One-particle measurement of the antiproton magnetic moment.

For the first time a single trapped antiproton (p) is used to measure the p magnetic moment µ(p). The moment µ(p)=µ(p)S/(ℏ/2) is given in terms of its spin S and the nuclear magneton (µ(N)) by µ(p)/µ(N)=-2.792 845±0.000 012. The 4.4 parts per million (ppm) uncertainty is 680 times smaller than previously realized. Comparing to the proton moment measured using the same method and trap electrodes gives µ(p)/µ(p)=-1.000 000±0.000 005 to 5 ppm, for a proton moment µ(p)=µ(p)S/(ℏ/2), consistent with the prediction of the CPT theorem.

Trapped antihydrogen in its ground state.

Antihydrogen atoms (H¯) are confined in an Ioffe trap for 15-1000 s-long enough to ensure that they reach their ground state. Though reproducibility challenges remain in making large numbers of cold antiprotons (p¯) and positrons (e(+)) interact, 5±1 simultaneously confined ground-state atoms are produced and observed on average, substantially more than previously reported. Increases in the number of simultaneously trapped H¯ are critical if laser cooling of trapped H¯ is to be demonstrated and spectroscopic studies at interesting levels of precision are to be carried out.

Adiabatic cooling of antiprotons.

Adiabatic cooling is shown to be a simple and effective method to cool many charged particles in a trap to very low temperatures. Up to 3×10(6) p are cooled to 3.5 K-10(3) times more cold p and a 3 times lower p temperature than previously reported. A second cooling method cools p plasmas via the synchrotron radiation of embedded e(-) (with many fewer e(-) than p in preparation for adiabatic cooling. No p are lost during either process-a significant advantage for rare particles.

Centrifugal separation of antiprotons and electrons.

Centrifugal separation of antiprotons and electrons is observed, the first such demonstration with particles that cannot be laser cooled or optically imaged. The spatial separation takes place during the electron cooling of trapped antiprotons, the only method available to produce cryogenic antiprotons for precision tests of fundamental symmetries and for cold antihydrogen studies. The centrifugal separation suggests a new approach for isolating low energy antiprotons and for producing a controlled mixture of antiprotons and electrons.

The thalamic midline nucleus reuniens: potential relevance for schizophrenia and epilepsy.

Anatomical, electrophysiological and behavioral studies in rodents have shown that the thalamic midline nucleus reuniens (RE) is a crucial link in the communication between hippocampal formation (HIP, i.e., CA1, subiculum) and medial prefrontal cortex (mPFC), important structures for cognitive and executive functions. A common feature in neurodevelopmental and neurodegenerative brain diseases is a dysfunctional connectivity/communication between HIP and mPFC, and disturbances in the cognitive domain. Therefore, it is assumed that aberrant functioning of RE may contribute to behavioral/cognitive impairments in brain diseases characterized by cortico-thalamo-hippocampal circuit dysfunctions. In the human brain the connections of RE are largely unknown. Yet, recent studies have found important similarities in the functional connectivity of HIP-mPFC-RE in humans and rodents, making cautious extrapolating experimental findings from animal models to humans justifiable. The focus of this review is on a potential involvement of RE in schizophrenia and epilepsy.

Interaction of nucleus reuniens and entorhinal cortex projections in hippocampal field CA1 of the rat.

The nucleus reuniens (RE) and entorhinal cortex (EC) provide monosynaptic excitatory inputs to the apical dendrites of pyramidal cells and to interneurons with dendrites in stratum lacunosum moleculare (LM) of hippocampal field CA1. However, whether the RE and EC inputs interact at the cellular level is unknown. In this electrophysiological in vivo study, low-frequency stimulation was used to selectively activate each projection at its origin; field excitatory postsynaptic potentials (fEPSPs) were recorded in CA1. We applied (1) paired pulses to RE or EC, (2) combined paired pulses to RE and EC, and (3) simultaneously paired pulses to RE/EC. The main findings are that: (a) stimulation of either RE- or EC-evoked subthreshold fEPSPs, displaying paired pulse facilitation (PPF), (b) subthreshold fEPSPs evoked by combined stimulation did not display heterosynaptic PPF, and (c) simultaneous stimulation of RE/EC resulted in enhanced subthreshold fEPSPs in proximal LM displaying a nonlinear interaction. CSD analyses of RE/EC-evoked depth profiles revealed a nonlinear enlargement of the 'LM sink-radiatum source' configuration and the appearance of an additional small sink-source pair close to stratum pyramidale, likely reflecting (peri)somatic inhibition. The nonlinear interaction between both inputs indicates that RE and EC axons form synapses, at least partly, onto the same dendritic compartments of CA1 pyramidal cells. We propose that low-frequency activation of the RE-CA1 input facilitates the entorhinal-hippocampal dialogue, and may synchronize the neocortical-hippocampal slow oscillation which is relevant for hippocampal-dependent memory consolidation.

Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance.

Approximately 25% of patients with Fanconi anemia (FA) have evidence of spontaneously occurring mosaicism as manifest by the presence of two subpopulations of lymphocytes, one of which is hypersensitive to cross-linking agents (e.g. mitomycin C) while the other behaves normally in response to these agents. The molecular basis of this phenotypic reversion has not yet been determined. We have investigated 8 FA patients with evidence of mosaicism. Epstein-Barr virus-immortalized lymphoblastoid cell lines established from these patients exhibited an IC50 for mitomycin C of 25 to > 100 nM compared to a mean of 2 +/- 2 nM for 20 nonmosaic FA patients and 49 +/- 11 nM for 8 healthy controls. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations the molecular mechanism of the mosaicism was investigated by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wild-type allele in the reverted cells and suggested two patterns of recombination. In 1 patient a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distally to the FAC gene; in the other 2 patients (sibs) the mechanism appears to have been gene conversion resulting in segregants which have lost one pathogenic mutation. In 6 of the 8 patients the hematological symptoms were relatively mild despite an age range of 9-30 years.

Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

Projections from the nucleus reuniens thalami to the entorhinal cortex, hippocampal field CA1, and the subiculum in the rat arise from different populations of neurons.

The entorhinal cortex, CA1, and the subiculum receive a major input from the thalamic midline nucleus reuniens. At present, it is not known whether reuniens projections to these intimately interconnected regions are collateralized or arise from different cell populations. We employed the multiple fluorescent retrograde tracing technique with Fast Blue, Diamidino Yellow, and Fluoro-Gold to examine the possible collateralization of reuniens projections to the entorhinal cortex, CA1, and the subiculum. In addition, we studied the extent of collateralization within each target area. The results indicate that different, yet morphologically indistinguishable, populations of reuniens cells selectively innervate the entorhinal cortex, CA1, or subiculum. Within each of these areas, reuniens fibers display a locally restricted collateralization instead of distributing collaterals throughout the entire target structure. The rostal two-thirds of the nucleus reuniens is the major source of ipsilateral projections to CA1, subiculum, and entorhinal cortex. The perireuniens nucleus selectively projects to the perirhinal cortex. Reuniens projections to CA1 and medial entorhinal cortex originate in the dorsolateral part and throughout the medial one-half of the nucleus, respectively. For these two projections, no topography could be established. However, subicular afferents are topographically organized such that a dorsal-to-ventral gradient in the nucleus reuniens corresponds to a dorsal-to-ventral gradient along the subicular axis. Lateral entorhinal afferents display a subtle topography such that a lateral-to-medial shift of terminal fields in the lateral entorhinal cortex corresponds to a lateral-to-medial shift of projection neurons in the ventral nucleus reuniens.

Bone marrow transplantation in children: consequences for renal function shortly after and 1 year post-BMT.

The aim of this study was to investigate the effect of a bone marrow transplantation (BMT) on renal function in children. In a 5-year period, 142 children received a BMT at the Department of Pediatrics of the University Hospital Leiden. The study was performed retrospectively using the estimated glomerular filtration rate before and 1 year after BMT, and weekly measurements of serum creatinine during the first 3 months after BMT for assessment of renal function. Patient characteristics (sex, age, diagnosis), conditioning regimen, type of BMT, major complications (sepsis, veno-occlusive disease and graft-versus-host disease (GVHD)) and the use of nephrotoxic medication were listed. In the first 3 months after BMT 17 (12%) patients died, 13 from transplant-related complications other than renal failure and four from relapse of the disease. Forty-eight children (34%) had a period with acute renal insufficiency. A high pre-BMT serum creatinine, transplantation with either a non-HLA-identical related or a matched unrelated donor were risk factors for acute renal insufficiency after BMT. Sepsis and the use of intravenous vancomycin were risk factors for acute renal insufficiency only for patients with a high pre-BMT serum creatinine. GVHD seemed to have a beneficial effect on renal function of BMT recipients. One year after BMT a total of 35 (25%) patients had died, 16 from transplant-related complications and 19 from relapse of the disease; another 17 patients could not be evaluated. Twenty-five of 90 evaluable children (28%) had chronic renal insufficiency. Chronic renal insufficiency 1 year after BMT was correlated with a high serum creatinine in the first 3 months after BMT. None of the children of this retrospective study on renal function after BMT needed dialysis.

Paediatric allogeneic bone marrow transplantation for homozygous beta-thalassaemia, the Dutch experience.

We reviewed the results of the Dutch paediatric bone marrow transplant (BMT) program for children receiving HLA-identical BMT for beta-thalassaemia major over an 18-year period. In all, 19 patients underwent a total of 21 transplants in our treatment centre between July 1984 and February 2002. Eight females (age 0.3-12 years; median 5 years) and 11 males (age 0.8-18 years; median 6 years) were included. Information, prospectively collected, included molecular defects, donor genotype, beta/alpha-globin expression rates, serum ferritin levels, hepato-splenomegaly, chelation history, virology screening, liver pathology together with post-transplant outcome inclusive of leucocyte chimerism. In total, 11 patients received standard busulphan/cyclophosphamide (Bu/Cy) conditioning, with or without ATG. Stable engraftment was seen in 5/11 with late rejection occurring in six patients. Of these, two children underwent a second successful SCT. For this group, overall event-free survival (EFS) and disease-free survival (DFS) were 90 (10/11) and 64% (7/11), respectively. The probability of rejection was 55%. Subsequent addition of melphalan to the conditioning regimen resulted in long-term stable engraftment in all patients with an EFS/DFS for this group of 90% (9/10). Treatment-related mortality, irrespective of conditioning, was low at 5% (1/19 patients). Veno-occlusive disease (VOD) occurred in 19% (4/21 transplants) and acute GvHD in 19% (4/21 transplants). Post-BMT beta/alpha synthetic ratio measurement monitored donor erythroid engraftment and predicted rejection with a return to transfusion dependency. Maintained full donor chimerism is indicative of stable engraftment both for leucocyte and erythroid lineages, whereas mixed donor chimerism is not. Our results emphasise the importance of the conditioning regimen and post-transplant chimerism surveillance predictive of rejection or long-term stable engraftment.

Multiple anterograde tracing, combining Phaseolus vulgaris leucoagglutinin with rhodamine- and biotin-conjugated dextran amine.

The simultaneous use of different neuroanatomical anterograde tracers provides a potentially powerful method to study the convergence of afferent systems in a particular brain area. However, a simple routine procedure to apply multiple anterograde tracers in conjunction with their simultaneous visualization is still missing. We report an easy and straightforward application of three sensitive anterograde tracers: Phaseolus vulgaris leucoagglutinin (PHA-L), rhodamine-conjugated dextran amine (RDA) and biotin-conjugated dextran amine (BDA). These tracers can be visualized simultaneously and permanently through a triple-staining procedure with nickel-enhanced diaminobenzidine (DAB-Ni), DAB and 1-naphthol/Azur B as chromogens. Our test model comprised the projections from the nucleus reuniens thalami and entorhinal cortex. Both projection systems show a high degree of overlap in their terminal fields in the hippocampus. Two tracers were injected in the left and right entorhinal cortex, respectively; a third tracer was injected in the nucleus reuniens. This combination of injections provided a good opportunity to compare the three tracers in one and the same animal. PHA-L, RDA and BDA, injected in either of the injection sites, turned out to be equally sensitive and revealed the morphology of the involved projection systems in great detail. The triple-staining protocol yielded an excellent, simultaneous detectability of the three tracers with a remarkably low background level. Thus, the combination of the anterograde tracers PHA-L, RDA and BDA, in conjunction with the triple-staining procedure, offers a very attractive approach for neuroanatomical research.

Lack of a dopamine autoreceptor selective profile of B-HT 920 in functional in vitro model systems of D2 receptors in rat striatum.

Based on the results of in vivo studies, the thiazoloazepine derivative B-HT 920 has been proposed to be a selective agonist of dopamine autoreceptors. In the present study, we investigated the effects of B-HT 920 in two functional in vitro model systems of D2 receptors and compared these effects with the effects of the classical D2 agonist LY 171555. B-HT 920 and LY 171555 concentration dependently inhibited the electrically evoked release of radiolabeled dopamine and acetylcholine and the forskolin-induced stimulation of adenylate cyclase activity in rat striatal tissue slices with comparable efficacies. In striatal tissue slices prepared after 6-hydroxydopamine-induced destruction of dopaminergic terminals, both drugs were still able to inhibit forskolin-stimulated adenylate cyclase activity with a efficacy similar to that in tissue obtained from unlesioned rats. It is concluded that, in vitro, B-HT 920 is an agonist at both presynaptic and 'normosensitive' postsynaptic D2 receptors showing relatively high intrinsic activity.

Nucleus reuniens thalami innervates gamma aminobutyric acid positive cells in hippocampal field CA1 of the rat.

The aim of the present study was to investigate whether the nucleus reuniens thalami (RE) innervates inhibitory cells in hippocampal field CA1. Therefore, we examined the RE-CA1 input at the ultrastructural level. RE axons were anterogradely labeled with biotin-conjugated dextran amine (BDA), in combination with pre-embedding gamma aminobutyric acid (GABA)-immunolabeling of neurons in CA1. We observed that part of the BDA-labeled axons formed asymmetrical (i.e. excitatory) synapses on GABA-positive dendrites. Based on these data, which are in line with our previously published electrophysiological observations (Dolleman-Van der Weel, M.J., Lopes da Silva, F.H. and Witter, M.P., Nucleus reuniens thalami modulates activity in hippocampal field CA1 through excitatory and inhibitory mechanisms. J. Neurosci., 17 (1997) 5640-5650), we propose that RE-CA1 input partially influences hippocampal transmission through activation of local inhibitory interneurons.

Differential membrane properties and dopamine effects in the shell and core of the rat nucleus accumbens studied in vitro.

Electrophysiological differences between the shell and core of the rat nucleus accumbens were investigated by intracellular recordings from an in vitro slice preparation. The average input resistance of neurons recorded in the shell was larger than in the core. Neurons in the core were characterized by a more negative resting membrane potential than neurons in the shell. Furthermore, bath-applied dopamine attenuated synaptic responses recorded in the shell, but not in the core. Thus, the two main subregions of the nucleus accumbens differ both in basal membrane properties and in dopaminergic modulation of synaptic transmission.

Antihydrogen production within a Penning-Ioffe trap.

Slow antihydrogen (H) is produced within a Penning trap that is located within a quadrupole Ioffe trap, the latter intended to ultimately confine extremely cold, ground-state H[over ] atoms. Observed H[over ] atoms in this configuration resolve a debate about whether positrons and antiprotons can be brought together to form atoms within the divergent magnetic fields of a quadrupole Ioffe trap. The number of detected H atoms actually increases when a 400 mK Ioffe trap is turned on.