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Long-term memory formation (LTM) is a process accompanied by energy-demanding structural changes at synapses and increased spine density. Concomitant increases in both spine volume and postsynaptic density (PSD) surface area have been suggested but never quantified in vivo by clear-cut experimental evidence. Using novel object recognition in mice as a learning task followed by 3D electron microscopy analysis, we demonstrate that LTM induced all aforementioned synaptic changes, together with an increase in the size of astrocytic glycogen granules, which are a source of lactate for neurons. The selective inhibition of glycogen metabolism in astrocytes impaired learning, affecting all the related synaptic changes. Intrahippocampal administration of l-lactate rescued the behavioral phenotype, along with spine density within 24 hours. Spine dynamics in hippocampal organotypic slices undergoing theta burst-induced long-term potentiation was similarly affected by inhibition of glycogen metabolism and rescued by l-lactate. These results suggest that learning primes astrocytic energy stores and signaling to sustain synaptic plasticity via l-lactate.

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. The role of extracellular α-synuclein (α-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the α-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric α-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric α-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, α-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric α-syn. The causal relationship between α-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on α-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of α-syn fibrillization (Tolcapone) or replacing monomeric α-syn by monomeric β-synuclein in α-syn mixture composition prevent α-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added α-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of α-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular α-syn play central roles in α-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable strategy for protecting against α-syn-induced toxicity and slowing the progression of neurodegeneration in PD and other synucleinopathies.

The CRISPR/Cas9 system is a powerful genome editing technique employed in a wide variety of organisms including recently the human malaria parasite, P. falciparum. Here we report on further improvements to the CRISPR/Cas9 transfection constructs and selection protocol to more rapidly modify the P. falciparum genome and to introduce transgenes into the parasite genome without the inclusion of drug-selectable marker genes. This method was used to stably integrate the gene encoding GFP into the P. falciparum genome under the control of promoters of three different Plasmodium genes (calmodulin, gapdh and hsp70). These genes were selected as they are highly transcribed in blood stages. We show that the three reporter parasite lines generated in this study (GFP@cam, GFP@gapdh and GFP@hsp70) have in vitro blood stage growth kinetics and drug-sensitivity profiles comparable to the parental P. falciparum (NF54) wild-type line. Both asexual and sexual blood stages of the three reporter lines expressed GFP-fluorescence with GFP@hsp70 having the highest fluorescent intensity in schizont stages as shown by flow cytometry analysis of GFP-fluorescence intensity. The improved CRISPR/Cas9 constructs/protocol will aid in the rapid generation of transgenic and modified P. falciparum parasites, including those expressing different reporters proteins under different (stage specific) promoters.

Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome. 22q11.2 deletion syndrome (22q11DS) is associated with learning and cognitive dysfunctions and a high risk of developing schizophrenia. It has become increasingly clear that dendritic spine plasticity is tightly linked to cognition. Thus, understanding how genes involved in cognitive disorders affect synaptic networks is a major challenge of modern biology. Several studies have pointed to a spine density deficit in 22q11DS transgenic mice models. Using the LgDel mouse model, we first quantified spine deficit at different stages using electron microscopy. Next we performed repetitive confocal imaging over several days on hippocampal organotypic cultures of LgDel mice. We show no imbalanced ratio between daily spine formation and spine elimination, but a decreased spine life expectancy. We corrected this impaired spine stabilization process by overexpressing ZDHHC8 palmitoyltransferase, whose gene belongs to the LgDel microdeletion. Overexpression of one of its substrates, the cdc42 brain-specific variant, under a constitutively active form (cdc42-palm-CA) led to the same result. Finally, we could rescue spine density in vivo, in adult LgDel mice, by injecting pups with a vector expressing cdc42-palm-CA. This study reveals a new role of ZDHHC8-cdc42-palm molecular pathway in postsynaptic structural plasticity and provides new evidence in favor of the dysconnectivity hypothesis for schizophrenia.

Betulinic acid (BA) is a widely available plant-derived triterpene with reported activity against cancer cells of neuroectodermal origin and leukaemias. Treatment with BA was shown to protect mice against transplanted human melanoma and led to tumor regression. In contrast, cells from healthy tissues were resistant to BA and toxic side-effects in animals were absent. These findings have raised interest in the chemotherapeutical anti-cancer potential of BA. A comprehensive assessment of the efficacy of BA against the clinically most important cancer types is currently lacking. Therefore, we tested the in vitro sensitivity of broad cell line panels derived from lung, colorectal, breast, prostate and cervical cancer, which are the prevalent cancer types characterized with highest mortalities in woman and men. Multiple assays were used in order to allow a reliable assessment of anti-cancer efficacy of BA. After 48 h of treatment with BA, cell viability as assessed with MTT and cell death as measured with propidium iodide exclusion showed clear differences in sensitivity between cell lines. However, in all cell lines tested colony formation was completely halted at remarkably equal BA concentrations that are likely attainable in vivo. Our results substantiate the possible application of BA as a chemotherapeutic agent for the most prevalent human cancer types.

Aim To evaluate kidney function before and after surgical correction of vesicoureteral reflux. The long-term effect was measured with quantitative nephro-scintigraphy using 99 Tc m labelled dimercaptosuccinic acid ( 99 Tc m -DMSA). Methods Forty-five children with a history of urinary tract infections due to vesicoureteral reflux (VUR) were studied. VUR grade was determined with contrast voiding cystourethrography. Planar scintigraphy was performed with 99 Tc m -DMSA and uptake measured as a percentage of injected dose. Kidney function was evaluated at baseline and 5 years after corrective surgery. Results Three months after surgery, persistent mild reflux was found in eight of 76 treated renal units. Kidney uptake at 5-year follow-up was unchanged in the majority of children, indicating preservation of renal function found at baseline. The split renal function showed an excellent correlation (r = 0.99) between baseline and follow-up studies (regression slope 1.01). Percentage uptake had a regression slope of 0.89 significantly different from unity (P < 0.05). Empirical kidney-depth correction techniques were compared. The scintigraphic pattern worsened in six kidneys, indicative of increased scarring in a minority of children. Conclusion Planar nephro-scintigraphy with 99 Tc m -DMSA was well tolerated in our paediatric population, and appeared appropriate to evaluate kidney function in time. After surgical correction of VUR, the baseline function was maintained in 94% of kidneys.

Evaluation of severe functional gastrointestinal motility disorders requires an investigation of the entire gastrointestinal tract. This should be possible with a single radionuclide imaging study. The purpose of this study was (1) to define normal values of small-bowel transit in men and women and (2) to assess a possible difference between gender or test meal, since it has been shown that women have slower gastric emptying than men, and gastric emptying of solids is slower than liquids. A standard gastric-emptying test for a solid (technetium-99m sulphur colloid, 230 Kcal) and liquid (indium-111 DTPA water) test meal was performed in 12 healthy male and 12 healthy female volunteers. After 135 min, the volunteer was placed in the supine position for static imaging of the abdomen every 15 min for 6 h. Decay and crossover-corrected geometric mean gastric-emptying data were fit to a modified power exponential function to determine the 10% stomach emptying time for solids and liquids separately. An ROI was drawn around the caecum and ascending colon to determine the arrival time of at least 10% of the solid and liquid test meal. Ten percent small-bowel transit time (10% SBTT) and orocaecal transit time (OCTT) were calculated. The OCTT for males and females, respectively for solids and liquids, are 294.6 +/- 18.8; 301.3 +/- 24.5; 294.6 +/- 18.8 and 301.3 +/- 24.5 min. The 10% SBTT for males and females, respectively for solids and liquids, are 280.3 +/- 18.4; 280.6 +/- 24.0; 288.2 +/- 18.9 and 297.4 +/- 24.4 (mean +/- SEM) min. We observed a simultaneous transfer of solids and liquids from the terminal ileum to caecum (correlation coefficient 0.90). There is no statistically significant difference in SBTT between gender or solids and liquids. In contrast to the gastric-emptying time, the SBTT of solids and liquids were not significantly different nor was a gender difference found. Determination of the OCTT seems to be the simplest and most accurate approach to measure SBTT. Since ileocaecal transfer occurs as a bolus phenomenon, a 111In-labelled test meal can also be used for the determination of colon transit in a single imaging study protocol.

We perform a generalised Scherk-Schwarz reduction of the effective action of the heterotic string on T^6 to obtain a massive N=4 supergravity theory in four dimensions. The local symmetry-group of the resulting d=4 theory includes a Heisenberg group, which is a subgroup of the global O(6,6+n) obtained in the standard reduction. We show explicitly that the same theory can be obtained by gauging this Heisenberg group in d=4, N=4 supergravity., Comment: 11 pages, LaTeX, no figures, one reference added

We give a classification of all multiple intersections of D-branes in ten dimensions and M-branes in eleven dimensions that corresponds to threshold BPS bound states. The residual supersymmetry of these composite branes is determined. By dimensional reduction composite p-branes in lower dimensions can be constructed. We emphasize in dimensions D greater or equal than two, those solutions which involve a single scalar and depend on a single harmonic function. For these extremal branes we obtain the strength of the coupling between the scalar and the gauge field. In particular we give a D-brane and M-brane interpretation of extreme p-branes in two, three and four dimensions., 28 pages, LaTeX, 4 figures, corrections in table 1 and figure 2

Sumatriptan, a 5-hydroxytryptamine1 (5-HT1) receptor agonist at enteric neuronal 5-HT receptors, causes a relaxation of the gastric fundus and inhibition of antral contractile activity. The present study examined the effect of sumatriptan on gastric emptying of solids and liquids in humans. In eight healthy subjects the gastric emptying rate for liquids and solids was measured using the carbon-labeled glycine and octanoic acid breath test after subcutaneous administration of placebo or sumatriptan. Sumatriptan increased the gastric half-emptying time of liquids (P < 0.0005) and induced a prolonged lag phase for liquids (P < 0.0005) in all subjects. Sumatriptan increased gastric half-emptying time (P < 0.005) and the lag phase of solids (P < 0.05) in all subjects. In two healthy subjects gastric emptying of liquids and solids after subcutaneous administration of sumatriptan was studied by radioscintigraphy. Radioscintigraphy confirmed the delayed emptying and the prolonged lag phases after sumatriptan. In conclusion, sumatriptan delays gastric emptying of solids and liquids in healthy subjects. Moreover, sumatriptan induces a lag phase for liquids. The mechanism by which sumatriptan alters gastric emptying remains to be studied.

The blood retention of 99Tcm-dimercaptopropionyl human serum albumin (99Tcm-DMP-HSA), prepared from a kit, was compared with that of five other 99Tcm-labelled blood pool tracers in two healthy volunteers. 99Tcm-DMP-HSA showed an almost identical behaviour to in vitro labelled red blood cells (RBCs), which are generally considered the reference standard for blood pool agents. The mean apparent blood mass of 99Tcm-DMP-HSA was 2.1% higher 10 min post-injection (p.i.) than that of in vitro 99Tcm-RBCs, 2.0% higher 30 min p.i., 4.7% higher 60 min p.i. and 2.3% higher 120 min p.i. In vivo labelling of RBCs yielded a labelling efficiency of 75-98%, depending on the stannous agent used. About 20 min after pertechnetate administration, the intravascular activity as a percentage of injected dose stabilized at levels close to that of in vitro labelled RBCs. One commercially available 99Tcm-HSA kit was found to be unsuitable as a blood pool tracer. As 99Tcm-DMP-HSA offers the same practical advantages as 99Tcm-HSA, but better biological characteristics, it shows promise as a new tracer for radionuclide ventriculography and further large-scale investigations are warranted.

Two strategies have been used to increase the 99 Tc m binding strength of human serum albumin (HSA) and thus enhance its blood retention. In a first approach, HSA was derivatized with a varying number of hydrazino nicotinyl (Hynic) side-chains using N-hydroxysuccinimidyl hydrazino nicotinate. Labelling of this albumin derivative with 99 Tc m resulted in labelling yields of 90-95%. On the other hand, a 99 Tc m -MAG3-HSA conjugate was prepared using the preformed chelate approach. In this way, non-specific binding of 99 Tc m to HSA could be excluded. The in vitro stability of both 99 Tc m -HSA derivatives was evaluated by cysteine challenge experiments and revealed a much higher stability for 99 Tc m -Hynic-HSA than for 99 Tc m -MAG3-HSA. The biological behaviour of the preparations was evaluated in mice and a rabbit using 125 I-HSA as an internal biological standard. The blood retention of 99 Tc m -MAG3-HSA decreased more rapidly than that of 125 I-HSA in both animal species, whereas 99 Tc m -Hynic-HSA seemed to provide a quasi-perfect 99 Tc m -labelled analogue for 125 I-HSA and 99 Tc m -red blood cells ( 99 Tc m -RBCs). In addition, the blood retention of 99 Tc m -Hynic-HSA appeared to be similar to that of 99 Tc m -RBCs in a volunteer. These results clearly indicate the superiority of 99 Tc m -Hynic-HSA over 99 Tc m -MAG3-HSA as a possible blood pool agent.

S-Benzyl-, S-benzamidomethyl- and S-benzoylmercaptoacetyltriglycine were synthesized and compared in exchange labelling experiments for the preparation of 99mTc-MAG3. The rate of exchange from 99mTc-tartrate to 99mTc-MAG3 starting from the respective precursors was determined in different conditions. Labelling proceeded most rapidly starting from the S-benzoyl protected precursor but efficient labelling was also accomplished using the more stable S-benzamidomethyl- and S-benzylmercaptoacetyltriglycine. 99mTc-MAG3 was also prepared by direct labelling of unprotected mercaptoacetyltriglycine at alkaline pH. Radiochemical purity in these conditions is mainly dependent on the pH during labelling.

Prosthetic vascular graft infection is a relatively uncommon complication of peripheral vascular surgery. We retrospectively analysed technetium-99m-d,l-hexamethylpropylene amine oxime (99Tcm-d,l-HMPAO) labelled leukocyte scans of 21 patients with a suspected vascular graft infection. Operative findings, bacteriological cultures, radiological findings or clinical follow-up were used to confirm the diagnosis. We found eight true-positive and six true-negative cases. There were no false-positive scintigraphic diagnoses. The false-negative rate was 33% (n = 7). Our results show a sensitivity of 53%, a specificity of 100% and an accuracy of 66%. The conclusion is that a negative 99Tcm-d,l-HMPAO-labelled leukocyte scan is of limited value in ruling out a vascular graft infection. A combination of computed tomography (CT-scan) and a 99Tcm-d,l-HMPAO-labelled leukocyte scan is probably the most efficient way of diagnosing a vascular graft infection.

BACKGROUND In patients with chronic coronary artery disease (CAD) and left ventricular dysfunction, flow/metabolic studies of the myocardium with positron emission tomography (PET) are able to distinguish viable but dysfunctional myocardium from irreversible ischemic injury and scar tissue. In this study, PET findings of blood flow and metabolism in chronically hypoperfused myocardium were correlated with histology. METHODS AND RESULTS We studied 33 patients suffering from CAD. In each patient, myocardial blood flow and metabolism were measured with PET 1 or 2 days before revascularization. During surgery, transmural biopsies were taken from the left ventricular anterior wall and planimetrically scored for the degree of myolysis (sarcomere loss). The amount of connective tissue was calculated using morphometric techniques. Contrast ventriculography demonstrated abnormal wall motion in 23 patients. Fourteen patients with a mismatch pattern (decreased flow with preserved metabolism) in the biopsy region after quantitative analysis of the PET data showed 11 +/- 6 vol% fibrosis and 25 +/- 13% cells with sarcomere loss. The space formerly occupied by sarcomeres was mainly replaced by glycogen and mitochondria. A significant wall motion improvement was noted 3 months after surgery. Nine patients showed a match pattern (concordant flow/metabolism defects). The biopsies revealed 35 +/- 25% fibrosis and 24 +/- 15% glycogen-storing cells. The biopsies of the 10 patients with normal anterior wall motion showed 8 +/- 4% fibrosis and 12 +/- 8% glycogen-accumulating cells. CONCLUSIONS It can be concluded that areas with impaired wall motion and a PET match pattern show extensive fibrosis. Regions with reduced flow and preserved FDG metabolism, however, contain predominantly viable cells. In these regions, significant recovery of wall motion is found after revascularization. Regions with normal wall motion contain predominantly viable cells. Cells with reduced contractile material and increased glycogen content are mainly found in areas with wall motion impairment but are also present in areas with normal wall motion and a severe stenosis of the coronary vessel.

To investigate the processing of visual form in human cerebral cortex, we used the PET (positron emission tomography) activation technique to compare the human brain regions that are involved in a visual detection task and two orientation discrimination tasks: the temporal same-different (TSD) task, which includes a short-term memory component, and the identification (ID) task, which is without this component. As a control task we used passive viewing. Stimuli were identical in all four tasks. Subtraction of passive viewing from detection showed that the detection task activates early visual cortical regions (areas 17/18) as well as several motor brain regions, while decreasing activity in several higher order frontal, temporal, and parietal regions. Comparing the ID task to the detection task revealed no further visual cortical activation, while comparison of the TSD task to the detection task revealed an activation of several right visual cortical regions, one of which remained significant after the subtraction of ID from TSD (right area 19). These experiments demonstrate the task dependence of visual processing, even for very closely related tasks, and the localization of the temporal comparison component involved in orientation discrimination in human area 19.

A number of derivatives of mercaptoacetyltriglycine in which one or more of the three glycylmoieties are replaced by other amino acids such as D- or L-alanine, D-serine, D-2-aminobutyric acid, D-valine or D-phenylglycine have been synthesized and labelled with technetium-99m. Labelling with technetium yielded in each a mixture of mainly two radioactive species, which probably are diastereomeric oxotechnetium (V) complexes originating from the presence of a chiral carbon atom in the ligands. The diastereomers were separated by reversed phase HPLC. Except for the serine derivative, all radiolabelled derivatives have a longer retention time than the parent compound 99mTc-MAG3. The relative amount of the two diastereomers formed upon labelling is dependent on the nature of the ligand but can be influenced to a limited extent by the pH of the exchange labelling mixture.

To establish the value of quantitative radionuclide bone scanning after total knee replacement, 21 patients were scheduled for examination. Eight patients were scanned more than 1 year after surgery (group 1), and 13 within the first postsurgical year (group 2). Ratios were calculated for three regions of interest. The ratio was defined as the counts per pixel for each region of interest, normalized by dividing them by the counts per pixel of the ipsilateral femoral shaft. There was no significant difference in uptake between control subjects and patients in group 2, indicating that the test was not reliable within this time period. No statistical difference was found between the uptake scores in groups 1 and 2, demonstrating that an uninterpretable period of 1 year is perhaps too short. Using a ratio of more than three, seen more than 1 year after surgery as pathologic, a sensitivity of 100%, a specificity of 33%, and an accuracy of 75% was found. Quantitative bone scanning is a very sensitive test for detecting complications, but it is nonspecific in diagnosing loosening of total knee arthroplasties. The value of quantitative scanning presumably lies in the follow-up of patients as an objective method for the evaluation of sequential scanning. Nevertheless, radionuclide data need to be interpreted in correlation with clinical and radiologic findings.

SummaryThe aim of the study was the functional re-evaluation of 296 patients 12 to 18 months after a double-blind trial evaluating the effect of tissue plasminogen activator (rt-PA) versus placebo given within 5 h of onset of symptoms caused by an acute myocardial infarction. All patients underwent rest-stress radionuclide angiography (Egna). For each exercise level the global left ventricular ejection fraction (LVEF) was calculated together with an estimate of regional wall motion abnormalities (RWMA). A clear difference of the total workload and the peak workload was found between both therapeutic groups. Discriminant analysis evaluating four parameters (LVEF at peak exercise and at the endpoint and the workload at those levels) revealed a beneficial therapeutic effect. The RWM at rest showed only a difference in the apico-inferior region. There were less wall motion abnormalities in the treated group. Radionuclide analysis demonstrated a larger functional capacity and a better coordination of myocardial contractility during stress RNA one year after thrombolytic therapy. At rest, no major differences were found between the hospital stage and the follow-up in both therapeutic groups one year later.

We quantise the classical gauge theory of $N=2\ w_\infty$-supergravity and show how the underlying $N=2$ super-$w_\infty$ algebra gets deformed into an $N=2$ super-$W_\infty$ algebra. Both algebras contain the $N=2$ super-Virasoro algebra as a subalgebra. We discuss how one can extract from these results information about quantum $N=2\ W_N$-supergravity theories containing a finite number of higher-spin symmetries with superspin $s\le N$. As an example we discuss the case of quantum $N=2\ W_3$-supergravity., Comment: 44 pages

We construct supersymmetric R + R 4 -actions in ten dimensions. Two invariants, of which the bosonic parts are known from string amplitude and sigma model calculations, are obtained. One of these invariants can be generalized to an R + F 2 + F 4 -invariant for supersymmetric Yang-Mills theory coupled to supergravity. Supersymmetry requires the presence of B ∧ R ∧ R ∧ R ∧ R -terms, ( B ∧ F ∧ F ∧ F ∧ F for Yang-Mills) which correspond to counterterms in the Green-Schwarz anomaly cancellation.

Three different neuro-imaging studies were performed in 3 infants with hemorrhagic shock and encephalopathy syndrome (HSE). Areas of cerebral infarction were noted on CT. Single photon emission computed tomography (SPECT) showed decreased perfusion in these areas in one infant. Magnetic resonance imaging (MRI) also identified the areas of infarction, noted on CT, but provided additional information showing non-haem iron deposition in the thalami and basal ganglia.

After showing in an earlier publication that Iomazenil is a potent benzodiazepine receptor antagonist, the substance has been distributed to 11 clinical centres in Europe for further tests. The protocol asked for volunteers, epileptic cases and patients with Alzheimer's disease. Prior to the Iomazenil examination, flow images by perfusamine or HMPAO were required, and as comparative methods EEG, computed tomography (CT) and magnetic resonance imaging (MRI) were performed. The results allowed first the determination of the normal distribution of the benzodiazepine receptors in the human brain. The highest uptake was found in medial occipital cortex. Second, the evaluation of the epileptic cases shows a 100% positive prediction value for Iomazenil compared to 92% for flow images. Negative prediction values were calculated as 81% for Iomazenil and 54% for flow images. Furthermore, one group reported the successful diagnosis of Alzheimer's disease at an early stage. The visual image examination was tentatively compared to a more objective semiquantitative one based on quotients of corresponding left/right regions of interest. This semiquantitative method has not proved successful yet, but the problems have been identified. A more precise protocol for further studies is therefore proposed.

Serum squamous cell carcinoma antigen (SCCa) concentrations were determined by a radioimmunoassay kit before and during the treatment of 50 patients with cervical carcinoma: 44 with squamous cell carcinoma (SCC) and 6 with adenocarcinoma. The positivity rate of SCCa was 50% (52% for SCC and 33% for adenocarcinoma). The sensitivity of SCCa for SCC was twice as high as that of CEA and CA-125. Low serum concentrations were observed in early-stage carcinoma, indicating that SCCa is not useful for diagnosis. In advanced cases, serum levels were directly and significantly correlated with the stage of the disease.

The use of an oblique transformation to obtain physiological factors from a factor analysis of dynamic scintigraphic studies was suggested ten years ago. The technique uses a vertex-seeking routine to enable these factors and their contribution images to be formed. This paper investigates a new vertex-finding algorithm, based on an optimization of a function of the vertices. The algorithm also converges in the cases where the previous algorithm of Barber and Cavailloles diverges.

Increasing evidence indicates that adhesion molecules are critically involved in the regulation of mechanisms of synaptic plasticity including synapse formation, but also synaptic remodeling associated to changes in synaptic strength. Among these, the Neural Cell Adhesion Molecule (NCAM) and its polysialylated form PSA-NCAM are important candidates. Here we review recent results that point to a possible role of these two molecules in regulating the structural properties of excitatory synapses and namely the composition and stability of the postsynaptic density, thereby accounting for their contribution to mechanisms of synaptogenesis and activity-dependent synaptic plasticity.

While changes in the efficacy of synaptic transmission are believed to represent the physiological bases of learning mechanisms, other recent studies have started to highlight the possibility that a structural reorganization of synaptic networks could also be involved. Morphological changes of the shape or size of dendritic spines or of the organization of postsynaptic densities have been described in several studies, as well as the growth and formation following stimulation of new protrusions. Confocal in vivo imaging experiments have further revealed that dendritic spines undergo a continuous turnover and replacement process that may vary as a function of development, but can be markedly enhanced by sensory activation or following brain damage. The implications of these new aspects of plasticity for learning and memory mechanisms are discussed.

With the use of the radionuclide gastric-emptying test and a new data processing method, the contraction characteristics of the stomach were analyzed. After ingestion of a radiolabeled test meal, dynamic images of the stomach were acquired and analyzed to determine the frequency, amplitude, and rate of gastric contractions in healthy subjects. The frequency of antral contractions was found to be inversely related with food retention in the stomach; in contrast, the amplitude of the contractions decreased progressively during the course of gastric emptying. The peaks of both antral contraction and filling rate and the time of their occurrence remained constant throughout gastric emptying. The observed patterns of phase distribution and sequential phase changes of the food in the stomach confirmed noninvasively what was already known from invasive technique, i.e., that the proximal stomach does not undergo phasic contractions and that, in the distal stomach, smooth muscle contraction originates in midcorpus and propagates aborally to the pylorus. The scintigraphic test can be used to noninvasively and quantitatively characterize gastric motor function and to delineate the spatial sequence of gastric contractions. This technique can be applied to study the pathophysiology of gastric emptying in various motor disorders.

External hydrocephalus was diagnosed using computed tomography in seven children presenting with macrocephaly. The value of different imaging techniques in distinguishing between subdural effusions and external hydrocephalus was investigated. High resolution ultrasonography combined with magnetic resonance imaging appeared to provide enough information to make a distinction between these two conditions. Radionuclide cisternography was still required to assess the flow pattern of the cerebrospinal fluid (CSF) which was important when placement of a lumboperitoneal shunt was considered.

SummaryPulmonary tumor embolism is an often missed antemortem diagnosis in patients with cancer and respiratory failure. Although rare, this complication is an important cause of additional morbidity. Referred for radionuclide pulmonary perfusion and ventilation scintigraphy, a typical pattern of multiple subsegmental peripheral defects on perfusion lung scanning without matching ventilation defects, suggesting a high probability for pulmonary thromboembolism, often leads to false conclusions.We present a case of bilateral multiple subsegmental mismatched defects in lung ventilation perfusion scintigraphy, where autopsy confirmed the diagnosis of pulmonary tumor embolism, secondary to an undifferentiated ductal type adenocarcinoma of the pancreas. Pulmonary tumor embolism is an entity to keep in mind in patients treated for carcinoma presenting with (sub) acute dyspnea.

Tumors have several mechanisms to escape from the immune system. One of these involves expression of intracellular anticytotoxic proteins that modulate the execution of cell death. Previously, we have shown that the serine protease inhibitor (serpin) SPI-6, which inactivates the cytotoxic protease granzyme B (GrB), is capable of preventing cytotoxic T lymphocyte (CTL)–mediated apoptosis. Despite its potent antiapoptotic activity, SPI-6 does not prevent membranolysis induced by cytotoxic lymphocytes. We now provide evidence that several colon carcinoma cell lines do resist membranolysis and that this protection is dependent on SPI-6 but also requires expression of a closely related serpin called SPI-CI (serine protease inhibitor involved in cytotoxicity inhibition). Expression of SPI-CI is absent from normal colon but observed in placenta, testis, early during embryogenesis, and in cytotoxic lymphocytes. SPI-CI encodes a chymotrypsin-specific inhibitor and irreversibly interacts with purified granzyme M. Moreover, SPI-CI can protect cells from purified perforin/GrM-induced lysis. Our data therefore indicate that SPI-CI is a novel immune escape molecule that acts in concert with SPI-6 to prevent cytotoxic lymphocyte-mediated killing of tumor cells.

We discuss the potential and mass-matrix of gauged N=4 matter coupled supergravity for the case of six matter multiplets, extending previous work by considering the dependence on all scalars. We consider all semi-simple gauge groups and analyse the potential and its first and second derivatives in the origin of the scalar manifold. Although we find in a number of cases an extremum with a positive cosmological constant, these are not stable under fluctuations of all scalar fields., 28 pages, LaTeX

We define an iterative procedure to obtain a non-abelian generalization of the Born-Infeld action. This construction is made possible by the use of the severe restrictions imposed by kappa-symmetry. We have calculated all bosonic terms in the action up to terms quartic in the Yang-Mills field strength and all fermion bilinear terms up to terms cubic in the field strength. Already at this order the fermionic terms do not satisfy the symmetric trace-prescription., 9 pp. Latex, to appear in the proceedings of the Strings 2000 conference

We discuss the non-abelian Born-Infeld action, including fermions, as a series in α � . We review recent work establishing the complete result to α � 2 , and its impact on our earlier attempts to derive the BornInfeld action using κ-symmetry.

We construct the order alpha'^3 terms in the supersymmetric Yang-Mills action in ten dimensions for an arbitrary gauge group. The result can be expressed in terms of the structure constants of the Yang-Mills group, and is therefore independent of abelian factors. The alpha'^3 invariant obtained here is independent of the alpha'^2 invariant, and we argue that additional superinvariants will occur at all odd orders of alpha'., Comment: 15 pages LaTeX

We define an iterative procedure to obtain a non-abelian generalization of the Born-Infeld action. This construction is made possible by the use of the severe restrictions imposed by kappa-symmetry. In this paper we will present all bosonic terms in the action up to terms quartic in the Yang-Mills field strength and all fermion bilinear terms up to terms cubic in the field strength. Already at this order the fermionic terms do not satisfy the symmetric trace-prescription., 26 pages, Latex

We determine the non-abelian Born-Infeld action, including fermions, as it results from the four-point tree-level open superstring scattering amplitudes at order alpha'^2. We find that, after an appropriate field redefinition all terms at this order can be written as a symmetrised trace. We confront this action with the results that follow from kappa-symmetry and conclude that the recently proposed non-abelian kappa-symmetry cannot be extended to cubic orders in the Born-Infeld curvature., 26 pages, Latex

We review an iterative construction of the supersymmetric non-abelian Born-Infeld action. We obtain the action through second order in the fieldstrength. Kappa-invariance fixes the ordenings which turn out to deviate from the symmetrized trace proposal., LaTeX, 8 pages, contribution to the proceedings of the workshop "The Quantum Structure of Spacetime and the Geometric Nature of Fundamental Interactions", Berlin, October 2000

Positron emission tomography (PET) with 18F-fluoride was utilized to determine the regional blood flow to the femoral head in early osteonecrosis. Five patients with a history of unilateral hip trauma and a normal contralateral side were selected. Skeletal flow and fluoride uptake in the abnormal and normal hips were compared directly, and the relation between bone blood flow and final outcome, i.e., surgical replacement or conservative treatment, was evaluated. In this pilot study, a flow ratio of at least 2 between the abnormal and normal femoral head was necessary to predict a successful outcome with a conservative regimen. A minimum flow of 0.04 ml/min/ ml was measured in one patient whose affected femoral head healed conservatively. Our preliminary study indicates that this type of highly technical investigation appears feasible in clinical practice and permits prediction of the outcome depending upon regional skeletal flow measurements in vivo.

Algoneurodystrophy (AND) is a complex disorder with a wide spectrum of clinical presentations. Patients referred for a work-up of unilateral upper extremity AND were reviewed, and 50 patients were enrolled with sufficient documentation on history, causal event, clinical stage, and final outcome. There were 27 females, 23 males, mean age 44 years. The affected area was: shoulder 5, arm 3, elbow 3, wrist 26 and hand 13. Main precipitating events were fracture, contusion, or prior surgery. Three-phase bone scintigraphy was performed followed by a 2-phase vascular scintigraphy on another day. Typical periarticular uptake on the delayed bone scan was used to diagnose AND. Staging was done with the dynamic phase of the vascular scan. The clinicians diagnosed 30 patients positive for AND, 14 negative, and 6 equivocal. Bone scintigraphy yielded 25 positive, 20 negative, and 5 equivocal scans, i.e. sensitivity 73% and specificity 86%. Of the positive bone scans, 21 had all 3 phases positive, and 16 were concordant on vascular scintigraphy. The remaining 5 vascular scans classified 3 patients in transition (stage I--II) and 2 in stage II. In other words, in 24% of patients vascular scintigraphy indicated restaging.dynamic bone scintigraphy is an accurate method to diagnose AND. Vascular scintigraphy changed AND stage in one quarter of the patients. Therefore, a combination of both studies is indicated in the work-up and treatment monitoring of AND.

Pulmonary tumor embolism is an often missed antemortem diagnosis in patients with cancer and respiratory failure. Although rare, this complication is an important cause of additional morbidity. Referred for radionuclide pulmonary perfusion and ventilation scintigraphy, a typical pattern of multiple subsegmental peripheral defects on perfusion lung scanning without matching ventilation defects, suggesting a high probability of pulmonary thromboembolism, often leads to false conclusions. We present a case of bilateral multiple subsegmental mismatched defects in lung ventilation perfusion scintigraphy, where autopsy confirmed the diagnosis of pulmonary tumor embolism, secondary to an undifferentiated ductal type adenocarcinoma of the pancreas. Pulmonary tumor embolism is an entity to keep in mind in patients treated for carcinoma presenting with (sub) acute dyspnea.

A recent case-control study in Indonesia suggested that the course of Brugian filariasis and in particular resistance to the development of elephantiasis was associated with certain HLA class II alleles. In order to see whether these data could be confirmed we conducted a similar study in another Indonesian population from South Sulawesi. We could not confirm our earlier results and therefore concluded that HLA-DR and -DQ alleles are at least not strongly associated with progression to elephantiasis in Brugian filariasis. The complete data are presented also for anthropological reference purposes.

Recently, a geometric model for the confinement of magnetic charges in the context of type II string compactifications was constructed by Greene, Morrison and Vafa. This model assumes the existence of stable magnetic vortices with quantized flux in the low energy theory. However, quantization of flux alone does not imply that the vortex is stable, since the flux may not be confined to a tube of definite size. We show that in the field theoretical model which underlies the geometric model of confinement, static, cylindrically symmetric magnetic vortices do not exist. While our results do not preclude the existence of confinement in a different low-energy regime of string theory, they show that confinement is not a universal outcome of the string picture, and its origin in the low energy theory remains to be understood., Latex, 8 pages

The aim of this study was to quantify regional bone blood flow and influx rate with PET and [18F]fluoride in patients with metabolic bone disorders.Dynamic imaging of the spine or pelvis was performed after administration of 300-370 MBq of 18F-. Plasma clearance of 18F- was determined in blood sampled from the radial artery. A three-compartment model was used to estimate the regional flow and fluoride influx rate.In this preliminary study, fluoride flux (in micromol/min/liter) could be measured regionally. The flux was consistent with the pathophysiology of the studied metabolic disorders and allowed the various disease states to be distinguished. Bone blood flow and influx rate were low in osteoporosis (in the "normal-appearing" bone) and high in Paget's disease.With PET and [18F]fluoride, local bone blood flow and fluoride influx rate can be quantified in patients in vivo. Metabolically active zones have an increased influx rate and an accordingly increased flow. In principle, this technique permits classification of bone disorders and has potential for the monitoring of therapy response in metabolic bone disease.