80 patients affected of soft tissue sarcomas. The results have dimonstrated that: the compartimentality and the cellular differentiation seem to be more influent to the insurgence of local recidives and metastasis; while the low malignity degree, the wide surgical margins and the histopatological characters of benignity can influense positively the survival.

Background: The need to perform procedural sedation for children has increased in recent years, and so has the experience of nonanesthesiologists in this field. The use of propofol increases the success of satisfactory deep sedation, but it can produce rapid and profound decreases in level of consciousness and cardiorespiratory function. Data are needed to assess the safety of this drug outside an anesthesiology setting., Objective: To assess safety and efficacy of procedural sedation with propofol in a pediatric ward of a tertiary-care pediatric teaching hospital with trained personnel and monitoring facilities., Methods: Patients admitted to the hospital who needed invasive procedures underwent procedural sedation by the pediatric sedation unit with intravenous propofol. A training protocol was developed to educate nurses and residents., Results: We performed 1059 procedures. Sedation was achieved in all procedures, and all but 1 were successfully performed. No patient required intubation. Transient desaturation resolving spontaneously occurred in 134 (12.7%) of 1059 patients. Major desaturation requiring a short course of ventilation occurred in 4 (0.8%) of 483 patients undergoing upper endoscopies, in 1 (0.3%) of 287 patients undergoing painful procedures, and in none of the 289 patients undergoing colonoscopies. Laryngospasm occurred in 10 (2.1%) of 483 patients undergoing upper endoscopies., Conclusions: In this experience, the use of propofol with concurrent oxygen administration allowed sedations in children with no significant complications for colonoscopies and painful procedures. Complications in the group of upper endoscopies appear too high for recommending propofol in a sedation unit with residents in attendance. This protocol of procedural sedation by nonanesthesiologists allowed a significant increase in the number of procedures performed with sedation and saved anesthesiology resources.

Alcohol dehydrogenase from Sulfolobus solfataricus (SsADH) is the only enzyme from Archaea among the structurally studied members of the medium-chain ADH family described so far. Here, we present the three-dimensional structure of the apo form of the mutant N249Y which exhibits increased catalytic activity when compared to the wild-type enzyme. The substitution, located in the coenzyme binding domain, decreases the affinity for NAD(H) cofactor. The rearrangement of segments 248-250 and 270-275, induced by the mutation, suggests an explanation for the lower coenzyme affinity. This study also highlights the role in SsADH catalysis of the flexible loops located at the interface between the catalytic and the coenzyme domains.

We report the case of a patient presenting with eyelid hernias who required bilateral upper and lower blepharoplasty; histological examination of the excised fat revealed B-cell non-Hodgkin's lymphoma. At diagnosis, the disease was already systemically advanced, but the patient was asymptomatic. No sign of disease had been detected in the preoperative tests. The bilateral orbital presentation of a systemic lymphoma is very rare, and is usually accompanied and revealed by exophthalmos, increased tear secretion, diplopia and decreased visual acuity. To our knowledge, this is the first case in which lid hernias were the first and only clinical sign of such a systemic disease.

Functional brain imaging plays an important role in seizure focus localisation. However, truly ictal single-photon emission tomography (SPET) studies are not routinely performed owing to technical problems associated with the use of tracers and methodological and logistical difficulties. In this study we tried to resolve both of these issues by means of a new procedure: technetium-99m ethyl cysteinate dimer (ECD) brain SPET performed during seizures pharmacologically provoked with pentylenetetrazol, a well-known central and respiratory stimulant. We studied 33 drug-resistant epileptic patients. All patients underwent anamnestic evaluation, neuropsychological and psychodynamic assessment, magnetic resonance imaging, interictal and ictal video-EEG monitoring, and interictal and ictal SPET with (99m)Tc-ECD. In order to obtain truly ictal SPET, 65 mg of pentylenetetrazol was injected every 2 minutes and, immediately the seizure began, 740 MBq of (99m)Tc-ECD was injected. The scintigraphic findings were considered abnormal if a single area of hyperperfusion was present and corresponded to the site of a single area of hypoperfusion at interictal SPET: the "hypo-hyperperfusion" SPET pattern. In 27 of the 33 patients (82%), interictal-ictal SPET showed the hypo-hyperperfusion SPET pattern. Video-EEG showed a single epileptogenic zone in 21/33 patients (64%), and MRI showed anatomical lesions in 19/33 patients (57%). Twenty-two of the 27 patients with hypo-hyperperfusion SPET pattern underwent ablative or palliative surgery and were seizure-free at 3 years of follow-up. No adverse effects were noted during pharmacologically provoked seizure. It is concluded that ictal brain SPET performed during pharmacologically provoked seizure provides truly ictal images because (99m)Tc-ECD is injected immediately upon seizure onset. Using this feasible procedure it is possible to localise the focus, to avoid the limitations due to the unpredictability of seizures, to avoid pitfalls due to late injection, to avoid intracranial EEG recording and to minimise costs. The clinical value of our method is confirmed by the good outcome after 3 years of follow-up in those patients submitted to ablative or palliative surgery.

The synthesis and biological activity of the marine cyclopeptide hymenamide C(1), showing an inhibitory effect on human neutrophil elastase degranulation release, were recently described. Based on this result, it was decided to undertake a systematic structure-activity relationship study of this cyclopeptide, based on the Ala-scan technique, in order to obtain useful information for the rational design of additional analogues. The synthesis and characterization of the seven Ala modified analogues are reported and their biological and pharmacological properties are described.

Aim: Diagnostic delay for inflammatory bowel disease (IBD) is frequent, especially in paediatric patients. Scintigraphy with labelled leucocytes has been proposed as a very sensitive diagnostic tool for detecting bowel inflammation. The aim of this study was to evaluate the sensitivity and specificity of immunoscintigraphy in the diagnosis and follow-up of children with IBD and to compare this technique with other diagnostic techniques., Methods: Sixty-six children with histologically confirmed IBD were enrolled in the study. Twenty-one children in whom IBD was suspected but subsequently not confirmed were used as controls. A total of 138 immunoscintigraphies were performed using 99mTechnetium-labelled monoclonal anti-granulocyte antibodies. Immunoscintigraphy was also compared with other diagnostic techniques., Results: Overall sensitivity of monoclonal antibody immunoscintigraphy (MoAb-IS) in patients with clinically active disease was 94% for Crohn's disease (CD) and 85% for ulcerative colitis (UC). Ultrasonography, endoscopy and radiology were carried out at the same time in 29 patients with CD and in 6 patients with UC: sensitivity of IS was 90% compared with 76% of colonoscopy, 75% for enemas, and 55% for sonography. IS was negative (specificity) in 24% of patients with CD and in 67% of patients with UC during remission, and in 64% of controls with other causes of intestinal inflammation. Diagnostic delay was significantly shorter when compared with a historical cohort of patients., Conclusion: Immunoscintigraphy is a highly sensitive detector of intestinal inflammation in young patients with IBD and can be useful for reducing diagnostic delay. However, its specificity is low and all positive cases must be confirmed histologically.

A new pyrroloiminoquinone alkaloid (1) belonging to the makaluvamine family has been isolated from the sponge Zyzzya cf. fuliginosa collected in the waters off the Vanuatu Islands. The compound, designated makulavamine P, was characterized on the basis of its spectral data and displayed cytoxicity in the microM range on KB cells and antioxidant activity.

Rosacelose, a new anti-HIV polysaccharide composed of glucose and fucose sulfate, has been isolated from an aqueous extract of the marine sponge Mixylla rosacea. Extensive use of 1H and 13C multidimensional NMR spectroscopy, combined with chemical analysis were used to establish a linear polysaccharide structure composed mainly of 4,6-disulfated 3-O-glycosylated alpha-D-glucopyranosyl and 2,4-disulfated 3-O-glycosylated alpha-L-fucopyranosyl residues (in a 3:1 molar ratio).

Chemical investigation of the Et(2)O extract of the marine sponge Rhaphisia lacazei resulted in the isolation of 13 pure bisindole alkaloids (1-13). Compounds (1-6) belong to the class of topsentins and have already been described. Compounds 7-13 are new products, closely related to the class of hamacanthins. The major compounds 1-3 were tested in vitro for antitumor activity; compounds 2 and 3 showed antiproliferative activity against human bronchopulmonary cancer cells (NSCLC-N6) with an IC(50) of 12 and 6.3 microg/mL, respectively.

Crystallographic and theoretical (ab initio) data on intermolecular nonbonded interactions have been gathered together in a computerised library ('IsoStar'). The library contains information about the nonbonded contacts formed by some 250 chemical groupings. The data can be displayed visually and used to aid protein-ligand docking or the identification of bioisosteric replacements. Data from the library show that there is great variability in the geometrical preferences of different types of hydrogen bonds, although in general there is a tendency for H-bonds to form along lone-pair directions. The H-bond acceptor abilities of oxygen and sulphur atoms are highly dependent on intramolecular environments. The nonbonded contacts formed by many hydrophobic groups show surprisingly strong directional preferences. Many unusual nonbonded interactions are to be found in the library and are of potential value for designing novel biologically active molecules.

This paper describes how the carbohydrate structures in the Complex Carbohydrate Structure Database (CCSD) can be represented by labelled graphs, in which the nodes and edges of a graph are used to denote the residues and the inter-residue linkages, respectively, of a carbohydrate. These graph representations are then searched with a subgraph-isomorphism algorithm. We describe the use of one such algorithm, that due to Ullmann, and demonstrate that it provides a very precise way of searching the structures in CCSD. We also describe the use of screening techniques that can eliminate many of the CCSD structures from the subgraph-isomorphism search, with a consequent increase in the speed of the search.

Two tris-indole alkaloids, (+/-) gelliusines A and B [1], have been isolated for the first time from a marine source, the New Caledonian sponge, Orina sp. (or Gellius sp.), along with five further indole constituents [2-6]. Compound 6 has been identified as 2,2-bis-(6'-bromo-3'-indolyl(-ethylamine, previously isolated from the tunicate Didemnum candidum, but the remaining four indoles [2-5] are novel compounds. These showed anti-serotonin activity and a strong affinity for somatostatin and neuropeptide Y receptors in receptor-binding assays.

Two new diastereomeric brominated tris-indole alkaloids occurring as enantiomeric pairs, (+/-)-gelliusines A [1] and B [2], have been isolated from a deep water New Caledonian sponge (Gellius or Orina sp.), whose crude extract exhibited cytotoxicity against KB cells. Their structures were elucidated by spectroscopic methods including one- and two-dimensional nmr spectroscopy. The major compound, (+/-) gelliusine A [1], which showed very weak cytotoxicity, proved to be active at the serotonin receptor.

Three new steroid sulfates 2-4 related to halistanol sulfate [1] were isolated along with the known halistanol sulfate C [5] from the marine sponge Pseudoaxinissa digitata. Halistanol sulfates F [2] and G [3] proved to be cytoprotective against HIV.

Four pentacyclic guanidine derivatives (crambescidin 800 [5], crambescidin 816 [6], isocrambescidin 800 [9], and crambine [10]) related to ptilomycalin A [11] have been isolated from the Mediterranean sponge Crambe crambe. Isocrambescidin 800 and crambidine are new derivatives, the structures of which have been determined on the basis of their spectral properties. The absolute configuration of crambescidin 816 at the stereogenic center C-43 has been determined by applying Mosher's method. Pharmacological and biological activities of the Crambe crambe alkaloids are reported. In particular, crambescidin 816 was found to have a potent Ca++ antagonist effect and to inhibit the acetylcholine-induced contraction of guinea pig ileum at very low concentrations.

This paper describes a complete analysis of the glycoside and polyhydroxysteroid constituents of the starfish Nardoa tuberculata, collected at Zampa, Okinawa, Japan. Besides a group of known non-sulfated steroidal diglycosides, halitylosides A [5], B [6], D [7], E [8], and F [9], and two known polyhydroxysteroids 10 and 11, N. tuberculata also contains four new sulfated steroidal glycosides 1-4 closely related to the previous halitylosides. The antifungal activities and the effects on the development of fertilized sea urchin eggs of some steroid components from this starfish were examined.