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.

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.

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.

Antiproton confinement in a Penning-Ioffe trap for antihydrogen.

Antiprotons (p[over]) remain confined in a Penning trap, in sufficient numbers to form antihydrogen (H[over ) atoms via charge exchange, when the radial field of a quadrupole Ioffe trap is added. This first demonstration with p[over] suggests that quadrupole Ioffe traps can be superimposed upon p[over] and e(+) traps to attempt the capture of H[over] atoms as they form, contrary to conclusions of previous analyses.

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.

Tube feeding and bone marrow transplantation.

BACKGROUND: Children undergoing bone marrow transplantation (BMT) have poor oral intake during the transplant period, caused mainly by the intensive therapy used for their conditioning. Nutritional support (NS) is almost always needed. Whenever possible, tube feeding (TF) is preferred to parenteral nutrition (PN) because its more physiologic and causes fewer complications. However, children undergoing BMT are usually parenterally fed. We, therefore, studied whether TF was tolerated in children undergoing BMT and whether the nutritional intake was adequate in comparison to PN. PROCEDURE: Two groups were compared: TF (n = 12) and PN (n = 22). If intolerance for TF occurred, additional or total PN was given. Nutritional status, intake, complications, and costs were assessed. RESULTS: Both groups had an adequate nutritional status and reached 85% of their nutritional requirements. TF was possible in 62% of the NS days and three children could be exclusively fed with TF. A longer pre-transplant duration of TF seemed to increase the enteral tolerance. Gastrointestinal symptoms were equally frequent in TF as in PN, but cholestasis was less frequent in TF. The mean nutritional cost per child in the TF group was 440 US dollars less than in the PN group. CONCLUSIONS: TF is possible and equal in efficacy to PN in children undergoing BMT, and may have budgetary benefits.

Immunoglobulins in chronic renal failure of childhood: effects of dialysis modalities.

BACKGROUND: It is not clear whether low serum levels of IgG (subclasses), previously demonstrated in children on peritoneal dialysis (PD), are related to the PD procedure or to factors associated with chronic renal failure (CRF). The aim of our study was to analyze the effect of PD on serum and PD effluent (PDE) IgG and subclass levels in children with end-stage renal failure. METHODS: We measured albumin, IgG, IgA, IgM, and IgG subclasses in serum and PDE from children on PD (N = 40) and compared the serum values with those of children treated with hemodialysis (HD, N = 23) or presenting with CRF but not yet dialyzed (CRF; N = 63), and with a group of healthy controls (HCs; N = 67). Sixteen PD children could be followed sequentially from before starting PD and eight during a peritonitis episode. RESULTS: Forty percent of the PD children showed reduced serum IgG2 levels (P = 0.0003) compared with 35% in HD (P = 0.006), 33% in CRF (P = 0.001), and 9% in HC children. IgG1 deficiencies were observed in 25% of PD patients (P < 0.0001), 4% of HD (P = NS), 16% of CRF (P = 0.0005), and 0% of HC children. IgG3 and IgG4 deficiencies were observed less frequently. Peritoneal clearances were similar for total IgG, IgG1, IgG2, and IgG4, but were lower for IgG3 (P < 0.05). No relationships were found between clearances and age or duration of PD treatment. Total IgG (P = 0. 003) and IgG1 (P = 0.002) levels declined just after starting PD. Peritonitis was associated with temporarily increased peritoneal loss of Ig, while the serum concentrations were unaffected. No significant relationship was found between the peritonitis incidence and reduced IgG or subclasses. However, all children with two or more peritonitis episodes per year had a reduced Ig level. CONCLUSIONS: Although the mean serum concentrations of immunoglobulins were normal in all studied groups, a deficiency of one or more IgG subclasses was present in all groups with renal failure, suggesting inhibition of their synthesis by the uremic state. Ig deficiencies were more frequently found in PD, likely caused by protein loss in PDE. A high peritonitis incidence was associated with reduced serum Ig levels.

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.

Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group.

BACKGROUND: Patients who receive bone marrow transplants have increased risk for new malignant conditions because of several risk factors, including conditioning with radiation and chemotherapy, immune stimulation, and malignant primary disease. The occurrence of and risk factors for malignant neoplasm in long-term survivors must be assessed. OBJECTIVE: To determine the risk and define potential risk factors for new malignant conditions in long-term survivors after marrow transplantation. DESIGN: Retrospective multicenter study. SETTING: Study of the Late Effects Working Party with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. PATIENTS: 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Transplantation was done before December 1985, and patients had survived more than 5 years. MEASUREMENTS: Reports on malignant neoplasms were evaluated, and the incidence was compared to that in the general population. Patient age and sex, primary disease and status at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. RESULTS: Median follow-up since transplantation was 10.7 years (range, 5 to 22.1 years). Malignant neoplasms were seen in 53 patients; the actuarial incidence (+/- SE) was 3.5% +/- 0.6% at 10 years and 12.8% +/- 2.6% at 15 years. The rate of new malignant disease was 3.8-fold higher than that in an age-matched control population (P < 0.001). The most frequent malignant diseases were neoplasms of the skin (14 patients), oral cavity (7 patients), uterus (including cervix) (5 patients), thyroid gland (5 patients), breast (4 patients), and glial tissue (3 patients). Median age of patients and their donors was 21 years. Malignant neoplasms were more frequent in older patients and in patients with chronic graft-versus-host disease. Older patient age and treatment of chronic graft-versus-host disease with cyclosporine were significant risk factors for new malignant neoplasms after bone marrow transplantation. CONCLUSIONS: The spectrum of neoplasms and immunosuppressive treatment with cyclosporine for chronic graft-versus-host disease as dominant risk factors indicate that immunosuppression is the major cause of malignant neoplasms in patients receiving marrow transplants.

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.

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.

Evidence for at least eight Fanconi anemia genes.

Fanconi anemia (FA) is an autosomal recessive chromosomal breakage disorder with diverse clinical symptoms including progressive bone marrow failure and increased cancer risk. FA cells are hypersensitive to crosslinking agents, which has been exploited to assess genetic heterogeneity through complementation analysis. Five complementation groups (FA-A through FA-E) have so far been distinguished among the first 20 FA patients analyzed. Complementation groups in FA are likely to represent distinct disease genes, two of which (FAC and FAA) have been cloned. Following the identification of the first FA-E patient, additional patients were identified whose cell lines complemented groups A-D. To assess their possible assignment to the E group, we introduced selection markers into the original FA-E cell line and analyzed fusion hybrids with three cell lines classified as non-ABCD. All hybrids were complemented for cross-linker sensitivity, indicating nonidentity with group E. We then marked the three non-ABCDE cell lines and examined all possible hybrid combinations for complementation, which indicated that each individual cell line represented a separate complementation group. These results thus define three new groups, FA-F, FA-G, and FA-H, providing evidence for a minimum of eight distinct FA genes.

Nucleus reuniens thalami modulates activity in hippocampal field CA1 through excitatory and inhibitory mechanisms.

The nucleus reuniens thalami (RE) originates dense projections to CA1, forming asymmetrical synapses on spines (50%) and dendrites (50%). The hypothesis that RE input modulates transmission in CA1 through excitation of both pyramidal cells and interneurons was tested using electrophysiological methods in the anesthetized rat. The RE-CA1 afferents were selectively stimulated at their origin; evoked field potentials and unit activity were recorded in CA1. RE-evoked depth profiles showed a prominent negative deflection in the stratum lacunosum-moleculare and a positive one in the stratum radiatum. The lacunosum-moleculare sink-radiatum source configuration is compatible with RE-elicited depolarization of apical dendrites of pyramidal cells. Despite a consistent and robust paired pulse facilitation of RE-evoked field potentials, population spikes in the stratum pyramidale were not detected at any tested condition. This indicates the inability of RE-CA1 input to discharge pyramidal cells. However, stimulation of RE-elicited spiking of extracellularly recorded units in strata oriens/alveus and distal radiatum, indicative of the activation of local interneurons. Thus, RE seems to modulate transmission in CA1 through a (subthreshold) depolarization of pyramidal cells and a suprathreshold excitation of putative inhibitory oriens/alveus and radiatum interneurons. RE-evoked monosynaptic or disynaptic field potentials were associated with stimulation of rostral or caudal RE, respectively. Anatomically, a projection from caudal to rostral RE was demonstrated that can account for the disynaptic RE-CA1 input. Because caudal RE receives input from the hippocampus via the subiculum, we propose the existence of a closed RE-hippocampal circuit that allows RE to modulate the activity in CA1, depending on hippocampal output.